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Mechanisms of allergen immunotherapy Speaker: Stephen R Durham

29 September 2012


Welcome

April 2012

Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy The International Scientific Committee is looking forward to welcoming you in Berlin for the Dear colleague

9 th Symposium on Specific Allergy 2012. Once again, the International Scientific Committee has planned an interesting and ambitious programme, which includes a comprehensive update on the most recent news and information Stephen R Durham, MD, FRCP in the field of specific allergy. SOSA 2012 will include main topics of allergy and optimal allergic disease management and focus on the natural development of Allergy allergic disease, in particular the interaction Section & Clinical Immunology, between innate and adaptive immune responses. SOSA 2012 will provide an overview of the College and Royal Brompton Hospital London current state-of-the-artImperial of specific immunotherapy including immunological mechanisms of action. Unique advantages of allergy immunotherapy tablets including recent clinical and immunological results will be highlighted, and management of anaphylaxis will be discussed. SOSA 2012 also offers the opportunity to discuss relevant issues with leading allergy experts. The posters include the latest results on allergen technology, immunology as well as clinical documentation featuring a scientific and practical update in the field of specific allergy. th


Disclosure

In relation to this presentation, I declare the following, real or perceived conflicts of interest:

Lecture honoraria from Merck, ALK Abelló and Glaxo Smith Kline Consultancy fees from ALK Abelló, Merck, Circassia, Boehringer Ingelheim, Glaxo Smith Kline Research support via Imperial College London from ALK Abelló, Glaxo Smith Kline


Mechanisms of allergen-specific Immunotherapy Natural exposure (Low-dose allergen)

Th2 cell

Th0

IL-9

IL-5 IL-4 IL-13

Eosinoph il Plasma cell

B cell

Dendritic cells (nasal mucosa)

Mast cell

B cell nTreg Foxp3+

Allergen-specific IgA1 and IgA2

Monocyte

iTreg

IL-10/ TGF-β

IL-10

Immunotherapy (High-dose allergen)

B cell

Th0 Dendritic cells (under skin or oral mucosa)

Allergenspecific IgE

Basophil

Th1

IFN-Îł

B cell

Allergen-specific IgG4

Allergen-specific IgG

IgG and IgG4 competes with IgE for allergen binding

Shamji & Durham Clin Exp Allergy. 2011 Sep;41(9):1235-46.


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35 cells)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35 cells)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Zimmer et al., J Allergy Clin Immunol 2012;129(4):1020-30.


Western blot analysis

Zimmer et al., J Allergy Clin Immunol 2012;129(4):1020-30.


CD4+ T cell-derived cytokines after coculture with treated DC subsets

Western blot analysis

Zimmer et al., J Allergy Clin Immunol 2012;129(4):1020-30.


C1Q and STAB1 gene expression: relation to immunotherapy and correlation with symptom scores

Zimmer et al., J Allergy Clin Immunol 2012;129(4):1020-30.


Conclusion

Zimmer et al., J Allergy Clin Immunol 2012;129(4):1020-30.


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35 cells)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35 cells)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Increases in nasal IFN-γ mRNA+  cells  after   immunotherapy (during late response)

Durham SR et al., J Allergy Clin Immunol 1996;97:1356-65


Immunotherapy changes Th1/Th2 balance in the nose

Durham SR et al., J Allergy Clin Immunol 1996;97:1356-65


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35 cells)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Induction of IL-10+ and FoxP3+Tregs following SLIT Suppression of Bet v1-stimulated PBMC proliferation

PBMC

CD25 depleted PBMC


Induction of IL-10+ and FoxP3+Tregs following SLIT Suppression of Bet v1-stimulated PBMC proliferation

PBMC

CD25 depleted PBMC

Induction of FoxP3+ T cells

sTGF-βRII Control


J Allergy Clin Immunol 2008;121:1467-72 p=0.1

p=0.01

p=0.35 (36.7)

+

Foxp3 CD4 2 cells/mm

+

20

10

0

CD3 CD25 Foxp3

CD3 IL-10 Foxp3

Normal controls Controls In season

Before Placebo hayfever

After

IT Immunotherapy Out of season


Rhinitis Symptom Scores

Effects of grass pollen sublingual immunotherapy on Rhinitis Symptom Scores and peripheral T cells p=0.002

20 15

43.7%

10 5 0 NA N=6 n=7

NA = Non-atopic controls

SAR SLIT n=6 n=6

n=7 n=6

SAR = Seasonal Allergic Rhinitis

SLIT = Sublingual immunotherapy Shamji and Durham


Proportions of IL-10+ Tregs after SLIT

Shamji and Durham


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


IL-10 induction and suppression of skin LPR precedes IgG inhibitory antibody activity IL-10

Skin LPR

IgG4

Skin EPR


Longterm tolerance after grass pollen immunotherapy: Study design

James LK, Shamji MH et al, J Allergy 2011; 127: 509-516


Clinical efficacy after withdrawal (tolerance) is associated with persistent IgG-associated blocking activity but not total allergen-specific IgG4

Clinical response

Inhibition of IgE-FAB

Specific IgG4

James LK, Shamji MH et al, J Allergy 2011; 127: 509-516


Relation between serum FAB, IgG4 and combined Sx/Rx scores

James LK, Shamji MH et al, J Allergy 2011; 127: 509-516


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Diamine oxidase compared to CD63, CD203c and CD107a by basophils: biomarkers of efficacy and tolerance following allergen-specific immunotherapy Mohamed H Shamji, Janice A Layhadi, Delica K M Cheung, Shireen Q Khan, Guy W Scadding, M A Calderon, Deborah Phipard and Stephen R Durham


Immunotherapy and rhinoconjunctivitis total symptom score (RTSS) 20

*

10 5

SAR SCIT SLIT SLIT-TOL

-T

O

L

n=10 n=7 n=7 n=4

SL

IT

SL

IT

0 SA R SC IT

RTSS

15

**

*

Shamji, Durham et al.,


Grass pollen-specific immunotherapy decreases ex-vivo allergen induced basophil reactivity

Shamji, Durham et al.,


Grass pollen-specific immunotherapy decreases ex-vivo allergen induced basophil reactivity

CD63

CD203c

CD107a

Shamji, Durham et al.,


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Mechanisms of allergen immunotherapy and surrogate biomarkers of efficacy 

Influence of SIT on dendritic cells

Immune deviation from Th2 to Th1 responses

Induction of regulatory T cells (Foxp3+, IL-10+(Tr1), TGF-β and iTR35)

Induction of ‘protective’ IgG antibodies

Suppression of basophil activation (surface markers and DAO)


Allergy and Clinical Immunology, Imperial College and Royal Brompton Hospital, London, UK

M Calderon S Radulovic SM Walker SJ Till

MH Shamji L James GW Scadding P Wurtzen

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