Mechanismen der allergenspezifischen Immuntherapie

Transcription

1 Mechanismen der allergenspezifischen Immuntherapie Medizinische Universität Wien Zentrum für Pathophysiologie, Infektiologie und Immunologie Institut für Pathophysiologie und Allergieforschung Abteilung Immunpathologie 1

2 Allergen-specific immunotherapy: Administration of gradually increasing quantities of allergen vaccines to an allergic subject, reaching a dose which is effective in ameliorating the symptoms associated with subsequent exposure to the causative allergen. WHO Position Paper, 1998 Noon L. Prophylactic inoculation against hayfever. Lancet 1, ,

3 First evidence that allergen-specific immunotherapy is a vaccination William Dunbar ( ) 3

4 Allergen-specific immunotherapy induces allergenspecific protective IgG antibodies The blocking antibody concept 1. Serum of an allergic patient taken before (A-serum) and after (P-serum) specific immunotherapy 2. Preincubation of sera with allergen extract 3. Injection into the skin of a non-allergic individual Cooke et al.,

5 Allergen-specific IgG induced by grass pollen extract-based SCIT inhibit specific basophil degranulation 5

6 Allergen-specific IgG are also present in nasal fluids Reisinger R., et al. J. Allergy Clin. Immunol. 2005, 116:

7 Loveless MH. Immunolgical studies of pollinosis. I. The presence of two antibodies related to the same pollen antigen in the serum of treated hay-fever patients. J. Immunol. 38, 25-50,

8 Effects of blocking allergen-specific antibodies on basophil degranulation 8

9 Mechanism 1: Allergen-specific IgG induced by SCIT inhibit specific IgEmediated mast cell and basophil degranulation A B Allergen Bg Bg Vaccination FceRI or FceRII APC MHC II TH2 IFN-g IL-4 IL-5 IL-13 TH2/1 TH2/1 TH2/1 TH2/ 1 IgE Be IgE IL-4 IL-5 IL-13 TH2 TH2 TH2 APC E O 9 9

10 Why is the induction of allergenspecific IgG not always correlated with clinical improvement? 10

11 Only allergen-specific IgG which compete with IgE have beneficial effects Flicker S, Valenta R, Int Arch Allergy Immunol,2003;132:

12 Allergen extracts lacking or containing low amounts of certain allergens do not induce sufficient levels of allergen specific blocking antibodies Mothes N, et al., Clin Exp Allergy 2003; 33:

13 Certain allergens are poorly immunogenic and therefore fail to induce sufficient levels of IgG 13

14 Certain forms of immunotherapy rather sensitize the patients than induce allergen-specific IgG J Allergy Clin Immunol :

15 Advantages of SIT with rbet v 1 over SIT with birch pollen extract 15

16 gg1 (ELISA Bet v1-specific IgG (CAP, kui/l rbet v 1 induces higher birch pollen-specific IgG than birch pollen extract A 40 Placebo nbet v 1 rbet v 1 Birch pollen B 4,0 Pauli et al, J. Allergy Clin. Immunol 2008; 122: ) 3,5 3,0 2,5 16

17 m) Wheal diameters to birch pollen extract (mm) Stronger reduction of cutaneous sensitivity to birch pollen under rbet v 1 treatment compared to treatment with birch pollen extract A Placebo nbet v 1 rbet v 1 Birch pollen p<0,0001 p<0, Pauli et al, J. Allergy Clin. Immunol 2008; 122: ) B 12 p<0,0001 p<0,

18 Monitoring of IT with recombinant allergens Monitoring of the immunological efficacy of IT Measurement of specific IgG Major allergens: Phl p 1, Phl p 5 Bet v 1, Ole e 1 Par j 2 18

19 Patient 6 SCIT (Grass) t1 ( ) Bet v 1 t2 ( ) t3 ( ) IgE Grass IgG 1 IgG 4 Egg 19

20 ISU Allergen-specific IgG antibodies induced by SIT cause a reduction of allergen-specific IgE binding on ISAC IgE-conc.: 312.5ng/ml x (0ng/ml) 1x (312.5ng/ml) 10x (3.1µg/ml) 100x (31.2µg/ml) 1,000x (312.5µg/ml) Bip1-excess (concentration) Lupinek, Methods 2014, 43:

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22 Development of allergen-specific IgG is associated with reduced boosts of allergen-specific IgE during the pollen season 22

23 Immunotherapy with CpG-conjugated Amb a 1 induces allergen-specific IgG which is associated with reduced seasonal boosts of IgE production 23

24 Mechanism 3: Allergen-specific IgG inhibit IgE-facilitated allergen presentation to T cells, T cell activation and secretion of pro-inflammatory cytokines 24

25 SCIT with natural allergen extracts induces allergen-specific IgG which inhibits IgE-facilitated allergen presentation to T cells, specific T cell activation and production of proinflammatory cytokines

26 Mechanism 3: Allergen-specific IgG inhibit IgE-facilitated allergen presentation to T cells, T cell activation and secretion of pro-inflammatory cytokines 26

27 The three mechanisms of action of immunotherapy Valenta R, Nature Rev. Immunol. 2002;2:

28 Unwanted and side effects of allergen-specific immunotherapy IgE-mediated unwanted effects Effector cell degranulation Priming and/or boosting of IgE response Allergen Allergen IgE Mast cell IgE FceRI Be cell T cell epitopes B cell epitopes FceRI or FceRII Allergen SIT IFN-g IL-4 IL-5 IL-13 Focke M. et al., Clin Exp Allergy. 2010; 40: T H 2 IL-4 IL-5 IL-13 APC MHC II TCR T cell epitope T H 2 T H 2 T H 2 T H 1 Allergen T cell epitope APC T H 2 TCR MHC II IgE-dependent IgE-independent T cell-mediated side effects 28

29 Evidence for IgE-independent, T cell-mediated side effects. Non-IgEreactive T cell epitope-containing peptides of the major cat allergen Fel d 1 29

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31 Synthetic allergy vaccines in clinical trials 31

32 Circassia ToleroMune Technology 32

33 Failure of the T cell epitope peptide approach 33

34 Towards the most hypoallergenic vaccine approach 34

35 Development of a recombinant B cell epitopebased grass pollen allergy vaccine (C) 35

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37 Towards prevention of allergy by vaccination and tolerance induction 37

38 The three mechanisms of action of BM32 Valenta R, Nature Rev. Immunol. 2002;2:

39 The BM32 team Christian Doppler Laboratory for Allergy Research Medical University of Vienna, Austria Biomay AG Vienna - Austria Dept. of ENT, Medical University of Vienna, Austria Div. of Hematology and Hemostaseology, Dept. of Internal Med. I Medical University of Vienna, Austria Vienna Challenge Chamber (VCC), Vienna, Austria 39

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