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

Slides:

Advertisements

Similar presentations

Mechanisms of sensitization, disease development and desensitization: towards novel approaches for prevention and therapy Ronald van Ree Academic Medical.

Advertisements

Developing Immunotherapy for Autoimmune Diseases

1 Oral Immunotherapy Wesley Burks, M.D. Professor and Chair Department of Pediatrics University of North Carolina.

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

J. Antipkin 1, T. Umanets 1, V. Lapshyn 1, A. Nakonechna 2 1) Institute of Pediatry, Obstetrics and Gynaecology, Kiev, Ukraine 2) Royal Liverpool and Broadgreen.

Use of Multiple Allergen Mixes in Immunotherapy Harold S. Nelson, MD Professor of Medicine National Jewish Health University of Colorado Denver School.

Diagnostic approach to the allergic patient. Allergic conditions in Israel.

Anti-IgE in Asthma and Other Allergic Diseases Harold S. Nelson. MD Professor of Medicine National Jewish Health And University of Colorado School of Medicine.

SLIT: dealing with trouble, doing it right. Giovanni B Pajno MD Professor of Pediatrics Department of Pediatrics – Allergy Unit University of Messina Italy.

Rush and Cluster Immunotherapy Harold S. Nelson, MD Professor of Medicine National Jewish Health University of Colorado Health Science Center Denver, Colorado.

Which Patients for Subcutaneous Immunotherapy? Harold S. Nelson. MD Professor of Medicine National Jewish Heath University of Colorado Denver School of.

Immune responses that are inadequately controlled, inappropriately targeted to host tissues, or triggered by commensal microorganisms or usually harmless.

Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy Ravi S. Swamy, MD, Neha Reshamwala,

Immunotherapy for Allergic Rhinitis

Fig. 3. IL-4, IFN-γ, and IL-17 production from α-GalCer-stimulated iNKT cells following FlaB treatment of PBMC cultures from asthma patients and healthy.

Volume 11, Pages (September 2016)

Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms Anna Slovick, MRCS, Abdel Douiri, PhD,

Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen- specific T-cell tolerance in human tonsils and peripheral blood

INVOLVEMENT OF DIFFERENT SUBSETS OF REGULAOTRY T CELLS AND CYTOKINES IN THE SUPRESSION OF PRO-INFLAMMATORY RESPONCES DURING PROGRESSION OF VISCERAL LEISHMANIASIS.

Volume 11, Pages (September 2016)

Efficacy and safety of birch pollen immunotherapy for local allergic rhinitis Andrzej Bożek, MD, PhD, Krzysztof Kołodziejczyk, MD, PhD, Jerzy Jarząb,

Immunotherapy for Food Allergy: Are We There Yet?

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

Cell-to-cell contact between activated CD4+ T lymphocytes and unprimed monocytes interferes with a TH1 response Miriam Wittmann, MD, Mareike Alter, Tanja.

Allogeneic mesenchymal stem cell treatment alleviates experimental and clinical Sjögren syndrome by Junji Xu, Dandan Wang, Dayong Liu, Zhipeng Fan, Huayong.

Birch pollen immunotherapy results in long-term loss of Bet v 1–specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies

Rush immunotherapy results in allergen-specific alterations in lymphocyte function and interferon-γ production in CD4+ T cells Gideon Lack, MD, Harold.

The effects of house dust mite sublingual immunotherapy tablet on immunologic biomarkers and nasal allergen challenge symptoms Natasha C. Gunawardana,

Grass pollen immunotherapy inhibits allergen-induced infiltration of CD4+ T lymphocytes and eosinophils in the nasal mucosa and increases the number of.

Characterization of pollen antigen–induced IL-31 production by PBMCs in patients with allergic rhinitis Mitsuhiro Okano, MD, Tazuko Fujiwara, BS, Takaya.

Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies Louisa K. James, PhD, Mohamed H. Shamji,

T lymphocytes in asthma: Bronchial versus peripheral responses

Triggering of specific Toll-like receptors and proinflammatory cytokines breaks allergen- specific T-cell tolerance in human tonsils and peripheral blood

Induction of IL-10–producing regulatory T cells with TCR diversity by epitope-specific immunotherapy in pollinosis Kei-ichi Yamanaka, MD, Atsushi Yuta,

Suppression of antigen-specific T- and B-cell responses by intranasal or oral administration of recombinant Bet v 1, the major birch pollen allergen,

Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang,

Induction of IL-10–producing regulatory T cells with TCR diversity by epitope-specific immunotherapy in pollinosis Kei-ichi Yamanaka, MD, Atsushi Yuta,

Update on Immune Mechanisms Associated with Sublingual Immunotherapy: Practical Implications for the Clinician Philippe Moingeon, PhD The Journal of.

