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T-cell Immunoregulation and the Response to Immunotherapy Harold S. Nelson. MD Professor of Medicine National Jewish Health and University of Colorado.

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Presentation on theme: "T-cell Immunoregulation and the Response to Immunotherapy Harold S. Nelson. MD Professor of Medicine National Jewish Health and University of Colorado."— Presentation transcript:

1 T-cell Immunoregulation and the Response to Immunotherapy Harold S. Nelson. MD Professor of Medicine National Jewish Health and University of Colorado School of Medicine Denver, Colorado, USA

2 Role of the T-cell in Asthma L Cosmi, et al. Allergy 2011;

3 Immunologic Response: Summary The immunologic response to allergen immunotherapy involves: 1) A shift from Th 2 to Th 2 cytokine profile 2) The generation of regulatory T cells secreting IL-10 and TGF- ,

4 Increases in IL-12 mRNA + Accompany Inhibition of Allergen Late Skin Test Responses after Successful Grass Pollen Immunotherapy 10 subjects who had received 4 years of grass pollen immunotherapy and 10 allergic controls had skin biopsies 24 hours afterintracutaneous injection of grass pollen extract. QA Hamid,et al.J Allergy Clin Immunol 1997;99:254-60

5 100 80 60 40 20 0 Counts/m Grass Pollen Count Median Score 80 70 60 50 40 30 20 10 0 Symptoms IT Treatment Placebo Median Score 150 120 90 60 30 0 Drugs IT Treatment Placebo 24 April 8 22 May 5 19 June 3 17 31 July 14 28 August 11 25 September Reduction in Rhinitis Symptoms and Medication from Immunotherapy (Varney et al. BMJ. 1991;302:265-269.)

6 Early Response Late Response p<0.001p<0.0001 50 40 30 20 10 0 Skin response (mm) 140 120 100 80 60 40 20 0 Control Immunotherapy Hamid JACI 1997;99:254

7 Late Skin Response to Allergen Following Successful Pollen Immunotherapy At site of late cutaneous response: - Increased cells with mRNA for IL-12 - Principal source of IL-12 tissue macrophages IL-12 + cells correlated positively with IFN-  + cells and inversely with IL-4 + cells. QA Hamid, et al JACI 1997

8 IL-12 Control Immunotherapy ns p=0.02 Cells/high power field Diluent Antigen Hamid JACI 1997;99:254 12 8 4 0 p=0.002

9 r = 0.64 p < 0.05 r = -0.67 p < 0.05 IFN-  mRNA+ cells/field IL-4 mRNA+ cells/field 10 8 6 4 2 00 2 4 6 8 12 14 024681012 IL-12 mRNA+ cells/field 024681012 Hamid et al, JACI 1997;99:254

10 IL-10 and TGF-  Cooperate in the Regulatory T Cell Response to Mucosal Allergens in Normal Immunity and Specific Immunotherapy Examined the normal immunoregulatory mechanism and the immunologic basis of specific immunotherapy (SIT) to Der p 1 and Bet v 1 M Jutel, et al. Eur J Immunol 2003;33:1205-14

11 Regulatory T Cell Response In normal immunity to HDM and birch pollen an allergen-specific peripheral T cell suppression to Der p 1 and Bet v 1 was observed. This was characterized by: - suppressed proliferative T cell, (Th 1 ) INF- , and (Th 2 ) IL-5, IL-13 responses - increased IL-10 and TGF-  secretion by allergen-specific T cells.

12 Regulatory T Cell Response Specific immunotherapy induced an allergen-specific suppressive activity in CD4+ CD25+ T cells of allergic individuals. Suppression was induced by IL-10 and TGF-  These results demonstrate a deviation towards a regulatory/suppressor T cell response during SIT similar to the “healthy” immune response to mucosal allergens.

13 Normal Immune Response: Downregulation of Th1 and Th2 Response by IL-10 and TGF-  *P <.01. TdR = thymidine. Jutel M et al. Eur J Immunol. 2003;33:1205-1214. 20 10 0 Control Anti-IL-10R sTGFbR Both Control Anti-IL-10R sTGFbR Both Der p 1 Unstimulated [ 3 H] TdR (cpm × 10 -9 ) * * * * * * Bet v 1 Unstimulated

14 IL-10 and TGF-  Mediated T-Cell Suppression During HDM-SIT *P <.01 versus day 0. Jutel M et al. Eur J Immunol. 2003;33:1205-1214. * * * * * * 18 12 8 4 0 [ 3 H] TdR [Stim. Index] 0728 70 Days +anti-IL-10R +sTGF-bR Der p 1 + Control Ab

