Emerging Biological and Molecular Therapies in Autoimmune Disease

Emerging Biological and Molecular Therapies in Autoimmune Disease

C H A P T E R 72 Emerging Biological and Molecular Therapies in Autoimmune Disease Lucienne Chatenoud INSERM U1151, CNRS UMR 8253, Institute Necker-E...

402KB Sizes 0 Downloads 40 Views

C H A P T E R

72 Emerging Biological and Molecular Therapies in Autoimmune Disease Lucienne Chatenoud INSERM U1151, CNRS UMR 8253, Institute Necker-Enfants Malades, University Paris Descartes, Sorbonne Paris Cite´, Paris, France

O U T L I N E Introduction Monoclonal Antibodies Used Clinically: Ways to Make Them More Efficient Engineering Fc Regions of Monoclonal Antibodies to Avoid Side Effects and Prolong Half-Life Engineering Variable Regions of Monoclonal Antibodies to Increase Affinity Engineering Variable Regions of Monoclonal Antibodies to Decrease Immunogenicity

The Breakthrough in Autoimmune Diabetes The Surprises and the Expectations of B Lymphocyte Targeting

1437 1438

1439 1439 1439

The Adequation of the Antibody Specificity to the Target Disease: From Immunosuppression to Immune Tolerance 1440 The Breakthrough in Rheumatoid Arthritis 1440 The Breakthrough in Multiple Sclerosis 1441

1443 1445

Bone-Marrow Transplantation

1445

Soluble Autoantigens

1447

Cell Therapy and Antigen Receptor GeneModified T Cells Cell Therapy Using Regulatory T Cells Cell Therapy Using Antigen Receptor GeneModified T Cells

1449 1449 1449

Perspectives and Conclusions

1451

References

1451

INTRODUCTION Autoimmune diseases represent a major therapeutic challenge. In many cases the disease is severe enough to significantly reduce longevity. In other cases the disease causes major handicaps and discomfort that justify the usage of aggressive treatments generating their own hazards. The past treatments were mainly palliative (substitutive), antiinflammatory, or immunosuppressive without any specificity for the pathogenic mechanisms of the disease. Over the last decades, modern technologies have made new agents available, in particular monoclonal antibodies (MAbs) directed to key immune cell receptors or cytokines, which have created a true revolution and fostered major advancements in the treatment of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel diseases. Many of these treatments that have been approved and are part of the regular armamentarium clinicians use to treat autoimmune patients have been described in previous chapters.

The Autoimmune Diseases. DOI: https://doi.org/10.1016/B978-0-12-812102-3.00072-5

1437

Copyright © 2020 Elsevier Inc. All rights reserved.

1438

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

We will return to some of these treatments in a more holistic perspective to understand how the use strategies have been adapted and continue to adapt to achieve better efficacy and fewer side effects. We will also discuss strategies still in development that may, in a not too distant future, fill important gaps. In particular an ambitious goal is to induce or, in the case of established autoimmune diseases, to restore immune tolerance to target autoantigens. This may be defined operationally as the possibility to harness the pathologic immune response following a short-term treatment while keeping intact the capacity of the host to respond normally to exogenous antigens. Restoration of self-tolerance has the major advantage of avoiding the side effects linked to chronic immunosuppression and, most importantly, to provide a real cure for the disease.

MONOCLONAL ANTIBODIES USED CLINICALLY: WAYS TO MAKE THEM MORE EFFICIENT Murine MAbs produced by mouse or rat hybridomas (Kohler and Milstein, 1975) specific for immune cell receptors were introduced in clinical practice close to 40 years ago and their use initially developed in the field of solid organ transplantation. Two major side effects, namely, the sensitization against the xenogeneic molecule and the cytokine-releasing potential observed with some particular specificities, explain why the use of rodent MAbs remained initially mostly confined to transplantation with only very few attempts in autoimmunity. The advent of humanized and human MAbs that are less immunogenic and better tolerated has completely changed the picture and allowed a more widespread use of these interesting therapeutic tools. At variance with conventional immunosuppressants, some MAbs specific for relevant lymphocytes receptors are unique in their capacity to induce, under adequate circumstances, immune tolerance to soluble proteins, foreign tissue alloantigens, and autoantigens (Cobbold et al., 2006; Chatenoud, 2003, 2010; Chatenoud and Bluestone, 2007). MAbs display a wide spectrum of pharmacological and biological activities highly relevant to their capacity to “reprogram” the immune system. Thus depending on their fine specificity, MAbs will remove target cells, inhibit or block the functional capacity of the target without depleting it, neutralize major cytokines, and/or serve as receptor agonists triggering activation signals for specialized T-cell subsets and in particular regulatory T cells (Tregs) (Sakaguchi et al., 2008; Bach, 2003). The repeated administration of murine MAbs invariably triggered a humoral immune response, a major clinical consequence of which was the neutralization of the antibody’s therapeutic activity. Interestingly, this was not a global antimouse or antirat response; it was very restricted in its specificity with essentially antiisotypic and antiidiotypic antibodies being produced (Chatenoud et al., 1986a,b; Benjamin et al., 1986). Antiidiotypic antibodies that compete with the therapeutic antibody for antigen binding represent the neutralizing component of the response while antiisotypic antibodies are mostly nonneutralizing (Baudrihaye et al., 1984). Another peculiarity of this humoral response is its oligoclonality (Chatenoud et al., 1986a,b; Villemain et al., 1986), which explains that, at variance with what observed in patients immunized to polyclonal antilymphocyte globulins, serum sickness was a rare consequence of sensitization to MAbs since the amount of immune complexes formed would be insufficient to elicit a generalized reaction. Antimonoclonal IgE responses associated with symptoms of anaphylaxis were reported but remained a very uncommon observation (Abramowicz et al., 1992, 1996). Until humanized MAbs or more recently fully human antibodies became available the only way to cope with the problem of sensitization was to associate adequate doses of chemical immunosuppressants (Hricik et al., 1990). Two types of humanized antibodies have been derived from molecular engineering. Chimeric MAbs express intact rodent variable regions linked to human immunoglobulin constant domains (Morrison et al., 1984). In fully reshaped or complementarity determining region (CDR)-grafted antibodies the rodent hypervariable regions interacting with the antigen (CDRs) are included within human heavy and light chain immunoglobulin frameworks (Riechmann et al., 1988). Fully human MAbs have been produced by different means. First, mice have been invalidated for the expression of endogenous (mouse) immunoglobulin genes and concurrently made transgenic for sufficient human constant and variable immunoglobulin-encoding sequences to provide for antibody diversity; B cells from these immunized mice produce human antibodies that can be used in conventional fusions to obtain hybridomas yielding high-affinity MAbs derived from in vivo antigen-driven selection (Lonberg et al., 1994). Second, there is a fully in vitro approach using cDNA libraries expressed on filamentous phages to derive high-affinity antibodies to a wide variety of antigens, including those for which the conventional hybridoma technology fails due to poor immunogenicity (Marks et al., 1991). Third, humanmouse chimeras can be established using normal mice irradiated and reconstituted with bone-marrow cells from severe

VIII.. MANAGEMENT

MONOCLONAL ANTIBODIES USED CLINICALLY: WAYS TO MAKE THEM MORE EFFICIENT

1439

combined immunodeficiency (SCID) mice; after human lymphocytes from presensitized donors are inoculated, these mice are boosted with the antigen of interest, and sensitized human B cells recovered and used for conventional fusions (Lubin et al., 1994). Humanized MAbs and fully human MAbs have significantly reduced though not totally avoided the risk of deleterious antiidiotypic responses. Both chimeric and reshaped humanized MAbs may be immunogenic when administered alone, without associated immunosuppressants (Herold et al., 2002; Keymeulen et al., 2005; Elliott et al., 1994). As for murine antibodies, combining low doses of chemical immunosuppressants, as is regularly done with anti-tumore necrosis factor (TNF) in rheumatoid arthritis, is a very efficient way to overcome sensitization (Feldmann, 2002; Nashan et al., 1997; Vincenti et al., 1998). Importantly, the frequency of immunization varies according to the fine specificity of the MAbs. For example, immunization is common for humanized CD3 and CD52 antibodies (Somerfield et al., 2010; Herold et al., 2002; Keymeulen et al., 2005). It is lower for anti-TNF antibodies, especially in rheumatoid arthritis because of the regular association with conventional immunosuppressants such as methotrexate (Feldmann, 2002). At variance, in inflammatory bowel diseases the problem is relevant because the immunization leads to the neutralization of the therapeutic effect, and the possibilities of switching to other immunotherapies are more limited than in rheumatoid arthritis, as soluble TNF receptors are ineffective in this indication.

Engineering Fc Regions of Monoclonal Antibodies to Avoid Side Effects and Prolong Half-Life Antibody engineering allows the design of tailor-made antibodies to fit at best therapeutic indications. Antibodies expressing human Fc portions have a significantly prolonged half-life. In addition, the choice of the human Fc portion will influence the antibody effector capacities, that is, its activity in terms of complement fixation, opsonization, and antibody-dependent cell cytotoxicity. In addition, in the case of CD3 antibodies, humanization can circumvent problems due to their intrinsic mitogenic and cytokine-releasing capacity that leads in vivo to a “flu-like” syndrome. This syndrome was regularly observed with murine CD3 MAbs such as OKT3, and although transient, it represented a major and troublesome side effect that totally precluded the use of CD3 MAbs for indications other than organ transplantation (Chatenoud et al., 1990; Abramowicz et al., 1989; Chatenoud, 2003). This mitogenic capacity is linked to the ability of the Fc portion of CD3 MAbs to interact with monocyte Fc receptors (Chatenoud, 2003). Thus “nonmitogenic,” non-Fc binding, CD3 antibodies were obtained by inserting adequate mutations into the Fc domains to hamper Fc receptor binding (Alegre et al., 1994; Bolt et al., 1993; Chatenoud, 2003). Clinical use of two different Fc-mutated CD3 MAbs, teplizumab (OKT3γ1Ala-Ala) and otelixizumab (ChAglyCD3), in autoimmunity and transplantation, confirmed that their use was free of major side effects (Friend et al., 1999; Herold et al., 2002; Sherry et al., 2011; Keymeulen et al., 2005; Woodle et al., 1999; Hering et al., 2004).

Engineering Variable Regions of Monoclonal Antibodies to Increase Affinity In case the affinity of a given MAbs is too low for in vivo use, phage display technology is an interesting approach to generate an improved fully human reagent with no requirement for prior immunization or use of hybridoma technology. Phage display can be used to mimic artificially the processes used in vivo by the immune system to obtain high-affinity antibodies. This has been achieved by shuffling the heavy or light chains by random or directed mutagenesis of CDR (Barbas et al., 1994), as done by error prone polymerase chain reaction. Using such artificial affinity maturation of phage antibody repertoires, affinities of MAbs in the nanomolar to picomolar range have been generated that are perfectly suitable for therapeutic use (Foote and Eisen, 1995; Barbas, 1995).

Engineering Variable Regions of Monoclonal Antibodies to Decrease Immunogenicity Herman Waldmann’s group made a very important observation in the mid-1980s, showing that immunization against idiotypic determinants of therapeutic MAbs, that as discussed earlier neutralizes the therapeutic effect, was essentially observed with MAbs recognizing cell-surface determinants but not with MAbs directed against soluble molecules (Benjamin et al., 1986). Building on these data, more recently, the working hypothesis they proposed is that a few mutations in key CDRs transforming a given cell-binding MAb into a nonbinder would generate a “tolerizing” form of the MAb. To directly test the hypothesis, humanized mice expressing the human

VIII.. MANAGEMENT

1440

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

CD52 molecule as a transgene at the T-cell surface were first used. Injection in these mice of the human IgG1 version of humanized CD52 MAb ablated mouse T lymphocytes as expected and induced a humoral response to the foreign antibody (mouse anti-CD52 idiotypic response). In sharp contrast, mice previously injected with nonbinding mutants of the human IgG1 CD52 MAb (the “tolerogens”) did not mount a humoral response when treated with the conventional therapeutic cell-binding CD52 Mab (Gilliland et al., 1999; Waldmann, 2019). Remarkably, the clinical proof-of-concept was obtained in patients presenting with multiple sclerosis and treated with the IgG1 CD52 antibody, alemtuzumab. A noncell binding MAb mutant, the “tolerogen,” injected prior to alemtuzumab treatment very significantly reduced the humoral response of the patients to both a first and a second course of alemtuzumab (Somerfield et al., 2010). Despite its effectiveness, it is clear that this two-step strategy is complicated to implement on a regular basis. In order to overcome the practical problem of consecutive administration of two different MAbs the authors engineered an antibody molecule they named “Stealth” with a covalently attached blocker antigen mimotope into the binding site leading to a transiently nonbinding MAb at the time of infusion that renders it “tolerogenic” (Waldmann, 2019). Within a few days the mimotope detaches itself from the antibody molecule, which thus “recovers” all its binding capacity and therefore its therapeutic potential (Waldmann, 2019). The Stealth version of the CD52 MAb is T-cell depleting in the humanized CD52 transgenic mouse but not immunogenic (Waldmann, 2019). It would be highly relevant for obvious reasons to further implement this technology on different MAbs specificities.

