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

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Presentation on theme: "Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK."— Presentation transcript:

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: 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: centres, n= ,000 SQ, 10,000 SQ and placebo

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

17 p<0.001 p=0.027 Rhinoconjunctivitis QoL score BaselineSeasonBaseline/Season 100,000 SQ-U10,000 SQ-UPlacebo P=0.027 Frew AJ et al, J Allergy Clin Immunol 2006; 117:

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

19 J Allergy Clin Immunol 2007; 120:

20 Sublingual Grass Tablet Immunotherapy J Allergy Clin Immunol 2007; 120:

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: 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: 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: 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:

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

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39 Can we predict success or failure of immunotherapy?

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

41 Early skin response late phase response IgE-FAB inhibition Duration of allergen immunotherapy (weeks) Change in response IgG4 Duration of allergen immunotherapy (weeks) 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): Pollen count Time course of biomarkers during immunotherapy

42 MAY JUNE JULY AUGUST

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48 r= p= 0.9 Symptom/Medication score Phl p 5 specific IgG4 (% binding) 100 p = r= % 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:

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


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