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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 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 Best Banting •24,400 in 2020 •Incidence to double in children <5 years…” •No known cure or spontaneous remission Marjorie Background I: pathology Insulin T lymphocytes (CD3) At diagnosis >80% of islets destroyed Background II: Large genome-wide studies John Todd and Linda Wicker, Cambridge •Pinpoint variants of normal genes that are more frequent in diabetes Type 1 diabetes: immune pathogenesis DC Proinflammatory cytokines 3. Via blood THelper α TCytotoxic β cells HLA II THelper TCytotoxic CTL DC 1. Islet HLA I Epitope discovery DC Insulin 2. Pancreatic lymph node Type 1 diabetes: immune pathogenesis DC Proinflammatory cytokines 3. Via blood THelper α TCytotoxic β cells HLA II TCytotoxic CTL DC 1. Islet HLA I THelper GENE SET 1: Ag presentation to T cells Epitope discovery DC Insulin 2. Pancreatic lymph node Type 1 diabetes: immune pathogenesis Antiinflammatory cytokines DC IL-10 3. Via blood TH TRegulatory α TCytotoxic β cells HLA II TCytotoxic CTL DC 1. Islet HLA I DC Insulin 2. Pancreatic lymph node THelper GENE SET 2: Immune regulation Type 1 diabetes: immune pathogenesis GENE SET 3: Pathogen susceptibility DC IL-10 3. Via blood TH TRegulatory α TCytotoxic β cells HLA II TCytotoxic CTL DC 1. Islet HLA I DC Insulin 2. Pancreatic lymph node THelper Type 1 diabetes: immune pathogenesis GENE SET 3: Pathogen susceptibility DC IL-10 3. Via blood TH TR α TCytotoxic β cells HLA II TCytotoxic CTL DC 1. Islet HLA I THelper GENE SET 2: Immune regulation GENE SET 1: Ag presentation to T cells DC Insulin 2. Pancreatic lymph node GENE SET 1: Ag presentation to T cells Epitope discovery β cell TCytotoxic DC 30 % Specific lysis HLA HLA-A2+ human islets with 1E6 clone 20 Tcytotoxic cells targeting insulin kill human β-cells. 10 A2+ islets/control clone A2- islets/1E6 clone 0 1 3 6 12 25 Number of Effectors per Target Are these cells in the islets where β-cells are killed? In situ staining for antigenspecific T cells Insulinspecific T cells Coppieters et al, JEM, 2012 GENE SET 1: Ag presentation to T cells Crystal β cell TCytotoxic DC A2+ human islets with 1E6 clone % Specific lysis 30 20 Tcytotoxic cells targeting insulin kill human β-cells. 10 A2+ islets/control clone A2- islets/1E6 clone 0 1 3 6 12 25 Number of Effectors per Target How does this interaction look at the molecular level? CTL β cell Dissociation constant Kd ~250μM (ie ultra-low vs tumour antigens (~50 μM) or virus (~5 μM)) In press Killer T cell α-chain 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 β-chain TcR insulin peptide HLA-A2 (*0201) β-cell •Bulek et al, Nat Imm 2012 •Major opportunities for cross-reactivity •The antigenic peptide that primed killer T cells may not be from insulin originally GENE SET 2: Immune regulation GENE SET 2: Immune regulation 7.5y No IL-10 response IL-10 response Balance of islet-specific TH cells in peripheral blood in Type 1 diabetes is abnormal •Candidate genes: CD25, CTLA4, IL-10 GENE SET 3: Pathogen susceptibility GENE SET 3: Pathogen susceptibility Candidate genes: IFIH1 EBI2 TLR7/TLR8 BACH2 FUT2 Sense pathogens: Set “response rheostat” 3. Via blood α TCytotoxic β cells HLA II TCytotoxic CTL DC 1. Islet HLA I DC Insulin 2. Pancreatic lymph node THelper Type 1 diabetes: the model GENE SET 3: Pathogen susceptibility DC IL-10 3. Via blood TH TR α TCytotoxic β cells THelper HLA II GENE SET 2: Immune regulation TCytotoxic CTL DC 1. Islet HLA I DC Insulin 2. Pancreatic lymph node B GENE SET 1: Ag presentation to T cells Islet cell AAbs 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 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 Figure 1 Benefit IL-10 TR Proinsulin peptide immunotherapy •Monthly i.d. injections of proinsulin peptide x 3; •10, 100 and 1000μg per dose 5 IL-10 (SI) 4 3 * ** 2 5µM 10µM •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 1 0 0 3 6 0 3 6 month of study 10g placebo •No pro-inflammatory cytokine induction •Improved glycaemic control Phase Ib (New T1D) Monthly Peptide administration Bi-weekly 0 3 Month of study Developmental programme (Phase I in 2014) •Multiple peptides from >1 β-cell antigen 6 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 Funders and collaborators •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: Naimit