REVUE FRANCAISE D'ALLERGOLOGIE ETD'IMMUNOLOGIECLINIQUE
Mechanisms of allergen specific immunotherapy C. A N D R e ,
R. F A D E L
Clinical efficacy of specific immunotherapy (SIT) in the treatment of respiratory allergic diseases as well as venom allergy has been demonstrated in various well-controlled studies. However the precise mechanisms of SIT have not been well defined, and for more than twenty years now, research on immunological markers of efficacy of SIT raised many theories on the mechanism of SIT. Recently, the use of molecular genetic techniques constituted a <
M6canismes de l'immunoth6rapie sp6cifique des ailerg~nes. - L'efficacit4 clinique de l'immunoth~rapie sp4ciflque (ITS) dans le t r a i t e m e n t des maladies allergiques respiratoires et de l'allergie aux venins a 6t4 d 4 m o n t r 4 e par diverses &udes bien contr616es. Cependant, les m6canismes pr4cis de I'ITS n ' o n t pas 4t6 bien d6finis, et depuis plus de 20 ans, les recherches sur les marqueurs immunologiques de l'efficacit6 de I'ITS ont suscit~ de nombreuses theories sur le mdcanisme de I'ITS. R6cemment, l'utilisation des techniques de la g6n&tique mol4culaire o n t permis u n e < dans la compr&hension des effets immunomodulateurs de I'ITS : il a 4t4 en effet clairement d6montrd que FITS induit u n d4calage de l'6quilibre T h l / Th2. Le premier effet est celui d ' u n e d6sensibilisation des cellules effectrices comme les basophiles, les mastocytes, les eosinophiles, entrainant une diminution de la lib4ration des m6diateurs inflammatoires. Simultan6ment les lymphocytes T et les cellules pr6sentatrices et antigene sont engag4s ~ produire des cytokines de type T h l , tandis qu'est frein6e la production des cytokines de type Th2. Le r6sultat est une modification du mod&le de production des IgE et IgG4 sp4cifiques d ' u n allerg6ne et une inhibition de l'activation et de la migration des cellules effectrices.
KEY-WORDS : Allergen - IgE - T h l - Th-2.
MOTS-CLI~S: Allerg&ne - IgE - Lymphocytes T h l et Th2.
Scientific and Medical Department Stallergenes S.A. ANTONY, (France). Correspondence : Dr. Claude Andr4, Scientific and Medical Department, Stallergenes S.A.,6 rue Alexis de Tocqueville, 92183 ANTONY,, (France). Interasma Marrakech' 98.
ANDRI~ C., FADEL R. - Mechanisms of allergen specific immunotherapy. Rev. ft. Allergol, 1998, 38 (7S), $227-$231.
© Expansion Scientifique Publications, 1998
• C. ANDRf~, R. FADEL /
INTRODUCTION Human allergic inflammation is characterized by I g E - d e p e n d e n t activation of mast cells basophils and tissue eosinophils. The discovery in mice, subsequently confirmed in humans [l] that helper T cells can be subdivided in two effector phenotypes based on their patterns of cytokine p r o d u c t i o n , with Thl-type cells p r o d u c i n g predominantly IFN-y and IL-2, whereas Th2-type cells produce mainly IL-4 (inducing IgE heavy chain isotype switching)  and IL-5 (promoting eosinophil differentiation, activation and survival) . Several in vitro studies suggest that allergen-specific cells from atopic subjects are directed towards secretion of IL-4 and IL-5 (Th2type), whereas stimulation of T cells from nonatopic subjects leads to IFN-y secretion (Thl-
type). This functional differentiation led to the concept that inappropriate Th2-type responses to allergen a c c o u n t for both i m m e d i a t e IgEmediated responses and chronic eosinophilic allergic inflammation. The efficacy of specific immunotherapy (SIT) for the treatment of allergic diseases has been demonstrated in numerous clinical studies [4, 5]. Although earlier work focused on circulating antibody and effector cells, recent studies suggest that these changes may be secondary to an influence of SIT on T cell responses to allergen. SIT mechanisms are heterogeneous depending on the nature of the allergen, the site of allergy, the route, dose and duration of immunotherapy, the use of different adjuvants and the genetic status of the host.
