Lung autoantibodies: Ready for prime time?

Lung autoantibodies: Ready for prime time? PERSPECTIVE Lung autoantibodies: Ready for prime time? Luke Milross, BMedSc,a,d Ramsey Hachem, MD,b Deborah Levine, MD,c a...

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Lung autoantibodies: Ready for prime time? Luke Milross, BMedSc,a,d Ramsey Hachem, MD,b Deborah Levine, MD,c and Allan R. Glanville, MBBS, MDa From the aDepartment of Thoracic Medicine, St. Vincent’s Hospital, Sydney, New South Wales, Australia; bDivision of Pulmonary and Critical Care, Washington University School of Medicine, St. Louis, Missouri, USA; cPulmonary Disease and Critical Care Medicine, University of Texas Health Science Center, San Antonio, Texas, USA; and the dSchool of Medicine, University of Notre Dame, Sydney, New South Wales, Australia.

KEYWORDS: Autoantibodies; lung transplantation; rejection; CLAD

Despite advances in our understanding of the immunology of lung allograft tolerance and a reduction in the rate of acute allograft rejection using contemporary immunosuppressive protocols, the rate of chronic lung allograft dysfunction (CLAD), both obstructive and restrictive, remains unacceptably high. CLAD, particularly the restrictive phenotype, is a harbinger of a foreshortened survival. The development of a consensus approach to the diagnosis of antibody-mediated rejection by the International Society for Heart and Lung Transplantation has highlighted the need for a uniform approach toward the investigation, diagnosis, implications and management of both human leukocyte antigen (HLA) and non–HLA-related antibody formation. This Perspective summarizes the current information that underpins the way forward in recognizing the potential importance of non–HLA-related antibody formation with respect to allograft injury and outcomes. J Heart Lung Transplant ]]]];]:]]]–]]] r 2017 International Society for Heart and Lung Transplantation. All rights reserved.

Lung transplantation (LTx) remains the ultimate treatment for patients with end-stage lung diseases for which there are no other effective medical or surgical therapies. Long-term outcomes are inferior to those of other solidorgan transplants, with current 5- and 10-year survival rates of 54% and 32%, respectively,1 largely due to obliterative bronchiolitis (OB), a progressive focal fibrotic and occlusive process of small airways, clinically apparent as bronchiolitis obliterans syndrome (BOS).2 BOS is the predominant phenotype of chronic lung allograft dysfunction (CLAD), with the other main phenotype being restrictive allograft syndrome (RAS). Well-established risk factors for these phenotypes of CLAD include cellular rejection and nonalloimmune injury, such as viral infection. There is increasing evidence that autoimmunity also plays a role in antibody-mediated rejection (AMR) and CLAD.2,3 Inflammation generated by allograft injury leads to tissue Reprint requests: Allan R. Glanville, MBBS, MD, Department of Thoracic Medicine, St. Vincent’s Hospital, Xavier 4, Victoria Street, Sydney, NSW 2010, Australia. Telephone: þ61 414910321. Fax: þ61 283823084. E-mail address: [email protected]

remodeling and subsequent exposure of usually sequestered or “cryptic” self-antigens (SAgs). Non-human leukocyte antigen antibodies (nHAbs; autoantibodies generated with specificity to SAgs) are potential drivers for the development of OB and pulmonary fibrosis (Figure 1). The 2 most frequently cited nHAbs post-LTx are those with specificity to collagen V (Col V), an extracellular matrix protein, and those with specificity to K-α1 tubulin (K-α1), a gap junction protein.2 Col V and K-α1 are both expressed in the architecture of the small airways and are continually released post-transplantation.2 Multiple studies have demonstrated the existence of other autoantibodies after LTx.4,5 Hagedorn et al found lung allograft recipients have widespread autoantibody reactivity, measuring significant nHAbs to no less than 28 SAgs.5 Similar to HLA antibody production, nHAbs may be preexisting or develop de novo. Pre-existing nHAbs are found in up to 33% of patients pre-LTx.6 Tiriveedhi et al demonstrated that prevalence of nHAbs differed across disease states. They found nHAbs in 34% and 29% of patients with pulmonary fibrosis and cystic fibrosis, respectively, but in only 18% of patients with emphysema.6 Indication for LTx may in this way impact outcome. Ultimately, up to 70% of LTx recipients develop

1053-2498/$ - see front matter r 2017 International Society for Heart and Lung Transplantation. All rights reserved.


