Mechanisms of Allergen-specific immunotherapy

Transcription

1 relative change relative change Mechanisms of Allergen-specific immunotherapy Cezmi A. Akdis Swiss Institute of Allergy and Asthma Research (SIAF) mechanisms of SIT. Basophil, mast cell desensitisation, early events related to APC (DC, B cell), effect of adjuvants. Regulation of T cells and related phenomena (Treg cells and allergen tolerance). Regulation of B cells, antibodies and related phenomena (Breg cells and IgG4 in allergen tolerance) Mechanisms of allergen-specific immunotherapy Mechanisms of allergen-specific immunotherapy Early desensitization: decrease in mast cell and basophil activity for degranulation and systemic anaphylaxis T cell tolerance induction of T Reg cells suppression of Th-Th cells - years Late desensitization: decrease in tissue mast cells and eosinophils and release of their mediators - years Type I skin test reactivity specific IgE specific IgG4 Q: which one will be the first and preferential APC to present the allergen which T cell? adjuvants, dose, place, age, status Th Q: how will the system avoid anaphylaxis as early and efficient as possible? adjuvants, dose, place, age, status mechanisms of SIT (very early events) PDC Th T reg Very early desensitization. Basophil, mast cell desensitisation, Th7-9- MDC Immature DC LC

2 Stimulation Index Stimulation Index Increased HR expression on basophils during very early VIT HR suppresses basophil activation Natalija Novak & Nihal Mete et al. JACI Natalija Novak & Nihal Mete et al. JACI HR suppresses basophils (IL-8 and sulfidoleukotrienes) Mechanisms of SIT. Regulation of T cells and related phenomena Induction of T regulatory cells Peripheral T cell tolerance Natalija Novak & Nihal Mete et al. JACI which one will be the first T cell to contact APC? It is very difficult to cope with a primed and established immune response -induced peripheral T cell tolerance in bee venom specific-immunotherapy neutralizing Th Th T reg before day 7 day 8 before day 7 day 8 T reg T reg T reg Th7-9- H-Thymidine incorporation IL- IFN- IL-4 IL- J. Clin. Invest. 996; 98: 676 J. Clin. Invest. 998; : 98

3 specific CD4 + T cells frequency / 4 cells events events cytokine (ng/ml) production in T cells during specific immunotherapy CD4 + CD + T cells day day 7 day 8 PLA stimulated T cells and TGF-b in peripheral T cell tolerance during aeroallergen SIT 4 IL - TGF-b IL- IL- IFN- Direct demonstration J. Clin. Invest. 998; : days 7 n=, SIT cluster protocol, Der p -stimulated PBMC M. Jutel et al. EJI T Reg cells in allergy: multiple suppressor factors CD4+ + CD+ CD4+ + IC R IC CTLA CD receptor / cytokine TGF-bRII TGF-bRI PD In vivo clonal switch and expansion of -secreting Tr cells in beekeepers in response to high dose venom exposure et al. J. Exp. Med. 4 Meiler et al. J. Exp. Med. 4 Nov, 8 Frequency of PLA-specific cytokine secreting T cells before and after live bee stings before 7 d after IL-4 IFN- Same T cells skew to Tr cells after bee stings Clonal T cell switch to +Treg cells before after IFN- IL-4 IFN- IL-4 P N TcRb 4-8 bp TCRb 7 - bp specimen control size ladder Decreased frequency of PLA-specific IL-4- and IFN- -secreting T cells, increased frequency of -secreting T cells is observed 7 days after bee stings : p<. n:6 beekeepers PLA-specific IL-4-, IFN- - and -secreting T cells are expanded and their clonality is determined Sven Klunker Flurina Meiler J. Exp. Med. 8

4 anti-pla IgE : IgG4 [log] Mechanisms of SIT. Regulation of B cells, antibodies and related phenomena Regulation of B cells, antibodies and related phenomena PLA-specific IgE:IgG4 antibody ratios inflammatory Ab isotypes IgG, IgG, IgG, IgM, IgE - - non-inflammatory Ab isotypes IgG4, IgA allergic SIT bee keeper, Tr and FoxP+Treg cells suppress IgE and induce IgG4 Human Breg cells in allergen tolerance and allergen-sit Meiler et al. Allergy 8 4

5 CD9 Circulating Human + Breg cells IgG4 production in -producing B cells.9 day culture after sorting Allergen-specific B cells produce IgG4 in allergen tolerance Increased -producing Breg cells during allergen-sit Isolate CD9+ B cells from beekeepers Stain with PLA-FITC Sort cells Determine immunoglobulin profile on mrna level PLA-specific B cells from beekeepers have elevated IgG4 production Immune tolerance to allergens in healthy immune response and successful SIT early and late desensitization suppression of effector cells eosinophil HR TGF-b decreased T H cytokines TGF-b allergen-specific T reg cell multiple suppressor factors, TGF-b, R, TGF-bR, CTLA4, PD, HR RUNX (Klunker et al. J. Exp. Med. 9) Allergen-specific Breg cells induction of IgG4, IgA suppression of IgE J Clin Invest 996 J Clin Invest 998 FASEB 999 FASEB Immunology Today Nature Eur J Imm FASEB Nature Rev Imm J Exp Med 4 JACI Nature Rev Imm 6 Curr Opin Imm 6 JACI 7-8 J Exp Med 8 Nature Drug Disc 9 Curr Opin Imm 9 J Exp Med 9 JI JACI, JACI Nat Med Nat Imm

6 frequency /. cells WIRM VII -6 March Davos Oscar Palomares Nihal Mete Natalija Novak Judith Zumkehr Flurina Meiler Sven Klunker Alison Taylor Johan Verhagen Andrea Joss Maya Zimmermann Christian Manhart Tomasz Basinski Tunc Akkoc Axel Trautmann Mübeccel Akdis Reto Crameri Liam O Mahony Roger Lauener, Davos Immune tolerance U. Müller, Bern M. Jutel, Wroclaw, SIAF T. Kündig, Zürich G. Sentii, Zürich B. Wüthrich, Zurich Natalija Novak, Bonn R. Valenta, Vienna M. van Hage, Stockholm G. Gavfelin, Stockholm M. Colonna, St Louis E. Flory, Langen S. Viehts, Langen H. Fiebig, Reinbek O. Cromwell, Reinbek E. Hamelmann, Berlin M. Larchè, London Ch. Heusser, Basel B. Ballmer-Weber, Zurich Effector Mechanisms R. Disch B. Wüthrich P. Schmid-Grendelmeier W. Kneist M. Schliz D. Kleeman W. Deglmann H. Behrendt, C. Traidl-Hoffmann, G. Menz Immune regulation by histamine T. Watanabe, R. Koga, Fukuoka M. Jutel, Wroclaw Body surfaces: Skin.% Mucosas 99.% Lung: m Gut: m / Tennis court Ton food per year mixed with water 4 bacteria kg species = liters billion particles ( perliter) kg Only one cell layer between life and death. mm thick Aeroallergen-specific T cell frequency in health and allergy Allergic Healthy 7.. Der p Bet v Pyr c Cor a IL-4 IFN- IL-4 IFN- et al. J Exp Med 4 6