Table I. - Modifications in immunological parameters during specific immunotherapy Parameters
Venoms Respiratory allergens
Venoms Respiratory allergens
Pollens H o u s e dust mites
$I sensitivity ~ histamine release
$1 migration ~ mediator release
~ migration $1 activation
~ CD4 + lymphocytes ~ CD25 + lymphocytes (IL2 receptor)
Pollens H o u s e dust mites-Cat
~l release by basophils a n d mast cells
Pollens H o u s e dust mites
~l secretion by mast cells
~ secretion by eosinophils
Pollens H o u s e dust mites-Cat
~ secretion by mast cells
~ expression of m R N A
IL-4 - IL-5
Venoms Pollens - H o u s e dust mites
$1 in vitro synthesis by m o n o n u c l e a t e d cells
Venoms - Pollens
~ synthesis a n d expression of m R N A
~ expression of m R N A
Rev.fr. Allergol., 1998, 38, 7S
/ MECHANISMS OF ALLERGEN SPECIFIC IMMUNOTHERAPY •
EFFECTS OF IMMUNOTHERAPY ON SERUM ANTIBODY CONCENTRATION
SIT causes modification of serum specific- IgE levels with an initial rise followed by a gradual long-term fall to normal [6,7] although pollen i m m u n o t h e r a p y may result in b l u n t i n g o f seasonal increases in IgE. Many studies have c o n f i r m e d significant increases in a l l e r g e n specific IgG, particularly IgG1 a n d IgG4 subclasses . The latter immunoglobulin was the background for a ~blocking antibody,, theory where IgG compete with IgE for allergen binding . This concept was validated in particular in insect venom immunotherapy . However in the case of respiratory allergens, the changes in serum IgG and IgE were not correlated with the clinical response to immunotherapy [11, 12]. Recently it was shown that h u m a n IgG antibodies had the capacity to block IgE binding to the major birch pollen Bet vl and inhibit Bet v l induced histamine release . Changes in IgG have been considered as an <
EFFECTS OF IMMUNOTHERAPY ON EFFECTOR CELLS
Several studies have shown a reduction of inflammatory cell recruitment, activation and mediator release during immunotherapy. Basophils and Mast cells.
During SIT, despite the increasing serum IgE levels, basophil histamine and leukotriene release may decrease after allergen stimulation and the sensitivity t h r e s h o l d of circulating basophils increases [14, 15]. During seasonal or perennial allergic rhinitis t h e r e is a t r a n s e p i t h e l i a l migration of mast cells in the nasal mucosae [ 16]. Study of nasal biopsies obtained before and after SIT showed a significant reduction in the n u m b e r of metachromatic cells (mast cells) in the treated patients . Eosinophils
A characteristic feature of allergic diseases is the migration of activated eosinophils at the site of the inflammatory allergic reaction . When measured in broncho-alveolar lavage fluids, the Re~fnAl~rgoL, 1998,3& 7S
n u m b e r of eosinophils decreased significantly after birch-pollen SIT. This r e d u c t i o n was observed during seasonal pollen exposure or after allergen b r o n c h i a l challenge and was a c c o m p a n i e d by a r e d u c t i o n in b r o n c h i a l hyperreactivity . In allergic rhinitis, after nasal allergen challenge, SIT leads to a significant decrease in the migration of eosinophils within the nasal m u c o s a e [19,20]. Moreover, this reduced chemotactic activity is accompanied by a decrease in the n u m b e r of activated eosinophils (EG2+ cells) . In the skin, studied by skin-chamber, the reduction of the late cutaneous response after SIT correlates with the reduction in the n u m b e r of eosinophils . Taken together, all these cellular modifications induced by SIT correlates were associated with clinical improvement.
EFFECTS ON INFLAMMATORY MEDIATORS
The cellular effects of SIT described above lead to a reduction in production of inflammatory mediators observed during the allergic reaction after allergen challenge. In patients who had received SIT and using nasal lavage techniques, several authors have demonstrated a reduction in the levels of PGD2, LTC4, kinins and tryptase in nasal fluids measured after pollen-nasal challenge [22, 23]. Similarly, Rak et al. showed a decrease in ECP (eosinophil cationic protein) release in broncho-alveloar lavage fluid in patients receiving birch-pollen SIT which c o r r e l a t e with the reduction in the n u m b e r of eosinophils . Recently using sublingual route for immunotherapy in dust-mite allergic patients, Passalacqua et al.  demonstrated, in the treated group, a significant decrease of serum ECP release associated with a reduction in the n u m b e r of eosinophil and expression of ICAM-1 in conjunctival e p i t h e l i u m after allergen conjonctival provocation test.