The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

Figure 1 Model for the generation of an autoimmune response to sequestered antigens. In Phase 1, tissue injury, including ischemia– reperfusion injury, permits release of sequestered self-antigens (SAgs). Antigen-presenting cells then bind SAgs, thereby priming elements of the adaptive immune system. Antigen presentation under these circumstances leads to a shift in T-helper cell balance toward a predominance of Th-17 cells, with down-regulation of T-regulatory cells. Non-human leukocyte antigen antibodies (nHAbs) (autoantibodies generated with specificity to SAgs) are then released by activated B cells. Cytokines TGF-β and IL-17 perpetuate SAg release, driving a feed-forward process. Autoantibody ligation causes further inflammation, fibroproliferation and, ultimately, obliterative bronchiolitis.

nHAbs, believed to represent indirect antigen presentation as recipient antigen-presenting cells (APCs) replace donor APCs.7 The ratio of T-helper (Th) cells may be key to the development of nHAbs and OB after LTx.2 The proportion of Th-17 cells relative to T-regulatory (T-reg) cells is critical, as Th-17 cells promote autoimmunity and T-reg cells enforce peripheral tolerance. Alloimmunity provides one explanation for the relationship between Th cell shift and nHAb development. In a murine model, anti–MHC Class I antibodies administered intrabronchially led to inflammation, fibrosis, interleukin-17 (IL-17) production and generation of T cells and nHAbs with reactivity to Col V and K-α1.8 In addition, in a group of patients who developed de-novo donor-specific antibodies (DSA), 96% also developed nHAbs.7 Th-17–dependent autoimmunity is proposed to behave in a feed-forward fashion, which parallels an accelerating clinical and histologic course of OB.9 Vittal et al found that IL-17 and transforming growth factor-beta (TGF-β), both implicated in the development of nHAbs, exacerbated expression of Col V by cultured airway epithelial cells (AECs).9 Col V was found to be overexpressed throughout the fibrotic foci of lungs from patients with OB. Hence, blockade of the IL-17 pathway, perhaps by the use of azithromycin, is an appealing target for future clinical studies. It is not entirely clear whether nHAbs are directly pathogenic, but there is increasing evidence they may be associated with worse outcomes. Goers et al demonstrated anti–K-α1 ligation to cultured airway epithelial cells led to increased expression of fibrogenic growth factors, activation of cell cycle signaling and

fibroproliferation, indicating that complement-independent pathogenicity may be significant.10 Anti–K-α1 nHAbs were also associated with bronchiolitis obliterans syndrome (BOS), and a temporal relationship existed between de-novo development and BOS onset.10 nHAbs were shown to correlate with both primary graft dysfunction (PGD) and BOS2; however, their potential relevance to acute cellular rejection (ACR) requires further clarification. A recent case report implicated nHAb-driven acute AMR in 2 patients who were DSA negative before and after transplantation.11 Regardless of whether nHAbs are pathogenic, it is likely that an autoantibody profile may assist in the risk stratification of LTx patients. Reinsmoen et al showed that preLTx presence of autoantibodies to angiotensin type 1 receptor (AT1R) and endothelin type A receptor (ETAR) was associated with decreased freedom from AMR, ACR and de-novo DSA development.4 Freedom from de-novo DSA development was further reduced when patients displayed both non-HLA autoantibodies and alloantibodies.4 Recently, it was shown that DSA induced a transcription factor (Zbtb7a) in alveolar macrophages that regulates both humoral and cellular autoimmune responses.12 Hence, immunologic risk stratification may be useful both pre- and post-transplant. The pathogenesis of nHAbs is uncertain but exosomes may be implicated where antigens remain sequestered or intracellular. In a recent study, exosomes isolated from LTx recipients with ACR and BOS, but not stable recipients, were found to carry donor HLA and SAgs along with proinflammatory micro-RNAs.13 One potential explanation is that cells under stress after LTx “cross-dress” surrounding

Milross et al.

