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