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T-cell Immunoregulation and the Response to Immunotherapy

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. Role of the T-cell in Asthma. L Cosmi, et al. Allergy 2011;. Immunologic Response: Summary.

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T-cell Immunoregulation and the Response to Immunotherapy

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  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 Th2 to Th2 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. Reduction in Rhinitis Symptoms and Medication from Immunotherapy 100 80 70 80 60 50 60 40 40 30 20 20 10 0 0 (Varney et al. BMJ. 1991;302:265-269.) Drugs 150 Symptoms Grass Pollen Count IT Treatment IT Treatment Placebo Placebo 120 90 Median Score Counts/m Median Score 60 30 0 24 April 8 22 May 5 19 June 3 17 31 July 14 28 August 11 25 September

  6. Early Response Late Response p<0.001 p<0.0001 50 140 120 40 100 30 80 Skin response (mm) 60 20 40 10 20 0 0 Control Immunotherapy 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 Immunotherapy Control ns p=0.002 12 8 Cells/high power field 4 0 p=0.02 Diluent Antigen Diluent Antigen Hamid JACI 1997;99:254

  9. 14 10 r = 0.64 p < 0.05 r = -0.67 p < 0.05 12 8 10 6 8 IFN-g mRNA+ cells/field IL-4 mRNA+ cells/field 6 4 4 2 2 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 IL-12 mRNA+ cells/field IL-12 mRNA+ cells/field 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, (Th1) INF-, and (Th2) 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-b 20 10 0 Der p 1 Unstimulated Bet v 1 Unstimulated * * * * * * [3H] TdR (cpm × 10-9) Both Both Control Control sTGFbR sTGFbR Anti-IL-10R Anti-IL-10R *P < .01. TdR = thymidine. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

  14. IL-10 and TGF-b Mediated T-Cell Suppression During HDM-SIT +anti-IL-10R +sTGF-bR Der p 1 + Control Ab 18 12 8 4 0 * * * [3H] TdR [Stim. Index] * * * 0 7 28 70 Days *P < .01 versus day 0. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

  15. Cytokine Production During HDM-SIT 4 3 2 1 0 IL-10 TGF-b IFN-g IL-13IL-5 * Cytokine (ng/mL) 0 7 28 70 Days HDM-SIT = house dust mite-specific immunotherapy. *P < .001. Jutel M et al. Eur J Immunol. 2003;33:1205-1214.

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

  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. 1000 500 100 IgE Antibody to SRW, ng/ml 50 10 J73O J74O M J76O J77O J78O J79O 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 Th2 to Th1cytokine 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. Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars) Bet v 1 40 * * 30 * Proliferation (dpm x 103) 20 10 0 0 52 4 Time (weeks) B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

  26. 80 80 60 60 40 40 20 20 0 0 0 0 4 4 52 52 Allergen stimulated proliferation of PBMCs (solid bars) and CD25+ depleted PBMCs (open bars) Tetanus toxoid Mal d 1 * * * * Prolifcration (SI) Time (weeks) Time (weeks) B Bohle, et al. J Allergy Clin Immunol 2007;120:707-13

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

  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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