Lung Autoantibodies

responder cells with antigens, through a “semi-direct” pathway of antigen presentation. As our understanding of the potential pathogenicity of nHAb develops, the critical question remains regarding how and when to treat. Currently, identical therapeutic options for treating DSA-mediated AMR are used for possible nHAb-mediated AMR, but their efficacy is uncertain. nHAb clearance does appear to lower the risk of BOS development independent of DSA status; however, nHAbs seem more resistant to clearance for reasons that remain unknown.7 To further our knowledge base regarding nHAbs after LTx and to drive the clinical translation of this largely experimental field, we need prospective, multicenter, longitudinal studies to better characterize the frequency and specificity of autoantibody carriage, risk factors for development and outcome analysis, particularly focusing on CLAD phenotypes and, ultimately, responses to therapeutic endeavors. This will be contingent on the development of widely available validated assays for nHAbs that can be used in the clinical domain, as a major restriction to our way forward is the current limitation imposed by the inability of most centers to measure these types of antibodies. Finally, it appears we are beginning to understand another piece of the puzzle as to why the lung allograft fails. It is about time!

Disclosure statement R.H. reports grants from Mallinckrodt Pharmaceuticals, outside the submitted work. The remaining authors have no conflicts of interest to disclose.













References 13. 1. Yusen RD, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third

adult lung and heart–lung transplant report—2016; Focus theme: Primary diagnostic indications for transplant. J Heart Lung Transplant 2016;35:1170-84. Wilkes DS. Autoantibody formation in human and rat studies of chronic rejection and primary graft dysfunction. Semin Immunol 2012;24:131-5. Levine DJ, Glanville AR, Aboyoun C, et al. Antibody-mediated rejection of the lung: a consensus report of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2016;35: 397-406. Reinsmoen NL, Mirocha J, Ensor CR, et al. A 3-center study reveals new insights into the impact of non-HLA antibodies on lung transplantation outcome. Transplantation 2017;101:1215-21. Hagedorn PH, Burton CM, Sahar E, et al. Integrative analysis correlates donor transcripts to recipient autoantibodies in primary graft dysfunction after lung transplantation. Immunology 2011;132: 394-400. Tiriveedhi V, Gautam B, Sarma NJ, et al. Pre-transplant antibodies to Kα1 tubulin and collagen-V in lung transplantation: clinical correlations. J Heart Lung Transplant 2013;32:807-14. Hachem RR, Tiriveedhi V, Patterson GA, et al. Antibodies to K-alpha 1 tubulin and collagen V are associated with chronic rejection after lung transplantation. Am J Transplant 2012;12: 2164-71. Fukami N, Ramachandran S, Saini D, et al. Antibodies to MHC class I induce autoimmunity: role in the pathogenesis of chronic rejection. J Immunol 2009;182:309-18. Vittal R, Fan L, Greenspan DS, et al. IL-17 induces type V collagen overexpression and EMT via TGF-β-dependent pathways in obliterative bronchiolitis. J Immunol 2013;304:L401-14. Goers TA, Ramachandran S, Aloush A, et al. De novo production of K-alpha1 tubulin-specific antibodies: role in chronic lung allograft rejection. J Immunol 2008;180:4487-94. Fernandez R, Chiu S, Raparia K, et al. Humoral human lung allograft rejection by tissue-restricted non-HLA antibodies. Ann Thorac Surg 2016;102:e339-41. Nayak DK, Zhou F, Xu M, et al. Zbtb7a induction in alveolar macrophages is implicated in anti-HLA-mediated lung allograft rejection. Sci Transl Med 2017:9. Gunasekaran M, Xu Z, Nayak DK, et al. Donor-derived exosomes with lung self-antigens in human lung allograft rejection. Am J Transplant 2017;17:474-84.