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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”

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

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  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 dosei.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:

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