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Stephen R Durham Section Allergy and Clinical Immunology NHLI, Imperial College

Stephen R Durham Section Allergy and Clinical Immunology NHLI, Imperial College and Royal Brompton Hospital London. Mechanisms of subcutaneous allergen immunotherapy. WAO Cancun Dec 4 th 2011. APC. Th1. Treg. B cell. Th2. (-). (-).

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Stephen R Durham Section Allergy and Clinical Immunology NHLI, Imperial College

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  1. Stephen R Durham Section Allergy and Clinical Immunology NHLI, Imperial College and Royal Brompton Hospital London Mechanisms of subcutaneous allergen immunotherapy WAO Cancun Dec 4th 2011

  2. APC Th1 Treg B cell Th2 (-) (-) Mechanism of tolerance induced by allergen immunotherapy IL-4 IgE IL-13 Immunotherapy (high dose Ag) Natural exposure (low dose Ag) + IgE Allergy IL-5 Eosinophil IFNg TGF-b IL-10 IgG IgA IgG4 (Adapted from Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97 )

  3. J Allergy Clin Immunol 2008; 121: 1467-72

  4. Grass pollen immunotherapy: Local changes in nasal mucosa Pollen Before 2 years 2000 Count/m 3 Bx Bx 120 90 60 30 0 6 20 3 17 1 15 29 12 4 18 1 15 29 13 27 3 17 1 15 29 12 26 10 24 7 21 MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST Immunotherapy Placebo Baseline Treatment n=37 n=44 Wilson DR et al., J Allergy Clin immunol 2001;107:971-76 MAY JUNE JULY AUGUST

  5. Grass pollen immunotherapy for seasonal rhinitis/asthma Symptoms Medication 0 Immunotherapy group -50 % reduction from baseline (1998/1996) Placebo group P = .01 P = .007 -100 Wilson DR et al., J Allergy Clin immunol 2001;107:971-76

  6. EG2+ eosinophils in the nasal mucosa

  7. Eosinophils in the nasal mucosa Wilson DR et al., J Allergy Clin immunol 2001;107:971-76

  8. Eosinophils in nasal mucosa correlate with total symptom scores

  9. C-kit+ mast cells in the nasal mucosa Nouri-Aria KT, Pilette C et al, J Allergy Clin Immunol 2005

  10. Grass pollen IT increases Foxp3+ T cells in the nasal mucosa HF IT NC HF IT NC Foxp3+CD25+ Foxp3+CD4+ (b) (a) Blocking peptide CD25 Foxp3 CD4 Foxp3 Tonsil Tonsil Nose

  11. J Immunol 2004; 172: 3252-59

  12. Grass pollen immunotherapy: IL-10 in the nasal mucosa IL-10 IL-10 mRNA+ cells IL-10 protein+ cells Nouri-Aria K et al J Immunol. 2004; 172:3252-9

  13. A. Allergen-specific IgG4 p=0.000 p=0.000 Wachholz P et al J Allergy Clin Immunol 2003; 112, 915-922.

  14. J Immunol 2007; 178: 4658-66

  15. Grass pollen immunotherapy: TGF-b in the nasal mucosa and serum IgA2 100 80 Phl p5 IgA2 60 P= 0.0001 40 20 0 in in out out Before IT After IT TGF-b Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  16. Colocalization of TGF-β to CD3+ and CD68+ cells Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  17. Grass pollen immunotherapy: TGFb-positive and IgA-positive grass pollen-specific cells in the nasal mucosa Phl p5/IgA2 TGF-β (x400) (x200) Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  18. (73.1) (53.1) A 12 8 TGF- mRNA (cells/mm2) 4 r=0.61 p=0.009 0 0 50 100 150 200 Serum Phl p 5 IgA2 (a.u.) (73.1) (53.1) B 12 8 TGF- mRNA (cells/mm2) 4 r=0.45 p=0.06 0 0 50 100 150 200 250 Serum Phl p 5 p-Ig (a.u.) Figure 3 Grass pollen immunotherapy: Local nasal TGF-beta+ cells correlate with serum grass allergen-specific IgA Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  19. Post immunotherapy serum fractionation: Phl p-IgA1, Phl p-IgA2 and Phl p-IgG Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  20. Post-immunotherapy serum IgG fractions but not IgA fractions do inhibit IgE-FAB Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  21. Phl-p induced IL-10 from monocytes passively sensitised with post-IT serum fractions Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  22. Post immunotherapy serum IgA fractions induce IL-10 synthesis and release from monocytes IL-10: RT-PCR IL-10: ELISA IL-10: intracellular staining Pillette C, Nouri-Aria K et al J Immunol 2007; 178:4658-66.

  23. J Allergy Clin Immunol 2008; 121: 1120-5

  24. IL-10 induction and suppression of skin LPR precedes IgG inhibitory antibody activity IgG4 IL-10 Skin LPR Skin EPR

  25. J Allergy Clin Immunol. 2011 J Allergy J Allergy 2011; 127: 509-516

  26. Longterm tolerance after grass pollen immunotherapy: Study design James LK, Shamji MH et al, J Allergy 2011; 127: 509-516

  27. Longterm tolerance after grass pollen immunotherapy: combined scores and serum FAB James LK, Shamji MH et al, J Allergy 2011; 127: 509-516

  28. Longterm tolerance after grass pollen immunotherapy: serum IgG1 and IgG4 James LK, Shamji MH et al, J Allergy 2011; 127: 509-516

  29. Relation between serum FAB, IgG4 and combined Sx/Rx scores James LK, Shamji MH et al, J Allergy 2011; 127: 509-516

  30. APC Th1 Treg B cell Th2 (-) (-) Mechanism of tolerance induced by allergen immunotherapy IL-4 IgE IL-13 Immunotherapy (high dose Ag) Natural exposure (low dose Ag) + IgE Allergy IL-5 Eosinophil IFNg TGF-b IL-10 IgG IgA IgG4 (Adapted from Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97 )

  31. Allergy and Clinical Immunology, Imperial College and Royal Brompton Hospital, London, UK M H Shamji K T Nouri-Aria S J Till J N Francis C Pilette M Makatsori S M Walker L K James G Rotiroti D R Wilson M R Jacobson G W Scadding G Pajno P Wachholz M Calderon

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