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Immun tolerans mekanizmalar ı v e regülatör T hücreleri

Immun tolerans mekanizmalar ı v e regülatör T hücreleri. Mübeccel Akdis, MD, PhD. Swiss Institute of Allergy and Asthma Research SIAF Davos. naive T cell. innate immune response stimulating substances. antigen. differentiation signals. differentiation factors. IL-12. IL-4.

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Immun tolerans mekanizmalar ı v e regülatör T hücreleri

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  1. Immuntoleransmekanizmalarıve regülatör Thücreleri Mübeccel Akdis, MD, PhD Swiss Institute of Allergy and Asthma ResearchSIAF Davos

  2. naive T cell innate immune response stimulating substances antigen differentiation signals differentiation factors IL-12 IL-4 IL-4, TGF-b TGF-b, IL-6, IL21, IL-23 Th1 switch and expansion Th2 switch and expansion Th9 switch and expansion Th17 switch and expansion Th1 Th2 Th9 Th17 effector cytokines IFN-g IL-4,IL-5, IL-13 IL-9 IL-8, IL-17A, E, IL-22, IL-26 Akdis

  3. Suppression of Th17 effector cells induction of IgG4 suppression of IgE Suppression of Th1 effector cells Th17 Th1 Suppression of effector T cell migration to tissues Suppression of Th2 effector cells Th2 TReg endothelial cells mast cell basophil remodelling in the tissues Suppression of inflammatory dendritic cells. Induction of IL-10-producing dendritic cells eosinophil Direct and indirect suppressive effects on mast cells, basophils and eosinophils akdis

  4. Allergen-specific immunotherapy • 2. Natural high dose allergen • exposure • 3. Antibody regulation

  5. IL-10 and TGF- in peripheral T cell tolerance during aeroallergen SIT IL -10 4 * TGF-b IL-5 IL-13 3 IFN-g cytokine (ng/ml) 2 1 0 0 7 28 70 days n= 10, SIT cluster protocol, Der p 1-stimulated PBMC EJI.2003

  6. A Der p 1 before SIT after SIT u.s. 8 8 [3H] TdR [cpmx10 -3] 4 4 * * 0 0 PBMC PBMC 5x103 1x103 1x103 5x103 15x103 15x103 CD4+CD25+ CD4+CD25+ B Der p 1 20 20 u.s. * 10 10 [3H] TdR [cpmx10 -3] * 0 0 PBMC PBMC 1x103 5x103 1x103 5x103 15x103 15x103 CD4+CD25+ CD4+CD25+ CD4+CD25- CD4+CD25-

  7. Healthy ** ** ** ** * Pyr c 5 * Cor a 1 IL-4 IL-10 IFN-g Aeroallergen-specific T cell frequency in health and allergy Allergic 10 7.5 Der p 1 frequency / 10.000 cells Bet v 1 5 2.5 0 IL-4 IL-10 IFN-g J Exp Med 2004

  8. TReg cells in allergy: a question of antigen specificity 100 80 60 [3H]TdR cpmx1000 * * 40 20 0 + + + + + + + + +Der p 1 +Bet v 1 + + + + + + +Der p 1-IL-4+ +Bet v 1-IL-4+ +Der p 1-IL-10+ +Bet v 1-IL-10+ + + +Bet v 1-IL-10+ +Der p 1-IL-10+ + + J Exp Med 2004

  9. Beekeepers show way to allergen tolerance • The Journal of Experimental Medicine, November 10, 2008 • Nicole LeBrasseur

  10. Nature Reviews Immunology Beekeepers hold clues for T-cell tolerance By Sarah Allan, PhD New Scientist Magazine A sting a day keeps the allergy away 18 November 2008 by Ewen Callaway

  11. J J F F M M A A M M Ju Ju Jl Jl A A S S O O N N D D months of the year months of the year Antigen-specific peripheral T cell tolerance after live bee stings 14 12 10 8 bee stings / month 6 4 2 0 PLA 80 bee keeping season 60 [3H]-thymidine incorporation (cpm x 1000) 40 20 0 J. Exp. Med., 2008

