1. Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

2. Declaration Research funding, consultancy and lecture fees from ALK Abello Lecture fees from Allergy Therapeutics

3. wrong set up wrong patient wrong allergen(s) wrong dose wrong duration Why immunotherapy fails ?

4. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

5. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

6. Immunotherapy clinic

7. Leadership/organisation of allergy clinic Staff competencies (induction/training) Clinic facilities –bookings, observation space –storage for vaccines / skin test reagents –safety procedures –rescue equipment Immunotherapy protocols Alvarez-Cuesta E et al Allergy 2006; 61 Suppl. 82: 1-20

8. Staff competencies Evaluation of the patients’ condition Entering data in “Immunotherapy Record Form” Injection technique Dose modification Active observation of patients Early recognition of anaphylactic reactions Treatment /monitoring of anaphylactic reactions How to perform scheduled assessments Factors determining whether to continue/stop IT Alvarez-Cuesta E et al Allergy 2006; 61 Suppl. 82: 1-20

9. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

10. Selection of patients for immunotherapy Symptoms induced by allergen IgE to relevant allergen (SPT/RAST) Symptoms due to one or few allergens No contra-indications (severe asthma, beta/blockers, inability to comply with IT)

11. Arvidsson M, Löwhagen O Rak S J Allergy Clin Immunol 2002;109:777-83 Immunotherapy in adults with birch allergy

12. Franklin Adkinson N et al New Engl J Med 1999; Immunotherapy in children with perennial asthma and multiple allergen sensitivities

13. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

14. Selection of allergen extracts Standardisation - in-house reference standards (IHRs) - units of biologic potency - major allergen content (5-20 mcg major Ag) - recombinant allergens Documented benefit (controlled trials) - efficacy - safety - children and adults - longterm effects

15. J Allergy Clin Immunol 2006; 117: 319-25 26 centres, n=410 100,000 SQ, 10,000 SQ and placebo

16. Grass pollen immunotherapy: UK immunotherapy study Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25

17. p<0.001 p=0.027 Rhinoconjunctivitis QoL score 0 0.5 1 1.5 2 2.5 BaselineSeasonBaseline/Season 100,000 SQ-U10,000 SQ-UPlacebo 0 0.5 1 1.5 2 3 P=0.027 Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25

18. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

19. J Allergy Clin Immunol 2007; 120: 1338-45

20. Sublingual Grass Tablet Immunotherapy J Allergy Clin Immunol 2007; 120: 1338-45

21. Sublingual Grass Tablet Immunotherapy

22. Randomised DBPC trial (n=855). 3 doses v placebo 2,500 SQ-T 25,000 SQ-T 75,000 SQ-T Once daily 8 weeks pre-season and continued throughout season

23. Durham SR et al. J Allergy Clin Immunol 2006; 117: 802-9 Sublingual Grass Tablet Immunotherapy

24. right set up right patient right allergen(s) right dose right duration Why immunotherapy succeeds ?

25. right set up right patient right allergen(s) right dose right duration - efficacy - tolerance Why immunotherapy succeeds ?

26. 17% reduction in average seasonal daily rhinoconjunctivitis symptom (p<0.05) 23% reduction in average seasonal daily medication scores ( p<0.05) 8 Weeks Pre-Seasonal Treatment Calderon MA et al. Allergy 2007

27. > 8 Weeks Pre-Seasonal Treatment 37% reduction in average seasonal daily rhinoconjunctivitis symptom (p<0.0001) 47% reduction in average seasonal daily medication scores ( p<0.0001) Calderon MA et al. Allergy 2007

28. right set up right patient right allergen(s) right dose right duration - efficacy - tolerance (persistent efficacy after withdrawal) Why immunotherapy succeeds ?

29. Durham SR et al New Engl J Med 1999;341:468-75 Grass pollen IT in adults: 3 years duration induces tolerance

30. House dust mite IT in children : 3 years duration induces tolerance Des Roches A et al, Allergy 1996; 51 :430-3

31. J Allergy Clin Immunol 2008;12:512-518 Can sublingual immunotherapy induce tolerance?

32. right set up right patient right allergen(s) right dose right duration - efficacy - tolerance Why immunotherapy succeeds ?

33. wrong set up wrong patient wrong allergen(s) wrong dose wrong duration - no efficacy - no tolerance Why immunotherapy fails?

34. Immunotherapy (high dose Ag) Th1 IFN  IgG T r IL-10 TGF-  IgG4 IgA APC Natural exposure (low dose Ag) + IgE Th2 B cell Eosinophil IgE IL-4 IL-5 Allergy (-) Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97

35. Two types of regulatory T cells Tr1 Th3 Tr1 cells IL-10 Foxp3? Th3 cells TGF-  Adaptive Thn T reg CD4 + CD25 + T cells Foxp3 transcription factor Natural Thymus

36. J Allergy Clin Immunol 2008; April 17 th epub Phenotypic Tregs in the nasal mucosa CD3 CD25 Foxp3 CD3 IL-10 Foxp3 Controls hayfever Immunotherapy

37. Th2 responses prevent tolerance induction? Positive feedback Amplifier naivenaive TregTreg FOXP3 TGF-β, IL-10 IL-27IL-35 IL-27IL-35 NFAT Th2Th2 GATA3 resistor negative feedback Anti-IL-4 directed therapy to augment tolerance induction against allergens IL-4 TGF-  IL-10 Mantel P-Y et al, PLOS Biology 2007; 5 (12): e329

39. Can we predict success or failure of immunotherapy?

40. late phase response IL-10 production Duration of allergen immunotherapy (weeks) 024681216202428323640444852 Change in response 2 weeks Grass pollen count Time course of biomarkers during immunotherapy J Allergy Clin Immunol 2008; 121(5):1120-1125

41. Early skin response late phase response IgE-FAB inhibition Duration of allergen immunotherapy (weeks) 024681216202428323640444852 Change in response IgG4 Duration of allergen immunotherapy (weeks) 024681216202428323640444852 Change in response 4 weeks 8 weeks Late allergen-induced Skin Response Grass Pollen season Time course of changes in IL-10 and IgG-associated inhibitory activity J Allergy Clin Immunol 2008; 121(5):1120-1125 Pollen count Time course of biomarkers during immunotherapy

42. MAY JUNE JULY AUGUST

48. 025005000750010000 0 50 r= 0.0 5 p= 0.9 Symptom/Medication score Phl p 5 specific IgG4 (% binding) 100 p = 0.02 025005000750010000 40 60 80 100 r= - 0.6 5 % Inhibition of allergen/IgE binding to B cells Symptom/Medication score Correlation between clinical response (Sx/Rx) IgG4 and IgE-FAB inhibitory activity IgG4IgE-FAB Shamji M et al 2008, unpublished

49. Immunotherapy (high dose Ag) Th1 IFN  IgG T r IL-10 TGF-  IgG4 IgA APC Natural exposure (low dose Ag) + IgE Th2 B cell Eosinophil IgE IL-4 IL-5 Allergy (-) Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97

50. Allergy and Clinical Immunology, Imperial College and Royal Brompton Hospital, London, UK M Calderon K T Nouri-Aria G Paraskavopoulos D R WilsonM R JacobsonL Wilcock C Pilette J N Francis C Schmidt-Weber S RadulovicM Shamji S J Till