THE ADEQUATION OF THE ANTIBODY SPECIFICITY TO THE TARGET DISEASE: FROM IMMUNOSUPPRESSION TO IMMUNE TOLERANCE It is interesting to step back and observe that the biological products which made their way to approval were launched into a given autoimmune disease and then showed a more or less pronounced therapeutic efficacy in other autoimmune diseases. This is important because these results have strongly influenced our understanding of the pathophysiological heterogeneity within given autoimmune diseases. Indeed, for each pathology the response or not to a given treatment turned out a precious tool to define subgroups of patients, more commonly defined as patient’s endotypes. Defining subgroups of patients leads to the characterization of biological markers that make it possible to identify these different individual before any treatment, to better adapt the therapies and also the possible therapeutic combinations. This ultimately means moving toward a personalized treatment of autoimmunity to improve therapeutic efficacy, thereby reducing side effects. Another important point that should guide our thinking concerns the type of therapeutic effect obtained. Is it immunosuppression, with the necessity of repeating the treatment at regular intervals and, as a result, ultimately exposing patients to particularly infectious risks? Do some of the available biologics show an effect that is closer to operational tolerance with short term treatment leading to an effect which may be more long-lasting in the absence of chronic immunosuppression? Is this effect of operational tolerance more easily observed in certain subgroups of patients at precise stages of different diseases? This is the kind of thinking that we can finally have nowadays after years of experience with these quite numerous therapeutic tools applied for the regular treatment of autoimmune diseases (Chapter 71, Treatment of Autoimmune Disease: Established Therapies). To illustrate these points, we shall address three indications where biological therapies have changed patient management while opening up in-depth thinking on how to improve their use on the basis of a better understanding of the pathophysiology of the disease.

The Breakthrough in Rheumatoid Arthritis There is no doubt that the story of MAbs to TNF in rheumatoid arthritis consequent on the pioneering experimental and clinical work of Feldmann and Maini (Brennan et al., 1989; Feldmann, 2002) is a straightforward and beautiful one that constituted a real revolution in the field. The seminal finding was that neutralizing antibodies to TNF significantly decreased the production of most proinflammatory cytokines, that is, interleukin (IL-)1, IL-6, IL-8, GM-CSF, normally produced in in vitro cultures of cells that infiltrate synovial membranes in rheumatoid arthritis (Brennan and Feldmann, 1992; Feldmann, 2002). The relevance of this finding to events in vivo was validated in mice that expressed a human TNF transgene and developed a form of chronic arthritis fully preventable by MAbs to TNF (Brennan and Feldmann, 1992; Feldmann, 2002). In addition, in collagen-induced arthritis, neutralizing antibodies to murine

VIII.. MANAGEMENT

THE ADEQUATION OF THE ANTIBODY SPECIFICITY TO THE TARGET DISEASE: FROM IMMUNOSUPPRESSION TO IMMUNE TOLERANCE

1441

TNF given at onset of disease decreased the severity of objective and histopathological features (swollen joints and bone erosions) (Piguet et al., 1992; Williams et al., 1992, 1994). These data rapidly led to first clinical trials and to the approval of infliximab both in the United States and Europe. Other biologic agents against TNF were developed, in particular two fusion proteins linking the TNF receptor molecules p55 or p75 to a human IgG constant region (lenercept and etanercept/Enbrel) (Furst et al., 2003; Moreland et al., 1996, 1997). However, only etanercept was developed in the clinic and was approved. It soon became apparent that while the therapeutic effect of TNF blockers was important, it was of limited duration and required regular treatment. Then rapidly the number of new candidates tested and retained has increased with abatacept, rituximab, tocilizumab, and also small molecules blocking the Janus kinase, signaling pathway such as tofacitinib coming into the scene. Regardless of therapeutics per se, practice has evolved to treat patients at early stages of the disease, defined as early rheumatoid arthritis, in order to avoid progression to irreversible lesions, thus obtaining better long-term results. Presently, patients presenting early rheumatoid arthritis are mostly stratified according to their autoantibody patterns and, more recently, on very early joint lesions detected by sensitive imaging methods (de Brito Rocha et al., 2019; Ma et al., 2014; Seegobin et al., 2014). The absence or presence of anticitrullinated peptide antibodies (ACPA) and the seroconversion are important prognostic markers to monitor the effect of treatment. Furthermore, recent studies highlight that the effect of early antirheumatic therapy on ACPA seroconversions varies if responses against cyclic citrullinated peptides and citrullinated peptides derived from vimentin (cVim), fibrinogen, and α-enolase (CEP-1) are distinguished. The disappearance of particular ACPA reactivities (anti-cVim) in early rheumatoid arthritis is linked to a better radiological outcome (Kastbom et al., 2016). This is the best demonstration that the characterization of robust biomarkers derives very quickly from the use of effective treatments. It is now well established that anticitrullinated peptide antibodies (ACPA), rheumatoid factors, and some other specificities, for example, antibodies to carbamylated proteins, may be detected many years before onset of joint lesions (Rantapaa-Dahlqvist et al., 2003; Catrina et al., 2017); ACPAs are the first autoantibody to appear, rapidly followed by the occurrence of rheumatoid factors (van de Stadt et al., 2011). The group of Klareskog proposes that the distinct patterns of autoantibody development before disease onset might provide insight into disease pathogenesis, contemplating in particular that pathogenic local immunity toward citrullinated proteins is initiated at other sites than the joints and more particularly in the lungs (Catrina et al., 2017). Therapeutic tools targeting these very early disease-triggering immune events, therefore targeting “prerheumatoid arthritis,” before joint inflammation appears could lead to a real cure of the disease (Catrina et al., 2017). It is interesting before concluding to go back to the experimental setting to mention an unexpected and interesting observation. In established collagen-induced arthritis, combination of a suboptimal dose of anti-TNF (which had no significant effect per se) with a short course with monoclonal anti-T-cell antibodies such as CD4 and CD3 MAbs greatly improved joint inflammation and helped heal paw-swelling and bone erosions in the long term (Williams et al., 1994; Depis et al., 2012). Thus neutralizing inflammation, as done with anti-TNF, effectively “sensitizes” the immune system in rheumatoid arthritis to T celldirected immunointervention. Given the capacity of CD3 antibodies to restore tolerance, which will be described in more detail below, it is relevant to contemplate that combining agents targeting inflammation and T cells could be a novel and very powerful tool to achieve a long-term therapeutic effect in rheumatoid arthritis, even in established disease, thereby approaching operational tolerance.

The Breakthrough in Multiple Sclerosis The introduction of natalizumab (Tisabry), a humanized antibody specific for the α4-chain of α4β1 integrin (VLA-4) expressed by leukocytes, in 2004 was a decisive step in the use of biotherapies as major diseasemodifying drugs in multiple sclerosis. Integrins are adhesion molecules of fundamental importance to the recruitment of leukocytes in inflammation. The alpha4beta1 integrin VLA-4 is a leukocyte ligand for endothelial vascular cell adhesion molecule-1 (VCAM-1), fibronectin, and osteopontin. The interaction between VLA-4 at the surface of activated lymphocytes and monocytes with its ligand VCAM-1 is essential for cell migration into inflamed parenchyma. Promising data in experimental models of blockade of VLA-4 prompted use of natalizumab in patients with relapsingremitting or relapsing secondary progressive multiple sclerosis. A marked reduction in the number of new brain lesions [gadolinium-enhanced magnetic resonance imaging (MRI)] was observed in treated patients (Miller et al., 2003).

VIII.. MANAGEMENT

1442

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

Unfortunately, natalizumab is highly immunosuppressive and discontinuation of treatment precipitates relapses. Patients therefore receive repeated treatments to maintain remission. Reports rapidly focused on the risk of opportunistic brain infection caused by the polyoma JC virus (JCV). The use of natalizumab was temporarily stopped. In 2006 a panel of experts assessed 3417 patients with multiple sclerosis, Crohn’s disease, or rheumatoid arthritis, who had received the antibody for an average of 17 months, and did not identify additional cases of progressive multifocal leukoencephalopathy (PML). Given the beneficial effect of the antibody on the progression of multiple sclerosis, this reassuring assessment led to the antibody being reintroduced (Brandstadter and Katz Sand, 2017). The benefit/risk ratio of the drug being regarded as positive, natalizumab remains a therapeutic option of interest in multiple sclerosis, subject however to strict patient selection, for example, exclusion of patients with anti-JCV antibodies and limiting the duration of treatment [the risk is higher in patients treated for more than 2 years (Brandstadter and Katz Sand, 2017)]. It is interesting to discuss the case of the other major therapeutic tool for multiple sclerosis, the CD52 antibody Campath-1 (alemtuzumab), which is also immunosuppressive but whose long-term therapeutic efficacy does not require frequent treatment cycles such as natalizumab. We are here on a biological product which could, we will discuss it further, with a favorable combination, bring us closer to a situation of operational tolerance. Antibodies to CD52 target a small (12 amino acids) glycosylphosphatidylinositol-anchored protein of undefined function expressed at the surface of human B and T cells and monocyte/macrophages. CD52 MAbs are highly depleting and have potent efficacy in long-term acceptance of organ allografts and maintaining remission in established and otherwise intractable autoimmune diseases, notably multiple sclerosis and vasculitis (Calne et al., 1998; Lockwood et al., 1993, 1996; Mathieson et al., 1990). The first rat MAb to CD52, Campath-1H, was characterized in 1983. A fully reshaped humanized version, Campath-1H (human IgG1), was derived by genetic engineering (Riechmann et al., 1988) and is marketed as alemtuzumab (Lemtrada). Its depleting capacity has led to its extensive use in vivo to treat CD521 hematologic malignancies and in vitro to purge bone-marrow transplants to prevent graft-versus-host disease. Initial trials included patients with long-standing relapsing/remitting multiple sclerosis unresponsive to conventional treatments. Long-term follow-up showed a marked decrease in the appearance of new lesions in the central nervous system as assessed by MRI scanning that correlated with the persisting and significant depletion of peripheral CD41 T lymphocytes (Coles et al., 1999a,b, 2004). Phase III trials have been completed, and alemtuzumab has been approved for treatment of relapsing/remitting multiple sclerosis (Cohen et al., 2012; Coles et al., 2012). Treatment with alemtuzumab elicits some side effects including a long-lasting lymphopenia not associated with increased rate of opportunistic infections, a transient cytokine release syndrome after the first injection (Coles et al., 1999a,b), and a neutralizing antiidiotypic immunization is observed in a significant proportion of patients (Somerfield et al., 2010). Another more unexpected side effect was the development of autoimmune disorders, particularly autoimmune thyroiditis (in up to 30% of patients with multiple sclerosis) or more rarely autoimmune cytopenias (Coles et al., 1999a,b; CAMMS223 Trial Investigators et al., 2008; Jones et al., 2009). In one of the trials in multiple sclerosis, several cases (2.8%) of idiopathic thrombocytopenic purpura have been reported (CAMMS223 Trial Investigators et al., 2008; Cuker et al., 2011). The occurrence of these complications is independent of the therapeutic effect of the antibody but appears to be related to treatment-induced lymphopenia. These autoimmune manifestations occur in patients in whom homeostatic cell proliferation following depletion induced by the antibody is more important. This phenomenon is dependent on IL-21, a cytokine for which circulating levels are increased before treatment in patients who will develop the posttreatment autoimmune manifestations. It has been therefore proposed to use IL-21 pretreatment levels may serve as a predictive parameter to identify patients at risk of this type of side effect (Jones et al., 2009). Campath-1H also proved very effective in severe systemic small vessel vasculitis, in which the pathogenesis depends mainly on T cellmediated mechanisms. The long-term remissions that were obtained when combining antibodies to CD52 and CD4 were particularly impressive (Lockwood et al., 1993, 1996; Mathieson et al., 1990). In conclusion, alemtuzumab appears to be a treatment of choice in relapsing/remitting multiple sclerosis and also for severe autoimmune diseases such as vasculitis refractory to other treatment. It is obvious that the lymphopenia induced by alemtuzumab, and especially the period of reconstitution postlymphopenia, poses a clinical problem (i.e., thyroid disease). In the transgenic mouse model that expresses human CD52 on the surface of T lymphocytes, it has also been shown that lymphopenia prevents the induction of immune tolerance against organ allografts because reconstitution is accompanied by a significant homeostasis proliferation of T lymphocytes with emergence of pathogenic lymphocytes. This is a situation that can be effectively circumvented, at least in mice, by combining to alemtuzumab a MAb-neutralizing IL-7 that is mandatory to drive homeostatic proliferation (Piotti et al., 2014). This is a therapeutic combination that would be very interesting to test in clinic as soon as an antibody-neutralizing IL-7 becomes available. VIII.. MANAGEMENT

