Mechanismen der allergenspezifischen Immuntherapie
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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:
21 21
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
30
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
36 36
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
40
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