MODULATION OF T CELL FUNCTION
The allergic <
• c. ANDS, R. FADEL/
actually some evidence that SIT is associated with a shift in IL-4/IFN-~/ production resulting from down regulation of Th2 responses. Studies in the skin and nasal mucosae have demonstrated that SIT induces a reduction in CD4+ T helper cells infiltration . Moreover these changes were accompanied by increases in allergen-induced IFN-¥ mRNA + cells, whereas IL4+ and IL-5+ cells remains unchanged. More recently it was demonstrated that SIT induces a significant increase in the numbers of IL-12 mRNA + cells at the cutaneous site challenged with allergen . T h e r e was an inverse association between IL-12+ cell, numbers and IL4+ cells and a positive correlation between IFN-• + cells and IL-12+ cells indicating that IL-12 had an influence on Thl-type cytokine production. Studies on peripheral blood or T cell lines provide additional information on the role of SIT on the Th2-Thl balance. Secrist demonstrated a decrease in IL-4 production and no change in IFN-~/production in patients receiving SIT . In bee venom sensitive patients receiving <
could explain this T cells <
1. Wierenga A.E., Snoek M., De Groot C., et aL - Evidence for c o m p a r t i m e n t a l i s a t i o n of functional subsets of CD4 + T lymphocytes in atopic patients.j~ Immunol., 1990, 144, 4651-4656. 2. Del Prete G.F., Maggi E., Parronchi R, et aL - IL-4 is an essential factor for the IgE synthesis induced in vitro by h u m a n T cell clones and their supernatants.J. Immunol., 1998, 140, 4193-4198.
3. Lopez A.E, Sanderson CJ., Gamble J.R., Campbell H.D., Young I.G., Vadas M.A. - Recombinant h u m a n interleukin-5 is a selective activator of h u m a n eosinophil functions, j~ Exp. Med., 1988, 1~fi7, 219-225. 4. Bousquet J., Michel EB. - Specific immunotherapy in asthma: it is effective.J. Allergy Clin. Immunol., 1994, 94, 1-11. Rev. f~ Allergol., 1998, 38, 7S
5. Malling H.J., Weeke B. - EAACI Position immunotherapy. Allergy, 1993, 48(s14), 9-35.
6. Lichtenstein L.M., Ishizaka K., Norman ES., et al. - IgE antibody measurements in ragweed hay"fever.j~ Clin. Invest.,1973, 52, 472482. 7. Gleich G.J., Zimmermann E.M., Henderson L.L., YnngingerJ.W. Effect of i m m u n o t h e r a p y on i m m u n o g l o b u l i n E and immunoglobulin G antibodies to ragweed antigens: a six-year prospective study.J. Allergy Clin. Immunol., 1982, 70, 261-271. 8. Nakagawa T. - The role of IgG subclass antibodies in the clinical response to immunotherapy in allergic disease• Clin. Exp. Allergy, I991, 21, 289-296. 9. Djurup R., Malling H.J. - High IgG4 antibody level is associated with failure of immunotherapy with inhalant allergens. Clin. Allergy, 1987, 17, 459-468. 10. Muller U., Helbling A., Bischof M. - Predictive value of venomspecific IgE and IgG subclass antibodies in patients on immunotherapy with honey bee venom. Allergy, 1989, 44, 412-418. 11. Djurup R., Osterballe O. - IgG subclass antibody response in grass pollen-allergic patients undergoing specific immunotherapy. Prognostic value of serum IgG subclass antibody levels early in immunotherapy. Allergy, 1984, 39, 433-441. 12. Aalberse R,C., Van Milligen E, Tan K.Y., Stapel S.O. - Allergenspecific IgG4 in atopic disease. Allergy, 1993, 48, 559-569. 13. Visco V., Dolecek C., Denepoux C., et al. - H u m a n IgG monoclonal antibodies that modulate the binding of specific IgE to birch pollen Bet v l . J . Immunol., 1996, 157, 956-962. 14. JuteI M., Muller U.R., Fricker M., et al. - Influence of bee venom immunotherapy on degranulation and leukotriene generation in h u m a n blood basophils. Clin. Exp. Allergy. 15. Mailing HJ., Skov ES., Pertain H., Norm S., Weeke B. - Basophil histamine release and humoral changes during immunotherapy. Dissociation between basophil-bound specific IgE, serum value, and cell sensitivity. Allergy, 1982, 37, 187-190. 16. Bentley A.M., J a c o b s o n M.R., C u m b e r w o r t h V., et al. Immunohistology of the nasal mucosa in seasonal allergic rhinitis: increases in activated eosinophils and epithelial mast cells, ji Allergy Clin. Immunol., 1992, 89, 877-883. 17. Otsuka H., Mezawa A., Ohnishi M., et aL - Changes in nasal metachromatic cells during allergen immunotherapy. Clin. Exp. Allergy, 1991, 21, 115-119• 18. Rak S., Bjornson A., Hakanson L., et al. - The effect ofimmunotherapy on eosinophil accumulation and production of eosinophil chemotactie activity in the lung of subjects with asthma during natural pollen exposure.J. Allerg3 Clin. Immunol., 1991, 88, 878-888. 19. Furin M.J., Norman ES., Creticos RS., et al. - Immunotherapy decreases antigen-induce eosinophil cell migration into the nasal cavity. J. Allergy Clin. Immunol., 1991, 88, 2%32. 20. Durham S., Ying S., VarneyV., et al. - Grass pollen immunotherapy inhibits allergen induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of cells expressing messenger RNA for interferon-y. J. Allergy Clin. IramunoL, 1996, 97, 1356-1365. 21. Nish W.A., Charlesworth E.N., Davis T.L., et al. - The effect of immunotherapy on the cutaneous late phase response to antigen• J. Allergy Clin. Immunol., 1994, 93, 484493. 22. Creticos RS., Adkinson EH., Kagey-Sobotka A., et aL - Nasal challenge with ragweed in hayfever patients. Effect of immunotherapy.J. Clin. Invest., I985, 76, 2247-2253. 23. Iliopoulos O., Proud D., Adkinson F., et al. - Effects of immunotherapy on the early, late, and rechallenged nasal reaction to provocation with allergen: changes in inflammatory mediators and cells.J. Allergy Clin. ImmunoL, 1991, 87, 855-866.