THE ADEQUATION OF THE ANTIBODY SPECIFICITY TO THE TARGET DISEASE: FROM IMMUNOSUPPRESSION TO IMMUNE TOLERANCE

1443

The Breakthrough in Autoimmune Diabetes The story of CD3 MAbs is paradoxical and remarkable. They were the first therapeutic antibody introduced in clinical practice in 1981, about 4 years before the molecular complexities and the key functional role of the CD3 molecule were discovered (Clevers et al., 1988). OKT3, a mouse IgG2a MAb directed to human CD3 (Kung et al., 1979), was initially used to treat and prevent renal allograft rejection (Cosimi et al., 1981; Debure et al., 1988; Vigeral et al., 1986). This occurred without any in vivo preclinical data available due to the tight species-specificity of anti-T-cell MAbs in general and CD3 antibodies in particular. Chimpanzees are in fact the only nonhuman primates harboring T lymphocytes cross-reacting with MAbs to human CD3. In addition, antibodies to mouse CD3 were difficult to produce, the first one being characterized by Leo et al. (1987). Over the 1980s, controlled studies clearly demonstrated that MAb OKT3 was a potent immunosuppressant very efficient at reversing early acute renal allograft rejection episodes (Cosimi et al., 1981; Ortho, 1985), an indication for which this MAb was rapidly licensed both in the United States and Europe. Through the study of OKT3-treated patients an enormous knowledge was gained on the mode of action of murine anti-T-cell monoclonals and their side effects. These studies have been invaluable for the design of more refined approaches using humanized MAbs. As other immunosuppressants developed, the use of OKT3 was abandoned, essentially because of its cytokine-releasing potential (Chatenoud et al., 1989, 1990; Abramowicz et al., 1989). CD3 MAbs used in vitro in functional studies and in vivo, both in the experimental and the clinical setting, are specific for the ε chain of the CD3 complex. The experimental work conducted in different rat and mouse models suggested that more than simply depressing all immune responses, CD3 MAbs could also induce immune tolerance to both alloantigens and autoantigens (Nicolls et al., 1993; Plain et al., 1999; Goto et al., 2013; You et al., 2012). Perhaps more impressively, CD3 MAbs could restore self-tolerance in established autoimmunity (Belghith et al., 2003; Chatenoud et al., 1994, 1997; Chatenoud, 2003). Based on these data, CD3 MAbs have again entered the clinical arena but now as well-tolerated humanized nonmitogenic MAbs (Alegre et al., 1994; Bolt et al., 1993) used not only in transplantation, but also in autoimmunity in protocols aimed at antigen-specific long-term effects rather than just immunosuppression. CD3 Monoclonal Antibodies and Autoimmune Diabetes Trials have been conducted using CD3 MAb to treat patients with recent-onset type 1 diabetes based on our data in diabetes-prone nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Shortterm (5 days) treatment of overtly diabetic NOD mice with low doses (520 μg/day) of CD3 MAbs, in either their mitogenic (whole 145 2C11) or nonmitogenic version [F(ab0 )2 fragments of 145 2C11], induced disease remission by restoring self-tolerance (Belghith et al., 2003; Chatenoud et al., 1994, 1997; Chatenoud, 2003). The effect was long-lasting and specific to β-cell autoantigens (Belghith et al., 2003; Chatenoud et al., 1994, 1997; Chatenoud, 2003). Immune mechanisms mediating this tolerogenic capacity evolve in two distinct consecutive phases (Chatenoud, 2010; Chatenoud and Bluestone, 2007). The first, the induction phase, coincides with antibody administration and results in clearing of insulitis, explaining the rapid return to normoglycemia, with a transient Th2 polarization which is irrelevant to the long-term effect since there is prolonged remission of disease after anti-CD3 treatment of IL-4 deficient NOD mice (NOD IL-42/2) (Belghith et al., 2003; Chatenoud, 2003). The second maintenance phase results in upregulation and/or appearance of specialized subsets of CD41CD251FoxP31 and CD41CD62L1FoxP31 Treg that mediate transferable active tolerance, and that effectively control pathogenic effector cells as shown by cotransfer experiments in immunodeficient NOD SCID mice (Belghith et al., 2003; Chatenoud et al., 1994, 2001). The proportions of CD41CD251FoxP31 Treg increase in pancreatic and mesenteric lymph nodes of CD3 MAb-treated tolerant mice (Belghith et al., 2003). Interestingly, CD41CD251FoxP31 Treg induced by CD3 MAb may not derived exclusively from conventional natural regulatory CD41CD251FoxP31 T cells but also, and perhaps even essentially so, from CD41CD252 precursors that differentiate in the periphery (Belghith et al., 2003; You et al., 2007). In fact, CD3-specific MAb treatment induces diabetes remission also in NOD mice deficient for the costimulation molecule CD28 (NOD CD282/2) that are devoid of thymic CD41CD251FoxP31 Treg (Belghith et al., 2003). The immunoregulatory cytokine TGFβ appears to be a key player in this T cellmediated regulation. Thus CD41 T cells from mice tolerant after CD3 MAb treatment consistently produce high levels of TGFβ, and in vivo neutralization of TGFβ after injection of specific MAbs fully prevents anti-CD3-specificinduced remission (Belghith et al., 2003; Kuhn et al., 2011). Clinical trials have been conducted to explore modalities that would reproduce this remarkable effect. Results from an open trial using teplizumab (OKT3γ1Ala-Ala) in patients that present recent-onset type 1 diabetes were very encouraging (Herold et al., 2002, 2005). Thus at 1 year after a short-term treatment, a significant preservation

VIII.. MANAGEMENT

1444

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

of the β-cell mass was observed in treated patients compared with controls (Herold et al., 2002, 2005). The results of a European multicentric randomized placebo-controlled trial using the otelixizumab (ChAglyCD3) MAb, also in recent-onset autoimmune type 1 diabetes fully confirmed the expectations. Results obtained at 18 months of follow-up showed not only a significant preservation of the β-cell mass in otelixizumab versus placebo-treated patients but also an impressive decrease in the insulin needs that lasted for up to 4 years after the end of the short-course treatment (Keymeulen et al., 2005, 2010). Another important study also showing the efficacy and the good safety profile of teplizumab was the Autoimmunity-Blocking Antibody for Tolerance (AbATE) protocol, 2-year results of which were reported in 2013 (Herold et al., 2013). In AbATE the treatment group received a 14-day course of teplizumab at study entry and at 1 year. A post hoc analysis of the data identified metabolic and immunological variables that differentiated individuals who responded to treatment with teplizumab from the nonresponders; 45% or the drug-treated patients were classified as responders, and these individuals had lower HbA1c and lower insulin requirements prior to treatment, suggesting the presence of a functionally larger beta-cell mass at the time of treatment initiation (Herold et al., 2013). Recently, the long-term follow-up (7 years on average, range up to 9 years) of patients included in AbATE was reported (Perdigoto et al., 2018). Phase III trials were launched by two biotech companies in association with large pharmaceutical companies using designs, which were quite different from that of the previous Phase II studies. The Phase III trial using otelixizumab (Tolerx/GlaxoSmithKline trial) used a reduced dose with the aim to reduce side effects. This dose, which has not been validated for efficacy in a proper Phase II placebo-controlled study, was 16 times lower than the one used in the successful Phase II academic trial (3.1 mg compared to 48 mg). The Phase III study using teplizumab (Macrogenics/Eli Lilly trial) had a composite end point chosen arbitrarily (i.e., insulin requirement # 0.5 U/kg/day and HbA1c # 6.5%) that had not been previously validated in a controlled trial and which seemed to be unfortunate choice (Bach, 2011). Importantly, a post hoc analysis of the data from the teplizumab study was performed using the conventional end points validated by all previous trials in the field, namely, C-peptide production and insulin needs, which evidenced a significant therapeutic effect (Sherry et al., 2011). A better response was observed in patients presenting the highest stimulated C-peptide at inclusion (e.g., less than 6 weeks of insulin therapy since diagnosis) and in children and young adults (817 years). The response was dose-dependent, that is, only observed in patients receiving the higher dose tested of 17 mg (cumulated, equivalent for a 70 kg individual) (Sherry et al., 2011; Daifotis et al., 2013). A second Phase III trial using teplizumab is presently ongoing to extend the data of Prote´ge´. In a parallel effort, TrialNet conducted a prevention trial using teplizumab in young subjects “at risk of developing hyperglycemia” but screened as beta-cell autoantibody positive in families including at least one type 1 diabetic probant (Triolo et al., 2019). The rational here is to intervene earlier in disease progression to recruit patients with a higher number of functioning beta cells. The consensus is in fact that a large fraction of beta cells have been destroyed by the autoimmune process when hyperglycemia is first diagnosed: this is the case for patients enrolled in the Phases I, II, and III trials we described earlier. Estimates suggest that about 30% of the functional beta-cell mass is still present in such patients. Under these circumstances, it may be difficult to objectively evaluate any long-term efficacy due to an already reduced beta-cell mass at the beginning of treatment, hence the interest to perform trial in subjects/ patients who have already an ongoing immunological disease but who are not yet hyperglycemic. The TrialNet study recruited 76 patients who were randomized to receive a single course of 14 days of teplizumab (17 mg; cumulated, equivalent for a 70 kg individual) or placebo. The end point will address whether teplizumab, compared to placebo, may significantly delay and/or prevent progression to hyperglycemia. The trial is completed, the data are being analyzed, and results will be available mid-2019. As a whole, nearly 800 patients (166 young children aged 811 years, and 308 adolescents aged 1217 years) included in the various trials have received teplizumab. This further points to the therapeutic efficacy of the drug and its favorable safety profile of teplizumab, confirmed by the results of the 7-year follow-up of AbATE (Perdigoto et al., 2018). In conclusion, autoimmune diabetes is confronted to the dramatic increase in incidence in industrialized countries that is in addition affecting an increasingly younger patient population (Bach, 2002, 2018; Patterson et al., 2018). Presently, chronic insulin therapy, the only palliative treatment available, is far from satisfactory. There is yet no immunotherapy on the market. This lack of approved therapies to tackle the cause of the disease, namely, the autoimmune reaction, must be corrected as soon as possible. CD3 MAbs appear as very good candidates to start solving the issue. Major hopes for the future are also based on combination therapies. Potential candidates are numerous, including new biologicals, autoantigens, and also cell therapy (i.e., Treg). It is worth noting that a number of the proposed combination therapies include a CD3 MAb (Hu et al., 2013; Mamchak et al., 2012; You et al., 2013; Besancon et al., 2018).

VIII.. MANAGEMENT

BONE-MARROW TRANSPLANTATION

1445

Time will tell if the promising results obtained in autoimmune diabetes suggesting that CD3 MAb induces an “operational” restoration of immune tolerance can be extended to other autoimmune diseases.

The Surprises and the Expectations of B Lymphocyte Targeting Rituximab is a humanmouse chimeric MAb, specific for the CD20 B-cell antigen, which causes rapid depletion of B lymphocytes. Rituximab (MabThera) was approved to treat severe refractory CD20-positive non-Hodgkin’s B-cell lymphoma. The use of CD20 MAb has been extended to first-line therapy and maintenance therapy in lymphoma, for stem-cell transplantation procedures, and also for a variety of autoimmune disorders, including rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hemolytic anemia, SLE, vasculitis, dermatomyositis, multiple sclerosis, and autoimmune type 1 diabetes (De Vita et al., 2002; Leandro et al., 2002, 2005; Pescovitz et al., 2009; Rastetter et al., 2004; Silverman and Weisman, 2003; Gelfand et al., 2017; Greenfield and Hauser, 2018; Sabatino et al., 2019). Among these there are obvious indications since the pathophysiology of the disease involves pathogenic autoantibodies, and therefore it seems appropriate to destroy the B cells producing these autoantibodies. The surprise was that in some of these indications, such as SLE, the effectiveness of CD20 antibody was rather disappointing compared to the very encouraging results observed in multiple sclerosis a condition wherein pathogenic T cells more than autoantibodies are regarded as the main pathogenic actors. At a fundamental level, these results highlight the pathogenic role of B lymphocytes not only as antibody-producing cells but also as antigen-presenting cells, which hitherto had been considered of marginal importance. In SLE a first report, further supported by a series of off-label trials, described that B-cell depletion was successfully obtained in patients using rituximab and that disease remission could be achieved (Leandro et al., 2005). In most studies, better therapeutic efficacy correlated with the degree of B-cell depletion achieved and a good clinical response was accompanied by improvement in laboratory parameters. However, two multicenter randomized placebo-controlled trials, one in patients with moderate-to-severe nonrenal disease and the other in proliferative lupus nephritis, did not confirm such benefit (Merrill et al., 2010; Rovin et al., 2012). Numerous reasons may explain this discrepancy that have been cogently reviewed by Furtado and Isenberg (2013). These include differences in the clinical profile of patients, their ethnicity, the cumulative dose of rituximab administered, the duration of follow-up, the degree of B-cell depletion achieved, and, last but not the least, the choice of end points such as criteria for response and flares as well as their assessment (Furtado and Isenberg, 2013). Selecting end point criteria is in fact a major problem since there is a variety of scores to grade disease severity, and a very good clinical experience is mandatory to apply them wisely (Furtado and Isenberg, 2013). A consensus still exists for not abandoning the track of B cell in SLE. It is considered vital however that clinical trials make the most of the controversial experience with rituximab. The quest to find agents that will better and more efficaciously target B cells in SLE continues with agents targeting B-cell growth factors and with new-generation CD20 MAbs. One example, atacicept is a recombinant molecule (formerly referred to as transmembrane activator and CAML interactor (TACI)-Ig) coupling a human Fc fragment and soluble TACI that is the receptor for the cytokines BlyS/BAFF (B-lymphocyte stimulator/B-cell activating factor) and APRIL (a proliferation-inducing ligand). Results showing evidence of efficacy were recently reported in a Phase IIb study together with good safety (Merrill et al., 2018). New-generation CD20 MAbs include humanized antibodies, for example, ocrelizumab, veltuzumab, and obinutuzumab, and one fully human MAb ofatumumab. These CD20 antibodies have increased binding affinity to the Fc receptor on B cells and increased complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity ability. The next 45 years will be decisive for concluding. In multiple sclerosis a Phase II trial showed that a single course of rituximab reduced inflammatory brain lesions and clinical relapses (Hauser et al., 2008). Ocrelizumab has recently been granted US Food and Drug Administration (FDA) approval for both relapsing/remitting and primary/progressive multiple sclerosis. Further studies are in progress to better define the utility of ocrelizumab over the other biological therapies available (Gelfand et al., 2017; Greenfield and Hauser, 2018; Sabatino et al., 2019). From a more fundamental point of view, these clinical data underscore the importance of advancing rapidly on the issue of the role of B cells in multiple sclerosis.