  12. 80 bee keeping season 60 [3H]-thymidine incorporation (cpm x 1000) 40 20 0 S J F M A M Ju Jl A O N D months of the year late phase swelling lesion size 2: > 3 cm 1: < 3 cm 0: no lesion pain and immediate wheal and flare reaction do not change 30 20 lesion size 10 0 after 7 d first bee sting next year first bee sting after 1 m 5 beekeepers three years follow up

  13. * 7 d after * * Frequency of PLA-specific cytokine secreting T cells before and after live bee stings 15 before 10 specific CD4+ T cells frequency / 104 cells 5 0 IL-4 IFN-g IL-10 *: p<0.001 n:6 beekeepers Decreased frequency of PLA-specific IL-4- and IFN-g-secreting T cells, increased frequency of IL-10-secreting T cells is observed 7 days after ≥20 bee stings

  14. mast cell TReg Th1 Th2 HR2 suppresses APC capacity, increases IL-10 and suppresses IL-12 in maturing dendritic cells immature DC HR2 mature DC histamine IL-10 IL-10 histamine HR1 HR2 enhanced suppressive capacity of Treg cells HR1 on Th1 cell enhances IFN- and proliferation, increases effector functions and tissue injury HR2 on Th2 cell suppresses IL-4, IL-13 and proliferation

  15. HR2 is upregulated in specific T cells after multiple beestings and induces IL-10 production A B PLA PPD PHA 14 1.5 15 after 7 d before 1.0 10 4 HR1 15 0.5 5 HR2 2 0 0 0 10 b a b a b a 20 15 15 5 15 10 10 HR2 10 relative mRNA expression 0 5 5 5 relative mRNA expression 0 0 0 b a b a b a FoxP3 2.0 3.0 2.0 60 1.5 1.5 2.0 40 1.0 1.0 HR4 1.0 0.5 0.5 20 0 0 0 a b a b b a 0 CD4+ CD25+ 3.0 3.0 IL-4 CD4+ CD25+ IL-10 IL-10 IFN-g IL-4 3.0 CD4+ CD25- CD4+ CD25- IFN-g 2.0 2.0 2.0 FoxP3 1.0 1.0 1.0 0 0 0 b a b a b a C IL-4 IL-13 IL-10 1.4 6 1.2 3 5 1.0 cytokine (ng/ml) 4 0.8 2 3 0.6 2 0.4 1 histamine 1 0.2 +ranitidine 0 0 0 0 -6 -5 -4 0 -6 -5 -4 0 -6 -5 -4 histamine [M] log10 J. Exp. Med., 2008

  16. inflammatory Ab isotypes ? IgE IgG1, IgG2, IgG3 IgM non-inflammatory Ab isotypes ? IgG4 IgA Th1 Th2 Treg ? Th 17

  17. SIT bee keeper PLA-specific IgE:IgG4 antibody ratios 0 -1 -2 anti-PLA IgE : IgG4 [log10] -3 -4 -5 allergic

  18. IL-10 suppresses IgE and induces IgG4 IgG4 is non inflammatory Does not exist in mice Reflects dose of exposure and accompanies all high dose antigen exposure models, bee keepers, helminth infections (in the absence of high TLR triggers) Does not activate complement No specific Fc receptors for IgG4 are defined so far In vitro studies demonstrate nonanaphlactogenic activity by blocking of IgE binding and dual specificity Molar quantities are at least 1000 X higher than IgE

  19. Allergy, 2008

  20. Allergy, 2008

  21. Immune tolerance to allergens in healthy immune response and successful SIT IL-10 TGF-b IL-10 TGF-b suppression of effector cells induction of IgG4, IgA suppression of IgE decreased TH2 cytokines allergen-specific Treg cell multiple suppressor factors IL-10,TGF-b,IL-10R,TGF-bR,CTLA-4, PD-1, HR2 eosinophil J Clin Invest 1996 J Clin Invest 1998 FASEB 1999 FASEB 2001 Immunology Today Immunology 2001 Nature 2001 Eur J Imm 2003 FASEB 2003 Nature Rev Imm 2003 J Exp Med 2004 JACI 2005 Nature Rev Imm 2006 Curr Opin Imm 2006 JACI 2007-2008 JEM 2008

