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TYPE 1 DIABETES MELLITUS • increasing incidence [+ 3-4%/year] up to 50/105/year, earlier age at onset • multifactorial, polygenic disease • islet of Langerhans • b cell 1 autoantibody • islet cell autoantibodies anti-GAD anti-IA2 anti-insulin • prediabetes 2 autoantibodies 3 autoantibodies Kulmala et al.&1998, J Clin Invest Bottazzo Doniach 1974, Lancet MAIN ADVANCES 2003-2006 1- prediction autoantibodies genetic puzzle 2- proinsulin: the primary autoantigen 3- the importance of immune regulation 4- immunotherapy: the end of immunosuppression 5- the goal: b cell restoration + induction of immune tolerance STRATIFICATION OF RISK anti-IA2 & anti-insulin IgG2/IgG3/IgG4 anti-IA2b & IA2 multiepitopes anti-IA2 & anti-insulin autoantibody titers Achenbach et al, Diabetes, 2006 AUTOANTIBODY DETECTION: LIMITS POSITIVITY THRESHOLD % individuals predictive positive value in atypical forms of type 1 delay to diabetes onset in prediabetes other assays ? 0 50 90 95 97 99 autoantibody titer (percentiles) ANTIGEN RECOGNITION BY T CELLS TCD3 TCD3 CYTOKINES T cell receptor MHC class II CD8+ T CELL RESPONSE [ELISPOT assay] Patient A2/A3 B18/B38 34-42 tetramet 200,00 180,00 nb spots/106 cells 160,00 140,00 120,00 100,00 60,00 40,00 20,00 Toma et al. PNAS, 2005 Pha Seules Mat A2 A2 HIV 45-53 44-51 42-51 41-50 38-46 34-42 0,00 34-42 tetramet 80,00 CD8 Pinske et al. PNAS, 2005 MAIN ADVANCES 2003-2006 1- prediction autoantibodies genetic puzzle 2- proinsulin: the primary autoantigen 3- the importance of immune regulation 4- immunotherapy: the end of immunosuppression 5- the goal: b cell restoration + induction of immune tolerance ROLE OF PROINSULIN IN TYPE 1 DIABETES PROINS 2-/-NOD MICE acceleration of diabetes anti-insulin Abs ~ anti-GAD Abs ~ sialitis PROINS 1-/-NOD MICE: Ins1-/- absence of diabetes Moriyama H et et al. Proc Natl Acad Sci USA 2003 Thebault-Baumont, Tardivel et al. 2003, 2005 AUTOANTIBODY IN OFFSPRING OF DIABETIC PARENTS anti-insulin autoantibodies Ziegler et al, Diabetes, 1999 MAIN ADVANCES 2003-2006 1- prediction autoantibodies genetic puzzle 2- proinsulin: the primary autoantigen 3- the importance of immune regulation 4- immunotherapy: the end of immunosuppression 5- the goal: b cell restoration + induction of immune tolerance IMMUNE REGULATION IN TYPE 1 DIABETES T CD4+ CD62L+ T CD4+ CD25+ Th2 Th3 IL-4,5 IL-10 REGULATORY REGULATORY CELLS CELLS - Th3 T NK T CD8+ T CD4+ Th1 TGFb ISLET INFa TLRs EFFECTOR T CELL EFFECTOR T CELL b CELL cytokines 10 1 10 0 CD25 10 2 DETECTION EXPANSION IN small size HUMAN 10 0 10 1 CD4 10 2 NOD FoxP3 GITR number ? CTLA4 function ? protection Krukeja et al. 2002, J Clin Invest Tang Q et al. 2004, J Exp Med Lindley etal.al.Nat 2005, Diabetes Shimon Sakaguchi 1995 Kretschmer KSet Immunol 2005 MAIN ADVANCES 2003-2006 1- prediction autoantibodies genetic puzzle 2- proinsulin: the primary autoantigen 3- the importance of immune regulation 4- immunotherapy: the end of immunosuppression 5- the goal: b cell restoration + induction of immune tolerance TREATMENT OF DIABETES WITH ANTI-CD3 months months months n = 40 (placebo) n = 40 (anti-CD3) Keymeulen B et al. 2005, N Engl J Med MAIN ADVANCES 2003-2006 1- prediction autoantibodies genetic puzzle 2- proinsulin: the primary autoantigen 3- the importance of immune regulation 4- immunotherapy: the end of immunosuppression 5- the goal: b cell restoration + induction of immune tolerance GENERATION OF NEW BETA CELLS transdifferenciation from ductal cells acinar cells hepatic precursor cells [through a dedifferenciation stage] differenciation from embryonic adult stem cells embryonic stem cells DIFFERENCIATION OF b CELLS FROM ES CELLS definitive endoderm primitive gut tube posterior foregut pancreatic endoderm insulin cells D’Amour et al. Nat Biotechnol, 2006 C-PEPTIDE DIFFERENCIATION OF b CELLS FROM ES CELLS ESC-DERIVED CELLS HUMAN ISLETS D’Amour et al. 2006, Nart Biotech