BONE-MARROW TRANSPLANTATION Autoimmune diseases include genetic components expressed in lymphoid and macrophage lineages qualify as stem-cell disorders. This explains that, in particular, before the availability of biological disease-modifying drugs

VIII.. MANAGEMENT

1446

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

that patients with serious autoimmune diseases have been considered for high-dose immunosuppression followed by hemopoietic stem-cell transplantation (HSCT) (Ikehara et al., 1990; Ikehara, 1998; Tyndall and Gratwohl, 1997). In the clinic the strategy stemmed from observations in patients with malignancies and concurrent autoimmune diseases (McAllister et al., 1997). Experimental results also showed that whether allogeneic or autologous HSCT induced a high rate of disease remission provided adequate conditioning regimens were administered (van Bekkum, 1998; Karussis et al., 1992, 1993; Ikehara et al., 1985). The First International Symposium on Haemopoietic Stem Cell Therapy in autoimmune diseases took place in 1996 (Tyndall and Gratwohl, 1997) and inaugurated collaborations Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT); guidelines were proposed that participating centers reported their results in a dedicated registry. The EBMT ADWP database now includes over 2500 patients treated during the past 20 years (Alexander et al., 2018). Among 2606 HSCT procedures reported, 2417 patients have undergone autologous HSCT and 133 patients allogeneic HSCT. Main indications for autologous HSCT were multiple sclerosis, scleroderma, Crohn’s disease, and SLE. A similar registry was created in North America (Center for International Blood and Marrow Transplant Research). The source of the stem-cell transplant is mostly peripheral cells mobilized using cyclophosphamide in combination with hematopoietic growth factors, granulocyte-colony stimulating factor (G-CSF) alone, or combined with granulocyte macrophage-colony stimulating factor (GM-CSF). According to different studies, the grafts are either purged of mature T cells, which may contain autoreactive effectors, by selection of CD341 cells with or without additional MAb-dependent T-cell depletion, or are not manipulated. Pretransplant conditioning regimens, for which the aim is to ablate as completely as possible the diseased (autoreactive) component of the immune system, include total body irradiation, chemotherapy-based regimens such as BEAM (Carmustine (BCNU), etoposide, cytosine arabinoside, melphalan), cyclophosphamide with or without antilymphocyte globulins and with or without other drugs, or total body irradiation and busulfan (Daikeler et al., 2011). Results from both pilot and large trials show benefit in patients with systemic sclerosis in favor of HSCT over cyclophosphamide (Alexander et al., 2015, 2018). The first studies performed in patients with severe multiple sclerosis with significant functional disability allowed assessment of risk/safety ration but not of efficacy. Subsequently, with the implementation of the procedure in patients with less severe disease, significant clinical benefit was observed in some groups of patients, including those with aggressive recurrent/relapsing forms of the disease. A recent long-term retrospective study that included unselectively any transplants performed between 1996 and 2005 (n 5 281) in both relapsingremitting and progressive multiple sclerosis patients reported long-standing remissions (Muraro et al., 2017a,b). These data were confirmed by a meta-analysis (Sormani et al., 2017). These data and those from the retrospective analysis of the EBMT registry indicate that autologous bone-marrow transplantation is an option only in patients with severe and active multiple sclerosis unresponsive to other treatments (Daikeler et al., 2011; Mancardi et al., 2018). Trials comparing HSCT with the more recently introduced high-efficacy disease-modifying treatments such as alemtuzumab are being planned, although their development is hampered by difficulties in accessing financial support (Muraro et al., 2017a,b). Patients with severe SLE received an autologous stem-cell transplantation. Two major studies reported a disease-free survival rate at 5 years of 50%. The transplant not only induced an improvement in serological markers of disease activity but also a prolonged remission (at least 5 years) of lung damage and of the associated antiphospholipid syndrome. These data are fully confirmed by those of the EBMT registry (Alexander et al., 2018). Overall, when SLE is achieved, remissions last long term also in absence of chronic immunosuppression. However, these results must be considered side by side to the risk of mortality that ranges 4%12%. One controlled trial is currently in progress in Germany, comparing HSCT with best available biologicals, including rituximab (NCT00750971) (Alexander et al., 2018). Before the introduction of biological therapies (MAbs or fusion proteins blocking TNF), rheumatoid arthritis was one of the first indications for autologous stem-cell transplantation. The procedure was well tolerated and induced good clinical responses (Van Laar and Tyndall, 2003). Nowadays, given the progress with TNF blockers and other new biological therapies, autologous stem-cell transplants are rare (Alexander et al., 2018). To be complete, one should quote the results of a trial in autoimmune insulin-dependent diabetes that included 23 patients aged 1331 years (Couri et al., 2009; Voltarelli et al., 2007, 2008). Autologous hematopoietic stem cells mobilized with cyclophosphamide and G-CSF were injected intravenously after conditioning with cyclophosphamide and rabbit antithymocyte globulin. During the follow-up, 20/23 were weaned from insulin treatment; 12 patients were insulin independent for 1452 months. Eventually all patients relapsed and return to insulin dependency. Concerning side effects, two patients developed bilateral nosocomial pneumonia, three developed late

VIII.. MANAGEMENT

SOLUBLE AUTOANTIGENS

1447

endocrine dysfunction, and nine developed oligospermia (Couri et al., 2009; Voltarelli et al., 2007, 2008). Thus although this therapy afforded disease remission with insulin independency for 14 years, the conditioning regimen required was heavy, comparable to that used in life-threatening autoimmune diseases. Considering the risk/benefit ratio, it is difficult to recommend such a strategy for wide application in type 1 diabetes even limited to adolescent and adults. For obvious reasons, it is inappropriate for use in children. In conclusion, despite the fact that this strategy showed spectacular results that approach operational tolerance in patients with severe autoimmune diseases, the important and often vital side effects explain that over recent years, it represented less and less an alternative. In addition, the possibilities now accessible that we will discuss below to generate, using genetic engineering, tools of cellular therapy “a` la carte” further question the future use of bone-marrow transplantation in autoimmunity.

SOLUBLE AUTOANTIGENS This strategy has given and still gives rise to many studies and, at first glance, it may seem a paradox. In order to understand the rationale here, we have to go back to the early 1960s when challenging the prevailing dogma that clonal deletion during lymphocyte development was the main, if not the exclusive, mechanism explaining immune tolerance, Dresser described the first results showing that in the adult host, the immune system can be “inactivated” rather than “activated” upon challenge with an antigen, depending on the modalities of administration of the antigen in question (Dresser, 1962). The concept of tolerance was therefore extended to also encompass states of unresponsiveness termed “immune paralysis,” observed instead of the usual immunization, when an antigen was delivered according to particular protocols. The classical example is that of tolerance to human gammaglobulins (IgG) observed in adult mice upon intravenous injection of deaggregated IgGs. Not only the mice thus treated do not produce antibodies against human IgG but, remarkably, they become refractory to any immunization with this antigen, even when it is inoculated in the presence of complete Freund’s adjuvant, a condition that is otherwise very immunogenic leading to massive production of specific antibodies. These seminal experiments were confirmed by many other authors using different antigens. All reiterated in the various models that antigen-specific B cells in tolerant animals were still present but functionally inactive. Regarding the respective role of B and T lymphocytes in this tolerance, the data showed that both compartments were concerned: the tolerance was more rapidly induced and persisted longer in T cells than B cells (Chiller et al., 2013). It may be important to recall here that reprogramming the immune system toward immune tolerance using antigen-specific therapy has been successfully applied for several decades now in allergy where “desensitization” is common practice. Things turned out more complex in autoimmunity. Thus immunological tolerance to a wide spectrum of autoantigens can be induced upon administration of the autoantigen by different routes, for example, parenteral, nasal, or oral. The approach has proven very successful in several animal models of spontaneous or experimentally induced autoimmunity. Thus the onset of diabetes in NOD mice can be prevented by administration of insulin or glutamic acid decarboxylase (GAD) using various routes of administration s.c., i.v., nasal, or oral (Tisch et al., 1993, 1994; Charlton et al., 1994; Kaufman et al., 1993; Tian et al., 1996). Similarly, experimental autoimmune encephalomyelitis (EAE) can be effectively prevented by administration of soluble myelin antigens (Smilek et al., 1991, 1992; Weiner et al., 1995; Wraith, 1995; Wraith et al., 1989; Miller et al., 1992). Mechanistic studies confirmed the working hypotheses that soluble autoantigen treatment had a direct effect on pathogenic lymphocytes and on antigen-presenting cells involved in the autoreactive reaction. Depending on the experimental model, the route of delivery, the dose administered or the antigen-presenting cells involved a functional inhibition of autoreactive T lymphocytes was observed. This occurred notably through triggering of anergy and or Th1/Th2 immune deviation (Tisch et al., 2001; Tian et al., 1997), and elimination of antigen specific autoreactive T cells (especially when high doses of autoantigen are used) (Bercovici et al., 2000) and stimulation of various subsets of specialized Treg either FoxP3 1 or FoxP3 2 (this is particularly the case in oral tolerance protocols where TGFβ-dependent and producing FoxP3 2 Treg), formerly termed Th3, play a major role (Weiner et al., 1991, 1995). Much attention was focused on autoantigen-presenting cells as their functional capacities greatly vary depending on the anatomical sites and they are therefore important immune actors explaining the differences in effect depending on the route of administration of autoantigens (mucosal, subcutaneous, intradermal, intravenous, intraperitoneal). Based on these data translation to the clinic was attempted using different autoantigens under various forms, for example, proteins, peptides or altered peptide ligands and was rapidly confronted to major problems which were predictable from the experimental data collected. These included limitation of the therapeutic window to

VIII.. MANAGEMENT

1448

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

early disease stages with loss of effectiveness as disease progresses; a long lag time to achieve efficacy, which may represent a problem in the case of acute autoimmune responses; risk of disease acceleration by triggering rather than down-regulating the autoimmune response; the potential risks of sensitization (e.g., anaphylaxis and/or production of neutralizing antibodies leading to serious problems when the autoantigen molecule, for example, insulin is physiologically relevant). It is undoubtedly in insulin-dependent diabetes and multiple sclerosis that the largest amount of clinical data has been accumulated to date. In insulin-dependent diabetes Phases I, II and even Phase III protocols that included large number of patients were conducted with great methodological rigor. The trials included both patients presenting with overt hyperglycemia in whom, as previously discussed, the insulin-secreting beta cell is largely reduced and in “at risk individuals” (Chaillous et al., 2000; Ludvigsson et al., 2012; Nanto-Salonen et al., 2008; Pozzilli et al., 2000; Skyler, 2002; Walter et al., 2009; Krischer et al., 2017; Wherrett et al., 2011). These are subjects screened as betacell autoantibody positive in families including at least one type 1 diabetic patient; when two or more beta-cell autoantibodies are detected these high risk individuals have about a 70% risk to develop hyperglycemia within 57 years (Triolo et al., 2019). The problem is that results were disappointing. None of the autoantigens used in autoimmune diabetes gave, when reaching the stage of Phase III trials, any positive therapeutic effect in terms of decreasing disease progression even in at risk individuals whom, as detailed earlier, present at an earlier disease stage. No side effects were observed in these trials. Better defining the stage of disease were soluble antigen therapy in autoimmune diabetes may lead to effectiveness is very carefully considered. Subjects at risk already presenting with beta-cell autoantibodies may be at a too late stage as active beta-cell destruction is already ongoing, autoantibodies being the markers of this destruction. Hence the aim of the Pre-POINT study conducted by the groups of Ziegler and Bonifacio, a doubleblind, placebo-controlled, dose-escalation, Phase I/II international clinical pilot study enrolling 25 islet autoantibodynegative children aged 27 years with a family history of type 1 diabetes and susceptible human leukocyte antigen class II genotypes (Bonifacio et al., 2015). The children received a daily oral administration of 67.5 mg of insulin or placebo. The treatment was safe (no hypoglycemia), an immune response to insulin was observed (Bonifacio et al., 2015). These data pave the ground for a Phase III trial to determine whether oral insulin can prevent islet autoimmunity and diabetes in such children. In multiple sclerosis early clinical use of an altered peptide ligand of myelin basic protein was hampered by serious side effects including an aggravation/relapse of the disease and hypersensitivity reactions which forced stopping the trials (Bielekova et al., 2000; Pedotti et al., 2001; Smith et al., 2005). A myelin basic protein peptide that exhibited a good safety profile did not meet the efficacy end points in a Phase III trial enrolling patients with secondary progressive disease (Freedman et al., 2011). What conclusions should we draw? Should the strategy be abandoned? Should we somehow throw the baby with the bath water? The answer is of course no; the experimental data cannot be ignored and pursuing efforts to approach effective autoantigen-specific immunotherapeutic approaches are fully warranted. The problem has probably been the one of an overwhelming enthusiasm for a strategy that was expected to deliver immune tolerance without exposing to the side effects of long-term immunosuppression. Such enthusiasm led to a too rapid clinical translation that ignored major elements of the equation, not the least being the chemical formulation of the autoantigen administered and also the question of selecting subgroups of patients who would be more sensitive to the effect of treatment. Finally, one should not discard the possibility of combining antigenspecific therapy with other immune-interventions which may potentiate efficacy (Mamchak et al., 2012). Concerning the chemical formulation of autoantigen, the results of Wraith’s group are very interesting. Step by step, based on robust experimental data in humanized mice these authors have shown that complications linked to unwanted immune reactions are not seen when CD4 1 T-cell epitopes (e.g., synthetic peptides) that mimic naturally processed T-cell epitopes, for example, apitope (antigen processing independent epitope) are used. These are peptides that bind directly to major histocompatibility complex class II on immature dendritic cells which prime tolerogenic T-cell circuits. In vivo these soluble peptides inhibit both Th1 and Th2 immune responses and enhance secretion of the immunoregulatory cytokine IL-10. The authors identified a cocktail of 4 peptides (ATX-MS-1467), behaving as apitopes, that suppress EAE in a humanized mouse model (Streeter et al., 2015). Furthermore, a Phase I trial of antigen-specific immunotherapy with ATX-MS-1467 has shown that treatment with this apitope cocktail is safe and so far the date on the clinical efficacy in Phase II studies are promising (Streeter et al., 2015; Chataway et al., 2018; Wraith et al., 2015). Apitopes are in development for treatment of Grave’s disease; presently experimental preclinical data are encouraging (Jansson et al., 2018).