15 Cytokine Production During HDM-SIT HDM-SIT = house dust mite-specific immunotherapy. *P <.001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214. * 4321043210 0728 70 Days IL-10 TGF-b IFN-g IL-13 IL-5 Cytokine (ng/mL)

16 Antibody Response in Healthy Controls and Changes in Allergic Individuals During HDM-SIT HDM-SIT = house dust mite-specific immunotherapy. *P <.01. † P <.001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214. 60 40 20 0 60 40 20 0 U/mL Healthy 0 70 IgE IgG1 Days (SIT) 60 40 20 0 60 40 20 0 † Healthy 0 70 IgA IgG4 Days (SIT) U/mL * *

17 Gerald Gleich: Effect of 6 Years of Immunotherapy on IgE and IgG Antibodies to Ragweed (1982)  Antibody levels were monitored 2 years before and 4 years following institution of ragweed immunotherapy.  Before immunotherapy patients ragweed-specific IgE rose with each pollen season and declined off season.  With immunotherapy there was an abrupt rise in specific IgE, but the seasonal increases were blocked, and IgE levels gradually declined.  Specific IgG rose with immunotherapy and remained high. G Gleich et al. J Allergy Clin Immunol 1982;70:261-71

18 J 73 O J 74 O J 77 O J 79 OM J 76 O J 78 O 1000 500 100 50 10 IgE Antibody to SRW, ng/ml Effect of Ragweed Immunotherapy on Specific IgE Levels  Immunotherapy G Gleich et al. J Allergy Clin Immunol 1982;70:261-71

19 Immunologic Response: Summary The immunologic response to allergen immunotherapy involves: 1) A shift from Th 2 to Th 1 cytokine profile 2) The generation of regulatory T cells secreting IL-10 and TGF- , What is the relationship between the two immune responses?

20 Sublingual Immunotherapy Induces IL-10-producing T Regulatory Cells, Allergen-specific T-cell Tolerance, and Immune Deviation 9 subjects underwent SLIT with a 4-week build up to a daily dose of birch pollen extract containing 4.5 mcg Bet v 1. Assessments were made prior to treatment, on reaching maintenance after 4 weeks and after one year. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

21 Immune Response to Sublingual Immunotherapy: 4 Weeks After 4 weeks of SLIT: Circulating CD4+CD25+ cells were increased (from 15% to 35%) PBMC proliferation in response to Bet v 1, Mal d 1 (apple) and tetanus toxoid were decreased from baseline. Before treatment depletion of CD4+CD25+ cells decreased proliferation. After 4 weeks depletion resulted in increased proliferation with all 3 antigens. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

22 Immune Response to Sublingual Immunotherapy: 4 Weeks mRNA expression in antigen stimulated T- cells was decreased for IL-4 and IFN-  and increased for IL-10. Neutralization of IL-10 in cultures significantly increased PBMC proliferation. FoxP3 expression in CD3+ T-cells was increased. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

23 Immune Response to Sublingual Immunotherapy: 52 Weeks After 52 weeks of SLIT: Circulating CD4+CD25+ cells were decreased (from 35% to 21%) PBMC proliferation in response to Bet v 1, was decreased from baseline, but response to Mal d 1 and TT returned to baseline. CD4+CD25+ depletion decreased proliferation to antigen. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

24 Immune Response to Sublingual Immunotherapy: 52Weeks mRNA expression in antigen stimulated T- cells was decreased for IL-4 and IL-10 compared to baseline, while mRNA for IFN-  was increased. FoxP3 expression in CD3+ T-cells was normal. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

25 Time (weeks) * * * Bet v 1 40 20 0 4 52 30 10 Proliferation (dpm x 10 3 ) 0 Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars) B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

26 Prolifcration (SI) Time (weeks) 045204 Time (weeks) * * * * Mal d 1 Tetanus toxoid 60 80 40 20 0 60 80 40 20 0 Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars) B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

27 Fold increase of mRNA IL-4 IFN-  * 1.5 2.0 2.5 3.0 3.5 4.0 1.0 0.5 0 IL-10 TGF-  FoxP3 Changes from Baseline in mRNA Expression in Unstimulated PBMCs Open bars 4 weeks: Filled bars 52 weeks B Bohle, et al. JACI 2007;120:707-13 P <.05

28 SLIT Induces IL-10-producing T Regulatory Cells, Allergen-specific T-cell Tolerance, and Immune Deviation: Conclusions The early immune response to SLIT is IL- 10 secreting regulatory T cells with non- allergen specific T cell suppression. By one year, regulatory T cells have declined, replaced by allergen-specific T cell suppression and enhanced IFN-  production. B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

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