Mechanisms of allergen-specific immunotherapy

Transcription

1 2012 KAAACI/EAAS Spring Mechanisms of allergen-specific immunotherapy Woo-Jung Song, MD Division of Allergy and Clinical Immunology Department of Internal Medicine Seoul National University Hospital, Seoul, Korea

2 Pollen season

3 John Bostock, an England physician About the beginning or middle of June in every year, the following symptoms make their appearance, with a greater or less degree of violence. - a sensation of heat and fulness in the eyes, first along the edges of the lids a combination of sneezing, chest tightness, difficulty breathing in June - First accurate description of hay fever as a disease from his own experience

4 Hay fever

5 Allergen immunotherapy Repeated allergen injection modifies the course of allergic diseases.

6 Current evidence: from meta-analyses Study (Year) Subjects Allergens Allergic asthma Abramson (2010) Calamita (2006) 3,459 adults and children 1,706 adults and children SCIT Seasonal or perennial SLIT Seasonal and perennial Penagos (2008) 441 children SLIT Seasonal and perennial Compalati (2009) Allergic rhinitis 452 adults and children Symptom score, SMD (95% CI) Medication score, SMD (95% CI) (-0.83, -0.35) (-0.80, -0.27) (-0.79, -0.03) (-1.94, 0.12) (-2.10, -0.18) (-2.83, -0.44) SLIT HDM (-1.74, -0.15) (-2.70, -0.26) Calderon (2007) 2,871 adults SCIT Seasonal (-0.97, -0.50) (-0.82, -0.33) Radulovic (2010) 4,589 adults and children SLIT Seasonal and perennial Penagos (2006) 484 children SLIT Seasonal and perennial Compalati (2009) Di Bona (2010) 382 adults and children 2,971 adults and children (-0.64, -0.34) (-0.43, 0.21) (-1.01, -0.10) (-1.46, -0.06) SLIT HDM (-1.77, -0.14) (-3.65, -0.12) SLIT Grass pollen (-0.44, -0.21) (-0.50, -0.16)

7 Mechanisms of SIT Figure from AAIR 2011;3(1):11-20.

8 Advances during the 100 years Hay fever (allergic rhinitis) 1911 Allergic asthma 1961 SCIT SLIT Atopic dermatitis 2006 OIT Review previous works focused on mechanisms Present ~ Novel immunotherapy Recombinant allergen for better safety and efficacy

9 Findings by Noon (1911) Toxin in the pollens Lancet 1911 June Injection of toxin produces anti-toxin. More usual fate of the patient is to develop hypersensitivity with repeated toxin absorption. Some cured patients have the good fortune to develop an active immunity against the toxin.

10 Reasoning by Noon Cures of hay fever are ascribed to this remedy (toxin application), but admittedly in exceptional cases. The conditions are not understood, and the experience is not constantly repeated. :what degrees of immunity can be induced by inoculations of pollen toxin, :how the inoculations may best be regulated, :whether the affection by this means be permanently cured. Pollen off-season, no spontaneous inoculation Subcutaneous injection of pollen toxin at various quantities (units) Resistance: the strength of pollen extract to excite conjunctival reaction The sensibility of hay fever may be decreased by properly directed dosage. *Small frequent doses (initial) larger doses (2 weeks interval) for resistance

11 Loveless and Cooke (1935) How do injections of pollen extract lower the patient s hay fever symptoms during seasonal pollination? (Loveless) The concept of specific blocking antibody was proposed; the development under treatment of a peculiar blocking or inhibiting type of immune body that prevents the action of allergen on the sensitizing antibody (1935, Robert Cooke) Robert Cooke et al. J Exp Med 1955 (20 years later) Serum factor for inhibition was most likely gamma globulin (IgG) in electrophoretic mobility studies in ragweed treated patients. (quite different from sensitizing antibody)

12 IgG4 Unique structural features in the hinge region -does not fix complement -inhibits immune complex formation by others -captures allergen before binding to IgE -inhibits IgE-facilitated allergen presentation

13 Humoral changes with SIT Creticos et al. JACI 1984 Akdis et al. JACI 2011 IgE or IgG4 levels do not correlate well with clinical improvement after SIT. : They alone would not be the key mechanisms of allergen immunotherapy.