Toll-like receptors and atopy

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms Anna Slovick, MRCS, Abdel Douiri, PhD,

Mohamed H. Shamji, PhD, Janice A. Layhadi, MSc, Guy W

Katherine G. MacDonald, BSc, Nicholas A. J

T Cell Epitope-Specific Defects in the Immune Response to Cat Allergen in Patients with Atopic Dermatitis Raquel Carneiro, Amanda Reefer, Barbara Wilson,

A thymic stromal lymphopoietin–responsive dendritic cell subset mediates allergic responses in the upper airway mucosa Guro R. Melum, MD, Lorant Farkas,

Short-term subcutaneous grass pollen immunotherapy under the umbrella of anti–IL-4: A randomized controlled trial Adam M. Chaker, MD, Mohamed H. Shamji,

Volume 76, Issue 5, Pages (September 2009)

Role of IL-35 in sublingual allergen immunotherapy

Recruitment of T cells to the lung in response to antigen challenge

Allergen-specific immunotherapy with recombinant grass pollen allergens Marek Jutel, MD, Lothar Jaeger, MD, Roland Suck, PhD, Hanns Meyer, Dipl Math,

Grass tablet sublingual immunotherapy downregulates the TH2 cytokine response followed by regulatory T-cell generation Abel Suárez-Fueyo, PhD, Tania.

Lec.10 Immune response كلية المأمون الجامعة\قسم تقنيات التحليلات المرضية مادةالمناعة-النظري/المرحلةالثالثة م.م.رشد اياد عبدالحميد.

Enhanced CD46-induced regulatory T cells suppress allergic inflammation after Dermatophagoides pteronyssinus–specific immunotherapy Yi-Giien Tsai, MD,

Images in allergy and immunology: Regulatory T cells in allergic disease Susan C. Foley, MD, David Préfontaine, MSc, Michelle D'Antoni, BSc, Qutayba Hamid,

Omalizumab pretreatment decreases acute reactions after rush immunotherapy for ragweed-induced seasonal allergic rhinitis Thomas B. Casale, MD, William.

Mohamed H. Shamji, PhD, FAAAI, Stephen R. Durham, MD, FRCP

House dust mite sublingual immunotherapy: Results of a US trial

A major allergen gene-fusion protein for potential usage in allergen-specific immunotherapy Fatimah Kussebi, MD, Fariba Karamloo, PhD, Claudio Rhyner,

Is intralymphatic immunotherapy ready for clinical use in patients with grass pollen allergy? Marianne Witten, MD, PhD, Hans-Jørgen Malling, MD, Lars.

Harald Renz, MD, Chaya Brodie, PhD, Katherine Bradley, BS, Donald Y. M

Regulatory T Cells in Asthma

Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity James N. Francis, PhD, Louisa.

IL-10–producing monocytes differentiate to alternatively activated macrophages and are increased in atopic patients Antje Prasse, MD, Martin Germann,

IgG4 production is confined to human IL-10–producing regulatory B cells that suppress antigen-specific immune responses Willem van de Veen, MSc, Barbara.

Mechanism of topical glucocorticoid treatment of hay fever: IL-5 and eosinophil activation during natural allergen exposure are suppressed, but IL-4,

Advances and highlights in mechanisms of allergic disease in 2015

Amb a 1–immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response Meri K Tulic, PhD, Pierre-Olivier Fiset,

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

Presentation transcript:

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 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- ,

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

Counts/m Grass Pollen Count Median Score Symptoms IT Treatment Placebo Median Score Drugs IT Treatment Placebo 24 April 8 22 May 5 19 June July August September Reduction in Rhinitis Symptoms and Medication from Immunotherapy (Varney et al. BMJ. 1991;302: )

Early Response Late Response p<0.001p< Skin response (mm) Control Immunotherapy Hamid JACI 1997;99:254

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

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

r = 0.64 p < 0.05 r = p < 0.05 IFN-  mRNA+ cells/field IL-4 mRNA+ cells/field IL-12 mRNA+ cells/field Hamid et al, JACI 1997;99:254

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:

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.

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.

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: Control Anti-IL-10R sTGFbR Both Control Anti-IL-10R sTGFbR Both Der p 1 Unstimulated [ 3 H] TdR (cpm × ) * * * * * * Bet v 1 Unstimulated

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: * * * * * * [ 3 H] TdR [Stim. Index] Days +anti-IL-10R +sTGF-bR Der p 1 + Control Ab

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

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: U/mL Healthy 0 70 IgE IgG1 Days (SIT) † Healthy 0 70 IgA IgG4 Days (SIT) U/mL * *

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

J 73 O J 74 O J 77 O J 79 OM J 76 O J 78 O 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

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?

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

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

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

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

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

Time (weeks) * * * Bet v 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

Prolifcration (SI) Time (weeks) Time (weeks) * * * * Mal d 1 Tetanus toxoid 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

Fold increase of mRNA IL-4 IFN-  * 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: P <.05

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