1 / 27

Who gets the autoimmune disease Type 1 diabetes, and why?

Who gets the autoimmune disease Type 1 diabetes, and why?. Mark Peakman King’s College London. 35 years of Type 1 diabetes immunology research – an autoimmune disease model emerges How genes and environment may come together in the “perfect storm”

afra
Download Presentation

Who gets the autoimmune disease Type 1 diabetes, and why?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Who gets the autoimmune disease Type 1 diabetes, and why? Mark Peakman King’s College London • 35 years of Type 1 diabetes immunology research – an autoimmune disease model emerges • How genes and environment may come together in the “perfect storm” • Devising new immunological approaches for translation into therapies

  2. Type 1 diabetes • Type 1 diabetes 1921; universally fatal; discovery of insulin • Diabetic complications (renal failure, blindness, early cardiovascular disease) due to chronic hyperglycaemia • Diabetes costs NHS ~£8-10 billion (Type 1 diabetes £2-5b) 1922 • “Western Europe: • 15,000 new cases in 2005 • 24,400 in 2020 • Incidence to double in children <5 years…” • No known cure or spontaneous remission Best Banting Marjorie

  3. Background I: pathology Insulin T lymphocytes (CD3) At diagnosis >80% of islets destroyed

  4. Background II: Large genome-wide studies John Todd and Linda Wicker, Cambridge • Pinpoint variants of normal genes that are more frequent in diabetes

  5. Type 1 diabetes: immune pathogenesis DC DC Pro-inflammatory cytokines 3. Via blood α HLA II β cells TCytotoxic CTL 1. Islet DC HLA I THelper THelper Epitope discovery 2. Pancreatic lymph node Insulin TCytotoxic

  6. Type 1 diabetes: immune pathogenesis DC DC Pro-inflammatory cytokines 3. Via blood α HLA II β cells TCytotoxic CTL GENE SET 1: Ag presentation to T cells 1. Islet DC HLA I THelper THelper Epitope discovery 2. Pancreatic lymph node Insulin TCytotoxic

  7. Type 1 diabetes: immune pathogenesis DC DC Anti-inflammatory cytokines IL-10 3. Via blood α HLA II β cells TCytotoxic GENE SET 2: Immune regulation CTL 1. Islet DC HLA I TRegulatory THelper TH 2. Pancreatic lymph node Insulin TCytotoxic

  8. Type 1 diabetes: immune pathogenesis DC DC GENE SET 3: Pathogen susceptibility IL-10 3. Via blood α HLA II β cells TCytotoxic CTL 1. Islet DC HLA I TRegulatory THelper TH 2. Pancreatic lymph node Insulin TCytotoxic

  9. Type 1 diabetes: immune pathogenesis DC DC GENE SET 3: Pathogen susceptibility IL-10 3. Via blood α HLA II GENE SET 2: Immune regulation β cells TCytotoxic CTL 1. Islet DC HLA I THelper TR TH GENE SET 1: Ag presentation to T cells 2. Pancreatic lymph node Insulin TCytotoxic

  10. GENE SET 1: Ag presentation to T cells Epitope discovery βcell TCytotoxic HLA HLA-A2+ human islets with 1E6 clone Tcytotoxic cells targeting insulin kill human β-cells. Are these cells in the islets where β-cells are killed? DC A2+ islets/control clone A2- islets/1E6 clone

  11. In situ staining for antigen-specific T cells Insulin- specific T cells Coppieters et al, JEM, 2012

  12. GENE SET 1: Ag presentation to T cells Crystal βcell TCytotoxic A2+ human islets with 1E6 clone Tcytotoxic cells targeting insulin kill human β-cells. How does this interaction look at the molecular level? DC A2+ islets/control clone A2- islets/1E6 clone

  13. Dissociation constant Kd ~250μM (ie ultra-low vs tumour antigens (~50 μM) or virus (~5 μM)) βcell CTL In press

  14. Killer T cell • Unique features of insulin-specific TCR: • Weakest binding affinity to a natural agonist antigen ever described • highly peptide-centric binding dominated by hotspots focused on just two amino acids in the peptide α-chain β-chain TcR insulin peptide HLA-A2 (*0201) β-cell • Bulek et al, Nat Imm 2012

  15. Major opportunities for cross-reactivity • The antigenic peptide that primed killer T cells may not be from insulin originally

  16. GENE SET 2: Immune regulation

  17. GENE SET 2: Immune regulation 7.5y • Balance of islet-specific TH cells in peripheral blood in Type 1 diabetes is abnormal • Candidate genes: CD25, CTLA4, IL-10 No IL-10 response IL-10 response

  18. GENE SET 3: Pathogen susceptibility

  19. GENE SET 3: Pathogen susceptibility Candidate genes: IFIH1 EBI2 TLR7/TLR8 BACH2 FUT2 DC Sense pathogens: Set “response rheostat” 3. Via blood α HLA II β cells TCytotoxic CTL DC 1. Islet HLA I THelper 2. Pancreatic lymph node TCytotoxic Insulin

  20. Type 1 diabetes: the model DC DC GENE SET 3: Pathogen susceptibility IL-10 3. Via blood α HLA II GENE SET 2: Immune regulation β cells TCytotoxic CTL 1. Islet DC HLA I THelper TR TH GENE SET 1: Ag presentation to T cells B 2. Pancreatic lymph node Insulin TCytotoxic Islet cell AAbs

  21. Therapeutic options in T1D: “immune suppression” • Anti-CD3, transient depletion of T cells • Rituximab, anti-CD20, depletes B cells • Abatacept, CTLA4-Ig, co-stimulation blockade

  22. Emergence of the concept of Antigen Specific Immunotherapy (ASI) for autoimmune disease “The administration of auto-antigen in a form or by a route designed to induce or re-establish tolerance to the same antigen or to the target tissues of the autoimmune response” Lead disease setting: clinical allergy (multiple sclerosis) Inject whole proteins or peptides from allergens Good, sustained clinical efficacy 24/11/11

  23. Figure 1 Benefit IL-10 TR

  24. 5µM 10µM Proinsulin peptide immunotherapy • Monthly i.d. injections of proinsulin peptide x 3; • 10, 100 and 1000μg per dose • Induction of IL-10 response to proinsulin peptide C19-A3 after low dose i.d administration in T1D patients • No autoantibody increase or induction; no anti-peptide antibodies • No pro-inflammatory cytokine induction • Improved glycaemic control 5 ** * 4 3 IL-10 (SI) 2 1 0 0 3 6 0 3 6 month of study 10g placebo

  25. Phase Ib (New T1D) Monthly Peptide administration Bi-weekly 0 3 6 Month of study Developmental programme (Phase I in 2014) • Multiple peptides from >1 β-cell antigen

  26. Who gets the autoimmune disease Type 1 diabetes, and why? • 35 years of Type 1 diabetes immunology research – an autoimmune disease model emerges • Genes and environment come together in the “perfect storm” • New immunological approaches for translation into therapies are emerging: an exciting decade ahead

  27. Funders and collaborators Naimit • Department of Immunobiology at KCL • Clinical collaborators, Guy’s and St Thomas’ NHS Foundation Trust & King’s College Hospital • Cardiff University (Colin Dayan); Cambridge University (Catherine Guy, David Dunger, Linda Wicker, John Todd); University of Bristol (Polly Bingley) • Funding agencies:

More Related