VIII.. MANAGEMENT

CELL THERAPY AND ANTIGEN RECEPTOR GENEMODIFIED T CELLS

1449

Another completely different way to tackle the problem of autoantigen-specific therapies is to design strategies that through particular targeting of specific epitopes may trigger sustained expansion or reprogramming of preexisting autoreactive regulatory immune cells. Autoantigen delivery using nanoparticules appears as a promising path toward this aim as demonstrated in experimental models (Neef and Miller, 2017; Pearson et al., 2018; Clemente-Casares et al., 2016; Newbigging et al., 2016; Serra and Santamaria, 2018; Verdaguer et al., 1997). Many laboratories are rapidly making substantial progress in both the design of tools to apply at tolerogenic nanoparticles to mouse models of autoimmunity. The reader is referred to the work of the groups of Miller and Santamaria that are both contributing very extensively to this area (Neef and Miller, 2017; Pearson et al., 2018; Clemente-Casares et al., 2016; Newbigging et al., 2016; Serra and Santamaria, 2018; Verdaguer et al., 1997). Major efforts are also devoted to mechanistic studies to unravel the cellular and molecular key steps involved in the therapeutic effect. Autoantigen-specific therapies have many more things to reveal to us and still represent conceptually a fabulous approach, whether used alone or in combination, to approach immune tolerance in clinic.

CELL THERAPY AND ANTIGEN RECEPTOR GENEMODIFIED T CELLS Cell Therapy Using Regulatory T Cells After a long “crossing of the desert” during the 1990s, the existence of T lymphocytes that were called suppressors and which we now call regulatory T lymphocytes is no longer questioned. It is the discovery in 2003, simultaneously by three independent groups, that the FoxP3 transcription factor is a lineage marker of the CD4 1 CD25 1 T cells in the thymus and that it has a fundamental role in the expression of the regulatory function also in the periphery which has unlocked the situation (Hori et al., 2003; Fontenot et al., 2003; Khattri et al., 2003). Tregs underpin a fundamental mechanism of peripheral tolerance. Suffice is to observe the major, often life-threatening, polyautoimmune syndrome IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked) that is caused by loss of function mutations of FoxP3 (Wildin et al., 2001). The list of autoimmune diseases where the number or the functional capacity of Treg was shown to be abnormally reduced is long; this has sometimes been ascribed to a deficit in key Treg growth factors, in particular IL-2, or an excess of proinflammatory cytokine in the environment. Hence, the rationale for the attempts to use cell therapy with ex vivo expanded Tregs. Particular interest was focused in autoimmune diabetes. Experimental data in the NOD mouse showed the efficacy of expanded Treg, and in particular autoantigen-specific Treg, to treat established disease (Bluestone and Tang, 2004; Tang et al., 2004). Circulating Tregs were grown in culture in the presence of CD3 and CD28 antibodies and IL-2. Phase I studies have shown the safety of the inoculum and suggested of course preliminary clinical activity (Bluestone et al., 2015; Marek-Trzonkowska et al., 2013). The implementation of Phase II trials was, therefore, warranted, and the results from such a study are expected in 2019 (NCT02691247). Even if it concerns a single case it is interesting to quote here a recent report of adoptive polyclonal Treg treatment of a patient presenting SLE with active skin disease (Dall’Era et al., 2018). Deuterium tracking of infused Tregs revealed the migration of highly activated Tregs into diseased skin expressing a shift from Th1 to Th17 responses (Dall’Era et al., 2018).

Cell Therapy Using Antigen Receptor GeneModified T Cells In recent years the field of cell therapy has entered a new era, given on the one hand, the advances in our understanding of the molecular mechanisms that underlie the function of different immune cell subpopulations (effector T cells and Tregs) and, secondly, the incredible amount of technical resources that cell bioengineering has developed. The culture in vitro of specialized subsets of immune cells, and of antigen receptor genemodified T cells, that can be reinfused into patients with an autoimmune disease is becoming a reality. It all started in the field of oncology when it became possible to express at the surface of effector T cells with killing abilities an antigen receptor [T-cell receptor (TCR)] or chimeric antigen-specific receptors (CARs) specific for the tumor antigen. These CAR T cells expressed at their surface a fusion protein including an extracellular antibody domain specific to the antigen of interest (in this case the CD19 B-cell antigen) linked by a transmembrane domain to an intracellular-signaling portion that activates the T cell upon antigen binding. Initial trials were performed in 2013, using CAR T cells targeting the CD19 receptor and treating patients with B-cell acute lymphoblastic leukemia and then non-Hodgkin’s lymphoma and chronic

VIII.. MANAGEMENT

1450

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

lymphocytic leukemia (Brentjens and Curran, 2012; Brentjens et al., 2013; Gill and June, 2015). Based on the impressive results obtained in 2017, the FDA approved this adoptive cell-based gene therapy tisagenlecleucel (Kymriah) for acute lymphoblastic leukemia and in 2018 for non-Hodgkin’s lymphoma. This breakthrough also explains the great efforts made to extend this fascinating technology to solid tumors, infectious diseases, organ transplantation, bone-marrow transplantation, and autoimmunity (Maldini et al., 2018; Bluestone and Tang, 2018). In autoimmunity, one possibility would be to take advantage of CAR T cells to kill autoimmune pathogenic effector lymphocytes as recently proposed in a very elegant paper by Ellebrecht et al. (2016). These authors focused on pemphigus vulgaris a dermatological autoimmune disease where autoantibodies directed to desmoglein 3 (Dsg3) are the pathogenic effectors in the disease. Dsg3 is expressed on keratinocytes in the basal lower levels of the epidermis. Anti-Dsg3 autoantibodies provoke the loss of keratinocyte cellcell adhesion in the basal and immediate suprabasal layers of the deeper epidermis, leaving the superficial epidermis intact, thereby causing the blisters that are the hallmark of the disease. Ellebrecht et al. engineered T cells to express a chimeric autoantibody receptor, CAAR T cells, selectively destroy B lymphocytes producing anti-Dsg3 autoantibodies both in vitro and in vivo in humanized mouse models. As compared to the conventional CAR T cells discussed earlier in the case of hematological malignancies, CAAR T cells produced by Ellebrecht et al. expressed an extracellular domain that included Dsg3, the autoantigen which upon binding to the specific autoantibodies on the autoreactive B-cell surface triggered the signaling machinery of the T cell though the intracellular domains of the CAAR that in this case included molecules CD3ζ and CD137 (Ellebrecht et al., 2016). One of the humanized models used was set up with NSG (NOD-SCID-gamma) immunodeficient mice engrafted with human skin xenografts; injection of Dsg3 CAAR T cells in these recipients and no direct toxicity to keratinocytes was observed, supporting the lack of “off-target” effect of the approach and confirming its safety. The case of pemphigus vulgaris was ideal proof-of-concept for the CAAR T-cell strategy as the autoantigen structure has been very well dissected together with the specific binding sites of the pathogenic autoantibodies which, in addition, are known to be oligoclonal (Hammers et al., 2015). As discussed in a commentary I wrote on this interesting and provocative piece of work, it would be very important to identify other autoimmune diseases whose treatment could be enriched by this new tool that are CAAR T cells. The obvious first candidates are autoimmune diseases where autoantibodies, with well-identified autoantigen epitopes, are pathogenic. This is certainly the case for myasthenia gravis. Another potential target is a disease affecting the fetus in autoimmune pregnant mothers presenting with SLE or Sjo¨gren syndrome known as the autoantibody-associated neonatal lupus syndrome (e.g., congenital heart block) (Ambrosi et al., 2014; Skog et al., 2016). Here maternal autoantibodies to the Ro/SSA autoantigen, including the unrelated Ro52 and Ro60 proteins that cross the placenta are the pathogenic effectors (Ambrosi et al., 2014; Skog et al., 2016). Concerning the other autoimmune diseases in which autoantibodies have a clear pathogenic effect, it will be mandatory to attempt applying the CAAR T-cell technology to have better definition and molecular characterization of key autoantigen epitopes. The CAAR T-cell technology may also be exploited to target autoreactive B cells which rather than producing pathogenic autoantibodies act as autoantigen-presenting cells. The prototypic situation is for instance that of insulin-dependent diabetes a disease where the pathogenic effectors are exclusively autoreactive CD41 and CD81 T lymphocytes that selective destroy insulin-secreting beta cells within pancreatic islets of Langerhans. The autoantigens that are the targets of the autoreactive T cells are well characterized (e.g., insulin/proinsulin, GAD, the IA-2 phosphatase). Autoantibodies against these antigens are present, from early stages of the disease, and they are used to screen patients with genetic susceptibility who present early stages of beta-cell destruction and who are at risk to develop hyperglycemia within a relatively short time frame (Triolo et al., 2019). It is very well established that autoantibodies are not pathogenic but compelling experimental and clinical evidence has been accumulated to show that B cells play a key role in the disease as autoantigen-presenting cells. Thus CD20 antibodies, which eliminate B cells, have a transient yet clear therapeutic effect in NOD mice as well as in patients with recent-onset type 1 diabetes. Applying CAAR T-cell treatment at early disease stages when only few antibeta-cell autoantibody specificities are detected one could expect to target B cells before they become fully committed at efficacious autoantigen presentation and at mediating autoantigen spreading and progression to massive beta-cell destruction. Last but not least TCR or CAR gene transfer could be implemented to improve Treg therapy by generating antigen-specific Tregs which as discussed earlier have proved more effective in experimental models. Of course, a major obstacle will be that of defining very precisely the epitopes that are recognized by autoantigen-specific Treg. The task is not simple, but interesting data are emerging in autoimmune diabetes (Yeh et al., 2017).

VIII.. MANAGEMENT

REFERENCES

1451

PERSPECTIVES AND CONCLUSIONS As a conclusion, it is hoped if not anticipated that emergent therapies based on the progress of biotechnology, including gene and cell therapy, will progressively complement and in some cases even replace conventional treatments. The rapidity with which TNF blockers have become accessible to patients with rheumatoid arthritis and Crohn’s disease is most encouraging. The multitude of these drugs and their potential clinical applications are remarkable. Nevertheless, there are still numerous problems concerning the development and evaluation of the various drugs being studied. Major efforts should be made to identify the best applications and promote their development for the benefit of patients beyond commercial constraints. Increasing efficacy without side effects is the major long-term goal. Well-designed combination therapy appears as a sensible approach. The list of candidates is longer every day going from conventional chemical immunosuppressants to other biological and in particular cases cell therapy (Treg). Each disease has its own therapeutic profile, but manifestations differ between subgroups of patients as their response to treatment also do. An in-depth rejuvenation of the field of immunotherapy will come from our ability to characterize robust and reliable biomarkers to identify key subgroups of patients within a given disease entity and propose the most appropriate single or combination therapy. This is the essence of personalized medicine to offer to every patient the possibility of remission, as sustainable as possible, with the fewest side effects. The fact that our therapeutic arsenal was enriched with products such as CD3 antibodies that may achieve long-term remissions in the absence of chronic treatment is a major asset to go step by step and in well-identified subgroups of patients, toward clinical operational tolerance.