14 Mechanisms :It s the cell Figure from AAIR 2011;3(1):11-20.

15 Identification of suppressor cells (1980, Rocklin) Factors other than IgG could contribute to altered responsiveness to repeated challenge to antigen. Induction of specific-suppressor T cells in animal studies (1976, Ishizaka K) : Generation of allergen-specific suppressor cells may be the mechanism. Design n Ragweed SCIT Allergic rhinitis 10 O Allergic rhinitis 10 X Vasomotor rhinitis 10 X Ragweed IT > 6 mo 12 mo Blood sample

16 Identification of suppressor cells (1980) Allergen-induced PBMC proliferation was suppressed in desensitized allergic subjects. (generation of allergen-specific suppressor cells) Rocklin et al. N Eng J Med 1980

17 Characterization of IL-10 producing suppressor cells (1998, Akdis) Allergy Allergen-specific IgE IL-4 IFN-γ Desensitized allergy IgE IgG4 Normal immunity Allergen-specific IgG4 It s not simple as Th1/Th2 balance theory. IL-10 production may be a key factor in immune regulation. Bee venom (BV) n SCIT Hypersensitive 12 O BV SIT > Tolerant beekeepers 12 X 1 d 7 d 28 d Blood sample

18 Characterization of IL-10 producing suppressor cells (1998) SIT IL-10 Proliferation Cytokine response Antibody isotype switching Akdis et al. J Cin Invest 1998

19 Characterization of IL-10 producing suppressor cells (1998) IL-10 increased in antigen-specific CD4+CD25+T cells (treated patients) - acquired tolerance Same feature (tolerant beekeepers) - natural tolerance Akdis et al. J Cin Invest 1998

20 TGF-β T-bet Th0 GATA3 Th1 TGF-β Th2 Foxp3 Treg - isotype switch: IgE IgA - synergism with IL-10

21 IL-10 and TGF-β what s the difference in response? Allergic subjects Non-allergic subjects + allergen + encounter PBMC proliferation Th2 cytokine response Suppressed proliferation IL-10 and TGF-β response SIT Proliferate! by IL-10 / TGF-β blockade Suppressed! Induction of IL-10+CD4+CD25+T cells IL-10- and TGF-β-mediated suppression (Jutel et al. Eur J Immunol 2003)

22 Foxp3 Foxp3 is required for the development of Tregs and the maintenance of their functions. Sakaguchi et al. Cell 2008

23 Finding of Foxp3? Pathway by which CD4+CD25+Treg develops? More specific marker than CD25 Scurfy mouse : Foxp3 gene mutation Eczematous (scurfy) skin Early-onset multi-organ autoimmune disease Production of autoantibody Lethality at 3-4 weeks Reversed by Treg adoptive transfer

24 Subsets of regulatory T cells Corsini et al. J Immunotoxicol 2011

25 Delicate balance Allergen-specific Th2 Allergic subjects SIT boost Allergen-specific Tr1 Healthy subjects Akdis et al. J Exp Med 2004

26 Factors modulating Treg APC: Interpretation of environmental signals T R 1 tolerogenic IL-10 maturation immunogenic SIT Absence of proinflammtory signals

27 Metabolic controls of Treg Infection Treg Foxp3 Vitamin D3 Retinoic acid Tryptophan ATRA induces Th2 memory cells re-differentiation into Foxp3+Treg cells (Kang CY et al. Plos One 2009).

28 Trp pathways and IDO IDO (indoleamine 2,3-dioxygenase) Tryptophan in allergy (essential amino acids) IDO APC serum trp in pollinosis nitric oxide (NO) IFN-γ Intracellular pathogen depleting trp - Prevention of hyperinflammation IDO suppression - Impaired IDO activity in allergic subjects Allergen immunotherapy Activation of IDO -Degradation of trp -Generation of trp metabolites (KYN, 3-OH-KYN) - experimental evidence - Induction of tolerogenic DC peripheral tolerance JACI 2008;121: IAACI 2008;147: Allergy 2010;65: Allergy 2012 Epub

29 Innate receptors Allergen immunotherapy Impaired IFN response to TLR9 stimulation in allergic subjects (CpG, IDO inducer) Restoration of innate immune function (dendritic cell IFN response to TLR9 stimulation) Suppression of FcεRI activation prevention of late-phase allergen presentation to specific T cells Clin Exp Allergy 2009;40:

30 IL-35 - IL-12 family - p35 + Ebi3 - downstream target of foxp3 - counter-regulating Th17 inflammation - responsive cytokines in inflamed human tissues Naïve T + IL-35 = it R 35 a new subset Its SIT-relevance is still undiscovered. Nat Immunol 2010;11: Nat Immunol 2010;11: Plos One 2012 Epub

31 Summary Eos FcεRI activation Mast cell allergen-induced response T Allergen-specific proliferation Th2 cytokines Treg, IL-10, TGF-β -direct suppression of Th2/Th1 -antibody isotype switching -suppression of effector cells Allergen SIT B Less IgE More IgG4 IL-10 APC IL-10 T R 1 Clinical efficacy Quality of life Symptom score Medication score Allergen provocation Prevention of asthma Prevention of new sensit. Carry-over effects

32 Summary Hay fever (allergic rhinitis) Allergic asthma Atopic dermatitis 1911 SCIT 1961 SLIT 2006 OIT ~ Serum from SIT patients contained factors preventing allergen skin response. Generation of allergen-specific suppressor cells by SIT Characterization: IL-10+CD4+CD25+T cells Regulators: TGF-β, foxp3, inducible Tr1 Controller of regulatory T cells IL-35, Sialylated IgG, CD27

33 Thank you for attention.