Rev. f ~ Allergol., 1998, 38, 7S
$231 24. Passalacqua G., Albano M, Fregonese L., et aL - Treatment of mite rhinoconjunctivitis with local allergoid immunotherapy: effects on allergic inflammation. Lancet, 1998, 35, 629-632• 25. Tamir R., Castracane J.M., Rocklin R.E. - Generation of suppressor cells in atopic patients during immunotherapy that modulate igE synthesis.J. AUergy Clin. ImmunoL, 1987, 79, 591-598. 26. VarneyV.A., Hamid Q., Gaga M., et al. - Influence of grass pollen immunotherapy on the cellular infiltration and cytokine mRNA expression during allergen-induced late phase cutaneous responses.J. Clin. Invest., 1993, 92, 644-651. 27. Hamid Q.A., Schotman E.,Jacobson M.R., Walker S.M., Durham S.R. - Increases in IL-12 messenger RNA+ cells accompany inhibition of allergen-induced late skin responses after successful grass pollen immunotherapy. J. Alleygy Clin. Immunol., 1997, 99, 254-260. 28. Secrist H., Chelen C.J., Wen Y., Marshall J.D., Umetsu D.T Allergen immunotherapy decreases interleukin 4 production in CD4+ T cells from allergic individuals. Ji Exp. Med., 1993, 178, 2123-2130. 29. Jutel M., Pichler W.J., Skrbic D., et al. - Bee venom immunotherapy results in decrease of IL4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures.J~ ImmunoL, 1995, 154, 41874194. 30. McHugh S.M., Deighton J., Stewart A.G., Lachmann 'PJ., Ewan EW. Bee venom immunotherapy induces a shift in cytokine responses from a TH-2 to a TH-1 dominant patternt: comparison of rush and conventional immunotherapy. Clin. Exp. Allergy, 1995, 25, 828-838. 31. A k o u m H.I Tsicopoulos A., Vorng H., et al. - Venom immunotherapy modulates interleukin-4 and interferon-gamma messenger RNA expression of peripheral T lymphocytes. Immunol., 1996, 87, 593-598. 32. Till S., Walker S., Dickason R., et al. - IL-5 production by allergenstimulated T cells following grass pollen immunotherapy for seasonal allergic rhinitis. Clin. Exp. ImmunoL, t997, 110, 114-121. 33. Ebner C., Siemann U., Bohle B., et al. - hnmunological changes during specific immunotherapy of grass pollen allergyt: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin. Exp. Allergy, 1997, 27, 1007-1015. 34. Mc Menamin C., Holt P.G. - The natural inunune response to inhaled soluble protein antigens involves major histocompatibility complex (MHC) class I-restricted CD8+ T cellmediated but class II-restricted CD4+ T cell-dependent i m m u n deviation resulting in selective suppression of immunoglobulin E production.J. Exp. Med., 1993, 178, 889-899. 35. Renz H., Lack G., SalogaJ., et al. - Inhibition of IgE production and normalization of airways responsiveness by sensitised CD8+T cells in a mouse model of allergen-induced sensitization. J~ ImmunoL, 1994, 152, 351-360. 36. Akdis C.A., Akdis M., Blesken T., et aL - Epitope specific T cell tolerance to phospholipase A2 in bee venom immunotherapy and recovery by IL-2 and IL-5 in vitro.a( Clin. Invest., 1996, 98, 1676-1683. 37. Holt RG., VinesJ., Britten D. - Sublingual allergen administration. I. Selective suppression of IgE production in rat with high allergen doses. Clin. Allergy, 1988, 18, 229-234• 38. Van Wilsem EJ., van Hoograsten I.M., Breve J., Scheper R.J., Kraal G. - Dendritic cells of the oral mucosa and the induction of oral tolerance. A local affair. ImmunoL, 1994, 93, 128-132. 33. Andrfi C., Rougier N., Schmitt D., Vincent C. - Langerhans cell: a key cell of sublingual specific immunotherapy. Allergy, 1997, 52, 152 (Abs).