References Abramowicz, D., Crusiaux, A., Goldman, M., 1992. Anaphylactic shock after retreatment with OKT3 monoclonal antibody. N. Engl. J. Med. 327 (10), 736. Abramowicz, D., Crusiaux, A., Niaudet, P., Kreis, H., Chatenoud, L., Goldman, M., 1996. The IgE humoral response in OKT3-treated patients—incidence and fine specificity. Transplantation 61 (4), 577581. Abramowicz, D., Schandene, L., Goldman, M., Crusiaux, A., Vereerstraeten, P., De Pauw, L., et al., 1989. Release of tumor necrosis factor, interleukin-2, and gamma-interferon in serum after injection of OKT3 monoclonal antibody in kidney transplant recipients. Transplantation 47 (4), 606608. Alegre, M.L., Peterson, L.J., Xu, D., Sattar, H.A., Jeyarajah, D.R., Kowalkowski, K., et al., 1994. A non-activating “humanized” anti-CD3 monoclonal antibody retains immunosuppressive properties in vivo. Transplantation 57 (11), 15371543. Alexander, T., Bondanza, A., Muraro, P.A., Greco, R., Saccardi, R., Daikeler, T., et al., 2015. SCT for severe autoimmune diseases: consensus guidelines of the European Society for Blood and Marrow Transplantation for immune monitoring and biobanking. Bone Marrow Transplant 50 (2), 173180. Alexander, T., Farge, D., Badoglio, M., Lindsay, J.O., Muraro, P.A., Snowden, J.A., 2018. Hematopoietic stem cell therapy for autoimmune diseases—clinical experience and mechanisms. J. Autoimmun. 92, 3546. Ambrosi, A., Sonesson, S.E., Wahren-Herlenius, M., 2014. Molecular mechanisms of congenital heart block. Acta Obstet. Gynecol. Scand. 325 (1), 29. Bach, J.F., 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347 (12), 911920. Bach, J.F., 2003. Regulatory T cells under scrutiny. Nat. Rev. Immunol. 3 (3), 189198. Bach, J.F., 2011. Anti-CD3 antibodies for type 1 diabetes: beyond expectations. Lancet 378 (9790), 459460. Bach, J.F., 2018. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat. Rev. Immunol. 18 (2), 105120. Barbas III, C.F., 1995. Synthetic human antibodies. Nat. Med. 1 (8), 837839. Barbas III, C.F., Hu, D., Dunlop, N., Sawyer, L., Cababa, D., Hendry, R.M., et al., 1994. In vitro evolution of a neutralizing human antibody to human immunodeficiency virus type 1 to enhance affinity and broaden strain cross-reactivity. Proc. Natl. Acad. Sci. U.S.A. 91 (9), 38093813. Baudrihaye, M.F., Chatenoud, L., Kreis, H., Goldstein, G., Bach, J.F., 1984. Unusually restricted anti-isotype human immune response to OKT3 monoclonal antibody. Eur. J. Immunol. 14 (8), 686691. Belghith, M., Bluestone, J.A., Barriot, S., Megret, J., Bach, J.F., Chatenoud, L., 2003. TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat. Med. 9 (9), 12021208. Benjamin, R.J., Cobbold, S.P., Clark, M.R., Waldmann, H., 1986. Tolerance to rat monoclonal antibodies. Implications for serotherapy. J. Exp. Med. 163 (6), 15391552. Bercovici, N., Heurtier, A., Vizler, C., Pardigon, N., Cambouris, C., Desreumaux, P., et al., 2000. Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage. J. Immunol. 165 (1), 202210. Besancon, A., Goncalves, T., Valette, F., Dahllof, M.S., Mandrup-Poulsen, T., Chatenoud, L., et al., 2018. Oral histone deacetylase inhibitor synergises with T cell targeted immunotherapy to preserve beta cell metabolic function and induce stable remission of new-onset autoimmune diabetes in NOD mice. Diabetologia 61 (2), 389398.

VIII.. MANAGEMENT

1452

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

Bielekova, B., Goodwin, B., Richert, N., Cortese, I., Kondo, T., Afshar, G., et al., 2000. Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand. Nat. Med. 6 (10), 11671175. Bluestone, J.A., Buckner, J.H., Fitch, M., Gitelman, S.E., Gupta, S., Hellerstein, M.K., et al., 2015. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7 (315), 315ra189. Bluestone, J.A., Tang, Q., 2004. Therapeutic vaccination using CD4 1 CD25 1 antigen-specific regulatory T cells. Proc. Natl. Acad. Sci. U.S.A. 101 (Suppl. 2), 1462214626. Bluestone, J.A., Tang, Q., 2018. Treg cells—the next frontier of cell therapy. Science 362 (6411), 154155. Bolt, S., Routledge, E., Lloyd, I., Chatenoud, L., Pope, H., Gorman, S.D., et al., 1993. The generation of a humanized, non-mitogenic CD3 monoclonal antibody which retains in vitro immunosuppressive properties. Eur. J. Immunol. 23 (2), 403411. Bonifacio, E., Ziegler, A.G., Klingensmith, G., Schober, E., Bingley, P.J., Rottenkolber, M., et al., 2015. Effects of high-dose oral insulin on immune responses in children at high risk for type 1 diabetes: the Pre-POINT randomized clinical trial. JAMA 313 (15), 15411549. Brandstadter, R., Katz Sand, I., 2017. The use of natalizumab for multiple sclerosis. Neuropsychiatr. Dis. Treat. 13, 16911702. Brennan, F.M., Chantry, D., Jackson, A., Maini, R., Feldmann, M., 1989. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2 (8657), 244247. Brennan, F.M., Feldmann, M., 1992. Cytokines in autoimmunity. Curr. Opin. Immunol. 4 (6), 754759. Brentjens, R.J., Curran, K.J., 2012. Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen. Hematology (Am. Soc. Hematol. Educ. Program) 2012, 143151. Brentjens, R.J., Davila, M.L., Riviere, I., Park, J., Wang, X., Cowell, L.G., et al., 2013. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl. Med. 5 (177), 177ra38. Calne, R., Friend, P., Moffatt, S., Bradley, A., Hale, G., Firth, J., et al., 1998. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients [letter] [published erratum appears in Lancet 1998 Aug 1;352(9125):408] Lancet 351 (9117), 17011702. CAMMS223 Trial Investigators, Coles, A.J., Compston, D.A., Selmaj, K.W., Lake, S.L., Moran, S., et al., 2008. Alemtuzumab vs. interferon beta1a in early multiple sclerosis. N. Engl. J. Med. 359 (17), 17861801. Catrina, A.I., Svensson, C.I., Malmstrom, V., Schett, G., Klareskog, L., 2017. Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat. Rev. Rheumatol. 13 (2), 7986. Chaillous, L., Lefevre, H., Thivolet, C., Boitard, C., Lahlou, N., Atlan-Gepner, C., et al., 2000. Oral insulin administration and residual beta-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial. Diabete Insuline Orale group. Lancet 356 (9229), 545549. Charlton, B., Taylor Edwards, C., Tisch, R., Fathman, C.G., 1994. Prevention of diabetes and insulitis by neonatal intrathymic islet administration in NOD mice. J. Autoimmun. 7 (5), 549560. Chataway, J., Martin, K., Barrell, K., Sharrack, B., Stolt, P., Wraith, D.C., 2018. Effects of ATX-MS-1467 immunotherapy over 16 weeks in relapsing multiple sclerosis. Neurology 90 (11), e955e962. Chatenoud, L., 2003. CD3-specific antibody-induced active tolerance: from bench to bedside. Nat. Rev. Immunol. 3 (2), 123132. Chatenoud, L., 2010. Immune therapy for type 1 diabetes mellitus-what is unique about anti-CD3 antibodies? Nat. Rev. Endocrinol. 6 (3), 149157. Chatenoud, L., Baudrihaye, M.F., Chkoff, N., Kreis, H., Goldstein, G., Bach, J.F., 1986a. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J. Immunol. 137 (3), 830838. Chatenoud, L., Bluestone, J.A., 2007. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat. Rev. Immunol. 7, 622632. Chatenoud, L., Ferran, C., Bach, J.F., 1989. In-vivo anti-CD3 treatment of autoimmune patients. Lancet 2 (8655), 164. Chatenoud, L., Ferran, C., Legendre, C., Thouard, I., Merite, S., Reuter, A., et al., 1990. In vivo cell activation following OKT3 administration. Systemic cytokine release and modulation by corticosteroids. Transplantation 49 (4), 697702. Chatenoud, L., Jonker, M., Villemain, F., Goldstein, G., Bach, J.F., 1986b. The human immune response to the OKT3 monoclonal antibody is oligoclonal. Science 232 (4756), 14061408. Chatenoud, L., Primo, J., Bach, J.F., 1997. CD3 antibody-induced dominant self tolerance in overtly diabetic NOD mice. J. Immunol. 158 (6), 29472954. Chatenoud, L., Salomon, B., Bluestone, J.A., 2001. Suppressor T cells—they’re back and critical for regulation of autoimmunity!. Immunol. Rev. 182, 149163. Chatenoud, L., Thervet, E., Primo, J., Bach, J.F., 1994. Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc. Natl. Acad. Sci. U.S.A. 91 (1), 123127. Chiller, J.M., Habicht, G.S., Weigle, W.O., 2013. Pillars article: kinetic differences in unresponsiveness of thymus and bone marrow cells. Science. 1971. 171: 813-815. J. Immunol. 191 (3), 989991. Clemente-Casares, X., Blanco, J., Ambalavanan, P., Yamanouchi, J., Singha, S., Fandos, C., et al., 2016. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530 (7591), 434440. Clevers, H., Alarcon, B., Wileman, T., Terhorst, C., 1988. The T cell receptor/CD3 complex: a dynamic protein ensemble. Annu. Rev. Immunol. 6 (1), 629662. Cobbold, S.P., Adams, E., Graca, L., Daley, S., Yates, S., Paterson, A., et al., 2006. Immune privilege induced by regulatory T cells in transplantation tolerance. Immunol. Rev. 213, 239255. Cohen, J.A., Coles, A.J., Arnold, D.L., Confavreux, C., Fox, E.J., Hartung, H.P., et al., 2012. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380 (9856), 18191828. Coles, A., Deans, J., Compston, A., 2004. Campath-1H treatment of multiple sclerosis: lessons from the bedside for the bench. Clin. Neurol. Neurosurg. 106 (3), 270274. Coles, A.J., Twyman, C.L., Arnold, D.L., Cohen, J.A., Confavreux, C., Fox, E.J., et al., 2012. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380 (9856), 18291839.

VIII.. MANAGEMENT

REFERENCES

1453

Coles, A.J., Wing, M.G., Molyneux, P., Paolillo, A., Davie, C.M., Hale, G., et al., 1999a. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann. Neurol. 46 (3), 296304. Coles, A.J., Wing, M.G., Smith, S., Corradu, F., Greer, S., Taylor, C., et al., 1999b. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 354, 16911695. Cosimi, A.B., Colvin, R.B., Burton, R.C., Rubin, R.H., Goldstein, G., Kung, P.C., et al., 1981. Use of monoclonal antibodies to T-cell subsets for immunologic monitoring and treatment in recipients of renal allografts. N. Engl. J. Med. 305 (6), 308314. Couri, C.E., Oliveira, M.C., Stracieri, A.B., Moraes, D.A., Pieroni, F., Barros, G.M., et al., 2009. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 301 (15), 15731579. Cuker, A., Coles, A.J., Sullivan, H., Fox, E., Goldberg, M., Oyuela, P., et al., 2011. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 118 (24), 62996305. Daifotis, A.G., Koenig, S., Chatenoud, L., Herold, K.C., 2013. Anti-CD3 clinical trials in type 1 diabetes mellitus. Clin. Immunol. 149 (3), 268278. Daikeler, T., Labopin, M., Di Gioia, M., Abinun, M., Alexander, T., Miniati, I., et al., 2011. Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party. Blood 118 (6), 16931698. Dall’Era, M., Pauli, M.L., Remedios, K., Taravati, K., Sandova, P.M., Putnam, A.L., et al., 2018. Adoptive Treg cell therapy in a patient with systemic lupus erythematosus. Arthritis Rheumatol. 71 (3), 431440. de Brito Rocha, S., Baldo, D.C., Andrade, L.E.C., 2019. Clinical and pathophysiologic relevance of autoantibodies in rheumatoid arthritis. Adv. Rheumatol. 59 (1), 2. De Vita, S., Zaja, F., Sacco, S., De Candia, A., Fanin, R., Ferraccioli, G., 2002. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum. 46 (8), 20292033. Debure, A., Chkoff, N., Chatenoud, L., Lacombe, M., Campos, H., Noel, L.H., et al., 1988. One-month prophylactic use of OKT3 in cadaver kidney transplant recipients. Transplantation 45 (3), 546553. Depis, F., Hatterer, E., Lamacchia, C., Waldburger, J.M., Gabay, C., Reith, W., et al., 2012. Long-term amelioration of established collageninduced arthritis achieved with short-term therapy combining anti-CD3 and anti-tumor necrosis factor treatments. Arthritis Rheum. 64 (10), 31893198. Dresser, D.W., 1962. Specific inhibition of antibody production. II. Paralysis induced in adult mice by small quantities of protein antigen. Immunology 5, 378388. Ellebrecht, C.T., Bhoj, V.G., Nace, A., Choi, E.J., Mao, X., Cho, M.J., et al., 2016. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353 (6295), 179184. Elliott, M.J., Maini, R.N., Feldmann, M., Kalden, J.R., Antoni, C., Smolen, J.S., et al., 1994. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 344 (8930), 11051110. Feldmann, M., 2002. Development of anti-TNF therapy for rheumatoid arthritis. Nat. Rev. Immunol. 2 (5), 364371. Fontenot, J.D., Gavin, M.A., Rudensky, A.Y., 2003. Foxp3 programs the development and function of CD4 1 CD25 1 regulatory T cells. Nat. Immunol. 4 (4), 330336. Foote, J., Eisen, H.N., 1995. Kinetic and affinity limits on antibodies produced during immune responses. Proc. Natl. Acad. Sci. U.S.A. 92 (5), 12541256. Freedman, M.S., Bar-Or, A., Oger, J., Traboulsee, A., Patry, D., Young, C., et al., 2011. A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS. Neurology 77 (16), 15511560. Friend, P.J., Hale, G., Chatenoud, L., Rebello, P., Bradley, J., Thiru, S., et al., 1999. Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection. Transplantation 68, 16321637. Furst, D.E., Weisman, M., Paulus, H.E., Bulpitt, K., Weinblatt, M., Polisson, R., et al., 2003. Intravenous human recombinant tumor necrosis factor receptor p55-Fc IgG1 fusion protein, Ro 45-2081 (lenercept): results of a dose-finding study in rheumatoid arthritis. J. Rheumatol. 30 (10), 21232126. Furtado, J., Isenberg, D.A., 2013. B cell elimination in systemic lupus erythematosus. Clin. Immunol. 146 (2), 90103. Gelfand, J.M., Cree, B.A.C., Hauser, S.L., 2017. Ocrelizumab and other CD20(1) B-cell-depleting therapies in multiple sclerosis. Neurotherapeutics 14 (4), 835841. Gill, S., June, C.H., 2015. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol. Rev. 263 (1), 6889. Gilliland, L.K., Walsh, L.A., Frewin, M.R., Wise, M.P., Tone, M., Hale, G., et al., 1999. Elimination of the immunogenicity of therapeutic antibodies. J. Immunol. 162 (6), 36633671. Goto, R., You, S., Zaitsu, M., Chatenoud, L., Wood, K.J., 2013. Delayed anti-CD3 therapy results in depletion of alloreactive T cells and the dominance of Foxp3(1) CD4(1) graft infiltrating cells. Am. J. Transplant. 13 (7), 16551664. Greenfield, A.L., Hauser, S.L., 2018. B-cell therapy for multiple sclerosis: entering an era. Ann. Neurol. 83 (1), 1326. Hammers, C.M., Chen, J., Lin, C., Kacir, S., Siegel, D.L., Payne, A.S., et al., 2015. Persistence of anti-desmoglein 3 IgG(1) B-cell clones in pemphigus patients over years. J. Invest. Dermatol. 135 (3), 742749. Hauser, S.L., Waubant, E., Arnold, D.L., Vollmer, T., Antel, J., Fox, R.J., et al., 2008. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N. Engl. J. Med. 358 (7), 676688. Hering, B.J., Kandaswamy, R., Harmon, J.V., Ansite, J.D., Clemmings, S.M., Sakai, T., et al., 2004. Transplantation of cultured islets from twolayer preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am. J. Transplant. 4 (3), 390401. Herold, K.C., Gitelman, S.E., Masharani, U., Hagopian, W., Bisikirska, B., Donaldson, D., et al., 2005. A single course of anti-CD3 monoclonal antibody hOKT3gamma1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54 (6), 17631769. Herold, K.C., Gitelman, S.E., Ehlers, M.R., Gottlieb, P.A., Greenbaum, C.J., Hagopian, W., et al., 2013. Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Diabetes 62 (11), 37663774.