  22. Immune tolerance Mechanisms of atopy • U. Müller, Bern • B. Wüthrich, Zurich • M. Jutel, Wroclaw, SIAF • R. Valenta, Vienna • E. Jensen-Jarolim, Vienna • M. van Hage-Hamsten, Stockholm • G. Gavfelin, Stockholm • R. Kroczek, Berlin • M. Colonna, St Louis • E. Flory, Langen • S. Viehts, Langen • H. Fiebig, Reinbek • C. Heusser, Basel • E. Hamelmann, Berlin • M. Larchè, London • A. Verhoef, London • S. Alkan, Minneapolis • R. Lauener, Zurich • B. Ballmer-Weber, Zurich • Beate Rückert • Sven Klunker • Flurina Meiler • Willem Van De Veen • Judith Zumkehr • Mario Ziegler • Tunc Akkoc • Umut Kücüksezer • Günnur Deniz • Cezmi A. Akdis • Reto Crameri • Kurt Blaser • R. Disch • B. Wüthrich • P. Schmid-Grendelmeier • W. Kneist • M. Schliz • D. Kleeman • W. Deglmann • H. Behrendt, • C. Traidl-Hoffmann, Munich Immune regulation by histamine • T. Watanabe, Osaka • R. Koga, Fukuoka • Marek Jutel

  23. World Immune Regulation Davos 29 March- 1 April2009

  24. 2 3 2. Regulation of T cells and related phenomena 3. Regulation of B cells, antibodies and related phenomena mechanisms of SIT hours days weeks months years 1 1. Basophil, mast cell desensitisation, early events related to APC (DC, B cell), effect of adjuvants

  25. Early decrease in mast cell and basophil activity for degranulation and systemic anaphylaxis T cell tolerance induction of IL-10 and sometimes TGF-b secreting Tr1 cells suppression of Th2-Th1 cells decrease in tissue mast cells and eosinophils and decreased release of their mediators Mechanisms of allergen-specific immunotherapy relative change 1-3 years start day 1 day 7 1 month 6 months

  26. Type I skin test reactivity specific IgE Mechanisms of allergen-specific immunotherapy relative change specific IgG4 1-3 years start day 1 day 7 1 month 6 months

  27. IL-10 neutralizing 25 20 15 Stimulation Index 10 5 0 before day 7 day 28 IL-10-induced peripheral T cell tolerance in bee venom specific-immunotherapy 20 15 10 Stimulation Index 5 0 before day 7 day 28 3 IFN-  IL-4 H-Thymidine incorporation IL-5 IL-10 IL-13 J. Clin. Invest. 1996; 98: 1676 J. Clin. Invest. 1998; 102: 98

  28. PLA stimulated T cells day 0 events day 28 0 3 10 10 IL-10 day 7 IL-10 production in T cells during specific immunotherapy CD4+ CD25+ T cells events 0 3 10 10 IL-10 J. Clin. Invest. 1998; 102: 98 Direct demonstration

  29. Same T cells skew to Tr1 cells after bee stings before after P N IFN-g IL-4 IL-10 IFN-g IL-4 IL-10 TcRb 240 - 285 bp TcRb 240 - 285 bp TcRb 285 - 325 bp TCRb 170 - 210 bp specimen control size ladder PLA-specific IL-4-, IFN-g- and IL-10-secreting T cells are expanded and their clonality is determined J. Exp. Med., in press

  30. Same T cells skew to Tr1 cells after bee stings TcR vb2 TcR vb12 30 12.5 10.0 20 7.5 5.0 10 2.5 0 0.0 b a b a b a b a b a IL-4 IL-10 IFN-g IL-4 IL-10 PLA-specific IL-4-, IFN-g- and IL-10-secreting T cells are expanded and TcR vb are determined J. Exp. Med.2008

  31. C PBMC before SIT 10 8 PBMC before SIT +CD4+CD25 after SIT * [3H] TdR [cpmx10 -3] * 6 +anti-IL-10R * 4 +sTGF-bR 2 * +anti-IL-10R +sTGF-bR 0 0.1 0.5 0 Der p 1 [µM]

  32. A rapid in vivo switch to specific IL-10-producing T cells 6 before stings 7d after stings 600 Jan/Feb * 4 400 (IL-4/IL-13 pg/ml) * (IL-10/ IFN- ng/ml) * * 2 200 0 0 IL-13 IFN-g IL-10 IL-4

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