VIII.. MANAGEMENT

1454

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

Herold, K.C., Hagopian, W., Auger, J.A., Poumian Ruiz, E., Taylor, L., Donaldson, D., et al., 2002. Anti-CD3 monoclonal antibody in newonset type 1 diabetes mellitus. N. Engl. J. Med. 346 (22), 16921698. Hori, S., Nomura, T., Sakaguchi, S., 2003. Control of regulatory T cell development by the transcription factor Foxp3. Science 299 (5609), 10571061. Hricik, D.E., Mayes, J.T., Schulak, J.A., 1990. Inhibition of anti-OKT3 antibody generation by cyclosporine—results of a prospective randomized trial. Transplantation 50 (2), 237240. Hu, C., Ding, H., Zhang, X., Wong, F.S., Wen, L., 2013. Combination treatment with anti-CD20 and oral anti-CD3 prevents and reverses autoimmune diabetes. Diabetes 62 (8), 28492858. Ikehara, S., 1998. Bone marrow transplantation for autoimmune diseases. Acta Haematol. 99 (3), 116132. Ikehara, S., Kawamura, M., Takao, F., Inaba, M., Yasumizu, R., Than, S., et al., 1990. Organ-specific and systemic autoimmune diseases originate from defects in hematopoietic stem cells. Proc. Natl. Acad. Sci. U.S.A. 87 (21), 83418344. Ikehara, S., Ohtsuki, H., Good, R.A., Asamoto, H., Nakamura, T., Sekita, K., et al., 1985. Prevention of type I diabetes in nonobese diabetic mice by allogenic bone marrow transplantation. Proc. Natl. Acad. Sci. U.S.A. 82 (22), 77437747. Jansson, L., Vrolix, K., Jahraus, A., Martin, K.F., Wraith, D.C., 2018. Immunotherapy with apitopes blocks the immune response to TSH receptor in HLA-DR transgenic mice. Endocrinology 159 (9), 34463457. Jones, J.L., Phuah, C.L., Cox, A.L., Thompson, S.A., Ban, M., Shawcross, J., et al., 2009. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J. Clin. Invest. 119 (7), 20522061. Karussis, D.M., Slavin, S., Lehmann, D., Mizrachi-koll, R., Abramsky, O., Ben-nun, A., 1992. Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation. J. Immunol. 148 (6), 16931698. Karussis, D.M., Vourka-karussis, U., Lehmann, D., Ovadia, H., Mizrachi-koll, R., Ben-nun, A., et al., 1993. Prevention and reversal of adoptively transferred, chronic relapsing experimental autoimmune encephalomyelitis with a single high dose cytoreductive treatment followed by syngeneic bone marrow transplantation. J. Clin. Invest. 92 (2), 765772. Kastbom, A., Forslind, K., Ernestam, S., Geborek, P., Karlsson, J.A., Petersson, I.F., et al., 2016. Changes in the anticitrullinated peptide antibody response in relation to therapeutic outcome in early rheumatoid arthritis: results from the SWEFOT trial. Ann. Rheum. Dis. 75 (2), 356361. Kaufman, D.L., Clare-Salzler, M., Tian, J., Forsthuber, T., Ting, G.S., Robinson, P., et al., 1993. Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366 (6450), 6972. Keymeulen, B., Vandemeulebroucke, E., Ziegler, A.G., Mathieu, C., Kaufman, L., Hale, G., et al., 2005. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N. Engl. J. Med. 352 (25), 25982608. Keymeulen, B., Walter, M., Mathieu, C., Kaufman, L., Gorus, F., Hilbrands, R., et al., 2010. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia 53 (4), 614623. Khattri, R., Cox, T., Yasayko, S.A., Ramsdell, F., 2003. An essential role for Scurfin in CD4 1 CD25 1 T regulatory cells. Nat. Immunol. 4 (4), 337342. Kohler, G., Milstein, C., 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256 (5517), 495497. Krischer, J.P., Schatz, D.A., Bundy, B., Skyler, J.S., Greenbaum, C.J., 2017. Effect of oral insulin on prevention of diabetes in relatives of patients with type 1 diabetes: a randomized clinical trial. JAMA 318 (19), 18911902. Kuhn, C., You, S., Valette, F., Hale, G., van Endert, P., Bach, J.F., et al., 2011. Human CD3 transgenic mice: preclinical testing of antibodies promoting immune tolerance. Sci. Transl. Med. 3 (68), 68ra10. Kung, P., Goldstein, G., Reinherz, E.L., Schlossman, S.F., 1979. Monoclonal antibodies defining distinctive human T cell surface antigens. Science 206 (4416), 347349. Leandro, M.J., Cambridge, G., Edwards, J.C., Ehrenstein, M.R., Isenberg, D.A., 2005. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology (Oxford) 44 (12), 15421545. Leandro, M.J., Edwards, J.C., Cambridge, G., 2002. Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann. Rheum. Dis. 61 (10), 883888. Leo, O., Foo, M., Sachs, D.H., Samelson, L.E., Bluestone, J.A., 1987. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc. Natl. Acad. Sci. U.S.A. 84 (5), 13741378. Lockwood, C.M., Thiru, S., Isaacs, J.D., Hale, G., Waldmann, H., 1993. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 341 (8861), 16201622. Lockwood, C.M., Thiru, S., Stewart, S., Hale, G., Isaacs, J., Wraight, P., et al., 1996. Treatment of refractory Wegener’s granulomatosis with humanized monoclonal antibodies. QJM 89 (12), 903912. Lonberg, N., Taylor, L.D., Harding, F.A., Trounstine, M., Higgins, K.M., Schramm, S.R., et al., 1994. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368 (6474), 856859. Lubin, I., Segall, H., Marcus, H., David, M., Kulova, L., Steinitz, M., et al., 1994. Engraftment of human peripheral blood lymphocytes in normal strains of mice. Blood 83 (8), 23682381. Ludvigsson, J., Krisky, D., Casas, R., Battelino, T., Castano, L., Greening, J., et al., 2012. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366 (5), 433442. Ma, M.H., Scott, I.C., Dahanayake, C., Cope, A.P., Scott, D.L., 2014. Clinical and serological predictors of remission in rheumatoid arthritis are dependent on treatment regimen. J. Rheumatol. 41 (7), 12981303. Maldini, C.R., Ellis, G.I., Riley, J.L., 2018. CAR T cells for infection, autoimmunity and allotransplantation. Nat. Rev. Immunol. 18 (10), 605616. Mamchak, A.A., Manenkova, Y., Leconet, W., Zheng, Y., Chan, J.R., Stokes, C.L., et al., 2012. Preexisting autoantibodies predict efficacy of oral insulin to cure autoimmune diabetes in combination with anti-CD3. Diabetes 61 (6), 14901499.

VIII.. MANAGEMENT

REFERENCES

1455

Mancardi, G., Sormani, M.P., Muraro, P.A., Boffa, G., Saccardi, R., 2018. Intense immunosuppression followed by autologous haematopoietic stem cell transplantation as a therapeutic strategy in aggressive forms of multiple sclerosis. Mult. Scler. 24 (3), 245255. Marek-Trzonkowska, N., Mysliwec, M., Siebert, J., Trzonkowski, P., 2013. Clinical application of regulatory T cells in type 1 diabetes. Pediatr. Diabetes 14 (5), 322332. Marks, J.D., Hoogenboom, H.R., Bonnert, T.P., Mccafferty, J., Griffiths, A.D., Winter, G., 1991. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J. Mol. Biol. 222 (3), 581597. Mathieson, P.W., Cobbold, S.P., Hale, G., Clark, M.R., Oliveira, D.B., Lockwood, C.M., et al., 1990. Monoclonal-antibody therapy in systemic vasculitis. N. Engl. J. Med. 323 (4), 250254. McAllister, L.D., Beatty, P.G., Rose, J., 1997. Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis. Bone Marrow Transplant 19 (4), 395397. Merrill, J.T., Neuwelt, C.M., Wallace, D.J., Shanahan, J.C., Latinis, K.M., Oates, J.C., et al., 2010. Efficacy and safety of rituximab in moderatelyto-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62 (1), 222233. Merrill, J.T., Wallace, D.J., Wax, S., Kao, A., Fraser, P.A., Chang, P., et al., 2018. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled, parallel-arm, phase IIb study. Arthritis Rheumatol. 70 (2), 266276. Miller, D.H., Khan, O.A., Sheremata, W.A., Blumhardt, L.D., Rice, G.P., Libonati, M.A., et al., 2003. A controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 348 (1), 1523. Miller, S.D., Tan, L.J., Pope, L., McRae, B.L., Karpus, W.J., 1992. Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis. Int. Rev. Immunol. 9 (3), 203222. Moreland, L.W., Baumgartner, S.W., Schiff, M.H., Tindall, E.A., Fleischmann, R.M., Weaver, A.L., et al., 1997. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N. Engl. J. Med. 337 (3), 141147. Moreland, L.W., Margolies, G., Heck Jr., L.W., Saway, A., Blosch, C., Hanna, R., et al., 1996. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J. Rheumatol. 23 (11), 18491855. Morrison, S.L., Johnson, M.J., Herzenberg, L.A., Oi, V.T., 1984. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. U.S.A. 81 (21), 68516855. Muraro, P.A., Martin, R., Mancardi, G.L., Nicholas, R., Sormani, M.P., Saccardi, R., 2017a. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat. Rev. Neurol. 13 (7), 391405. Muraro, P.A., Pasquini, M., Atkins, H.L., Bowen, J.D., Farge, D., Fassas, A., et al., 2017b. Long-term outcomes after autologous hematopoietic stem cell transplantation for multiple sclerosis. JAMA Neurol. 74 (4), 459469. Nanto-Salonen, K., Kupila, A., Simell, S., Siljander, H., Salonsaari, T., Hekkala, A., et al., 2008. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet 372 (9651), 17461755. Nashan, B., Moore, R., Amlot, P., Schmidt, A.G., Abeywickrama, K., Soulillou, J.P., 1997. Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipientsCHIB 201 International Study Group [published erratum appears in Lancet 1997 Nov 15;350(9089):1484] Lancet 350 (9086), 11931198. Neef, T., Miller, S.D., 2017. Tolerogenic nanoparticles to treat islet autoimmunity. Curr. Diab. Rep. 17 (10), 84. Newbigging, S., Serra, P., Khadra, A., Chan, W.C.W., Santamaria, P., Clemente-Casares, X., et al., 2016. Expanding antigen-specific regulatory networks to treat autoimmunity. Nat. Nanotechnol. 530 (7591), 434440. Nicolls, M.R., Aversa, G.G., Pearce, N.W., Spinelli, A., Berger, M.F., Gurley, K.E., et al., 1993. Induction of long-term specific tolerance to allografts in rats by therapy with an anti-CD3-like monoclonal antibody. Transplantation 55 (3), 459468. Ortho, X., 1985. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. Ortho Multicenter Transplant Study Group. N. Engl. J. Med. 313 (6), 337342. Patterson, C.C., Harjutsalo, V., Rosenbauer, J., Neu, A., Cinek, O., Skrivarhaug, T., et al., 2018. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989-2013: a multicentre prospective registration study. Diabetologia 62 (3), 408417. Pearson, R.M., Podojil, J.R., Shea, L.D., King, N.J., Miller, S.D., Getts, D.R., 2018. Overcoming challenges in treating autoimmuntity: development of tolerogenic immune-modifying nanoparticles. Nanomedicine 18, S15499634. Pedotti, R., Mitchell, D., Wedemeyer, J., Karpuj, M., Chabas, D., Hattab, E.M., et al., 2001. An unexpected version of horror autotoxicus: anaphylactic shock to a self-peptide. Nat. Immunol. 2 (3), 216222. Perdigoto, A.L., Preston-Hurlburt, P., Clark, P., Long, S.A., Linsley, P.S., Harris, K.M., et al., 2018. Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis. Diabetologia 62 (4), 655664. Pescovitz, M.D., Greenbaum, C.J., Krause-Steinrauf, H., Becker, D.J., Gitelman, S.E., Goland, R., et al., 2009. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J Med. 361 (22), 21432152. Piguet, P.F., Grau, G.E., Vesin, C., Loetscher, H., Gentz, R., Lesslauer, W., 1992. Evolution of collagen arthritis in mice is arrested by treatment with anti-tumour necrosis factor (TNF) antibody or a recombinant soluble TNF receptor. Immunology 77 (4), 510514. Piotti, G., Ma, J., Adams, E., Cobbold, S., Waldmann, H., 2014. Guiding postablative lymphocyte reconstitution as a route toward transplantation tolerance. Am. J. Transplant. 14 (7), 16781689. Plain, K.M., Chen, J., Merten, S., He, X.Y., Hall, B.M., 1999. Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non-depleting anti-CD3 monoclonal antibody: association with TH2 cytokines not anergy. Transplantation 67 (4), 605613. Pozzilli, P., Pitocco, D., Visalli, N., Cavallo, M.G., Buzzetti, R., Crino, A., et al., 2000. No effect of oral insulin on residual beta-cell function in recent-onset type I diabetes (the IMDIAB VII). IMDIAB Group. Diabetologia 43 (8), 10001004. Rantapaa-Dahlqvist, S., de Jong, B.A., Berglin, E., Hallmans, G., Wadell, G., Stenlund, H., et al., 2003. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48 (10), 27412749.

VIII.. MANAGEMENT

1456

72. EMERGING BIOLOGICAL AND MOLECULAR THERAPIES IN AUTOIMMUNE DISEASE

Rastetter, W., Molina, A., White, C.A., 2004. Rituximab: expanding role in therapy for lymphomas and autoimmune diseases. Annu. Rev. Med. 55, 477503. Riechmann, L., Clark, M., Waldmann, H., Winter, G., 1988. Reshaping human antibodies for therapy. Nature 332 (6162), 323327. Rovin, B.H., Furie, R., Latinis, K., Looney, R.J., Fervenza, F.C., Sanchez-Guerrero, J., et al., 2012. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64 (4), 12151226. Sabatino Jr., J.J., Zamvil, S.S., Hauser, S.L., 2019. B-cell therapies in multiple sclerosis. Cold Spring Harb. Perspect. Med. 9 (2). Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M., 2008. Regulatory T cells and immune tolerance. Cell 133 (5), 775787. Seegobin, S.D., Ma, M.H., Dahanayake, C., Cope, A.P., Scott, D.L., Lewis, C.M., et al., 2014. ACPA-positive and ACPA-negative rheumatoid arthritis differ in their requirements for combination DMARDs and corticosteroids: secondary analysis of a randomized controlled trial. Arthritis Res. Ther. 16 (1), R13. Serra, P., Santamaria, P., 2018. Nanoparticle-based approaches to immune tolerance for the treatment of autoimmune diseases. Eur. J. Immunol. 48 (5), 751756. Sherry, N., Hagopian, W., Ludvigsson, J., Jain, S.M., Wahlen, J., Ferry Jr., R.J., et al., 2011. Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet 378 (9790), 487497. Silverman, G.J., Weisman, S., 2003. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum. 48 (6), 14841492. Skog, A., Lagnefeldt, L., Conner, P., Wahren-Herlenius, M., Sonesson, S.E., 2016. Outcome in 212 anti-Ro/SSA-positive pregnancies and population-based incidence of congenital heart block. Acta Obstet. Gynecol. Scand. 95 (1), 98105. Skyler, J., 2002. Effects of insulin in relatives of patients with type 1 diabetes mellitus Diabetes Prevention Trial-Type 1 Diabetes Study Group. N. Engl. J. Med. 346 (22), 16851691. Smilek, D.E., Gautam, A.M., Pearson, C., Steinman, L., McDevitt, H.O., 1992. EAE: a model for immune intervention with synthetic peptides. Int. Rev. Immunol. 9 (3), 223230. Smilek, D.E., Wraith, D.C., Hodgkinson, S., Dwivedy, S., Steinman, L., McDevitt, H.O., 1991. A single amino acid change in a myelin basic protein peptide confers the capacity to prevent rather than induce experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 88 (21), 96339637. Smith, C.E., Eagar, T.N., Strominger, J.L., Miller, S.D., 2005. Differential induction of IgE-mediated anaphylaxis after soluble vs. cell-bound tolerogenic peptide therapy of autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. U.S.A. 102 (27), 95959600. Somerfield, J., Hill-Cawthorne, G.A., Lin, A., Zandi, M.S., McCarthy, C., Jones, J.L., et al., 2010. A novel strategy to reduce the immunogenicity of biological therapies. J. Immunol. 185 (1), 763768. Sormani, M.P., Muraro, P.A., Schiavetti, I., Signori, A., Laroni, A., Saccardi, R., et al., 2017. Autologous hematopoietic stem cell transplantation in multiple sclerosis: a meta-analysis. Neurology 88 (22), 21152122. Streeter, H.B., Rigden, R., Martin, K.F., Scolding, N.J., Wraith, D.C., 2015. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurol. Neuroimmunol. Neuroinflamm. 2 (3), e93. Tang, Q., Henriksen, K.J., Bi, M., Finger, E.B., Szot, G., Ye, J., et al., 2004. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J. Exp. Med. 199 (11), 14551465. Tian, J., Atkinson, M.A., Clare Salzler, M., Herschenfeld, A., Forsthuber, T., Lehmann, P.V., et al., 1996. Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin-dependent diabetes. J. Exp. Med. 183 (4), 15611567. Tian, J., Lehmann, P.V., Kaufman, D.L., 1997. Determinant spreading of T helper cell 2 (Th2) responses to pancreatic islet autoantigens. J. Exp. Med. 186 (12), 20392043. Tisch, R., Wang, B., Atkinson, M.A., Serreze, D.V., Friedline, R., 2001. A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice. J. Immunol. 166 (11), 69256936. Tisch, R., Yang, X.D., Liblau, R.S., Mcdevitt, H.O., 1994. Administering glutamic acid decarboxylase to NOD mice prevents diabetes. J. Autoimmun. 7 (6), 845850. Tisch, R., Yang, X.D., Singer, S.M., Liblau, R.S., Fugger, L., McDevitt, H.O., 1993. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366 (6450), 7275. Triolo, T.M., Fouts, A., Pyle, L., Yu, L., Gottlieb, P.A., Steck, A.K., 2019. Identical and nonidentical twins: risk and factors involved in development of islet autoimmunity and type 1 diabetes. Diabetes Care 42 (2), 192199. Tyndall, A., Gratwohl, A., 1997. Blood and marrow stem cell transplants in autoimmune disease. A consensus report written on behalf of the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT). Br. J. Rheumatol. 36 (3), 390392. van Bekkum, D.W., 1998. New opportunities for the treatment of severe autoimmune diseases: bone marrow transplantation. Clin. Immunol. Immunopathol. 89 (1), 110. van de Stadt, L.A., de Koning, M.H., van de Stadt, R.J., Wolbink, G., Dijkmans, B.A., Hamann, D., et al., 2011. Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis. Arthritis Rheum. 63 (11), 32263233. Van Laar, J.M., Tyndall, A., 2003. Intense immunosuppression and stem-cell transplantation for patients with severe rheumatic autoimmune disease: a review. Cancer Control 10 (1), 5765. Verdaguer, J., Schmidt, D., Amrani, A., Anderson, B., Averill, N., Santamaria, P., 1997. Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J. Exp. Med. 186 (10), 16631676. Vigeral, P., Chkoff, N., Chatenoud, L., Campos, H., Lacombe, M., Droz, D., et al., 1986. Prophylactic use of OKT3 monoclonal antibody in cadaver kidney recipients. Utilization of OKT3 as the sole immunosuppressive agent. Transplantation 41 (6), 730733. Villemain, F., Jonker, M., Bach, J.F., Chatenoud, L., 1986. Fine specificity of antibodies produced in rhesus monkeys following in vivo treatment with anti-T cell murine monoclonal antibodies. Eur. J. Immunol. 16 (8), 945949. Vincenti, F., Kirkman, R., Light, S., Bumgardner, G., Pescovitz, M., Halloran, P., et al., 1998. Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N. Engl. J. Med. 338 (3), 161165.

VIII.. MANAGEMENT

REFERENCES

1457

Voltarelli, J.C., Couri, C.E., Stracieri, A.B., Oliveira, M.C., Moraes, D.A., Pieroni, F., et al., 2007. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 297 (14), 15681576. Voltarelli, J.C., Couri, C.E., Stracieri, A.B., Oliveira, M.C., Moraes, D.A., Pieroni, F., et al., 2008. Autologous hematopoietic stem cell transplantation for type 1 diabetes. Ann. N.Y. Acad. Sci. 1150, 220229. Waldmann, H., 2019. Human monoclonal antibodies: the benefits of humanization. Methods Mol. Biol. 1904, 110. Walter, M., Philotheou, A., Bonnici, F., Ziegler, A.G., Jimenez, R., 2009. No effect of the altered-peptide ligand NBI-6024 on beta cell residual function and insulin needs in new-onset type 1 diabetes. Diabetes Care 32 (11), 20362040. Weiner, H.L., Miller, A., Khoury, S.J., Zhang, Z.J., Al-sabbagh, A., Brod, S.A., et al., 1995. Treatment of autoimmune diseases by oral tolerance to autoantigens. Adv. Exp. Med. Biol. 371B, 12171223. Weiner, H.L., Zhang, Z.J., Khoury, S.J., Miller, A., Al-sabbagh, A., Brod, S.A., et al., 1991. Antigen-driven peripheral immune tolerance. Suppression of organ-specific autoimmune diseases by oral administration of autoantigens. Ann. N.Y. Acad. Sci. 636, 227232. Wherrett, D.K., Bundy, B., Becker, D.J., Dimeglio, L.A., Gitelman, S.E., Goland, R., et al., 2011. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet 378 (9788), 319327. Wildin, R.S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J.L., Buist, N., et al., 2001. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27 (1), 1820. Williams, R.O., Feldmann, M., Maini, R.N., 1992. Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. U.S.A. 89 (20), 97849788. Williams, R.O., Mason, L.J., Feldmann, M., Maini, R.N., 1994. Synergy between anti-CD4 and anti-tumor necrosis factor in the amelioration of established collagen-induced arthritis. Proc. Natl. Acad. Sci. U.S.A. 91 (7), 27622766. Woodle, E.S., Xu, D., Zivin, R.A., Auger, J., Charette, J., O’laughlin, R., et al., 1999. Phase I trial of a humanized, Fc receptor nonbinding OKT3 antibody, huOKT3gamma1(Ala-Ala) in the treatment of acute renal allograft rejection. Transplantation 68 (5), 608616. Wraith, D.C., 1995. Induction of antigen-specific unresponsiveness with synthetic peptides: specific immunotherapy for treatment of allergic and autoimmune conditions. Int. Arch. Allergy Immunol. 108 (4), 355359. Wraith, D.C., Smilek, D.E., Mitchell, D.J., Steinman, L., Mcdevitt, H.O., 1989. Antigen recognition in autoimmune encephalomyelitis and the potential for peptide-mediated immunotherapy. Cell 59 (2), 247255. Wraith, D.C., Streeter, H.B.S.O.C., Molecular, M., School of Clinical Bristol, U. K, 2015. Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurology 2 (3), e93. Yeh, W.I., Seay, H.R., Newby, B., Posgai, A.L., Moniz, F.B., Michels, A., et al., 2017. Avidity and bystander suppressive capacity of human regulatory T cells expressing de novo autoreactive T-cell receptors in type 1 diabetes. Front. Immunol. 8, 1313. You, S., Leforban, B., Garcia, C., Bach, J.F., Bluestone, J.A., Chatenoud, L., 2007. Adaptive TGF-{beta}-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc. Natl. Acad. Sci. U.S.A. 104 (15), 63356340. You, S., Piali, L., Kuhn, C., Steiner, B., Sauvaget, V., Valette, F., et al., 2013. Therapeutic use of a selective S1P1 receptor modulator ponesimod in autoimmune diabetes. PLoS One 8 (10), e77296. You, S., Zuber, J., Kuhn, C., Baas, M., Valette, F., Sauvaget, V., et al., 2012. Induction of allograft tolerance by monoclonal CD3 antibodies: a matter of timing. Am. J. Transplant. 12 (11), 29092919.

VIII.. MANAGEMENT