1 / 18

TYPE 1 DIABETES MELLITUS

increasing incidence [ + 3-4%/year ] up to 50/10 5 /year, earlier age at onset multifactorial, polygenic disease islet of Langerhans. 1 autoantibody. 2 autoantibodies. b cell. 3 autoantibodies. islet cell autoantibodies. prediabetes.

holland
Download Presentation

TYPE 1 DIABETES MELLITUS

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. increasing incidence [+ 3-4%/year] • up to 50/105/year, earlier age at onset • multifactorial, polygenic disease • islet of Langerhans 1 autoantibody 2 autoantibodies • b cell 3 autoantibodies • islet cell autoantibodies • prediabetes Bottazzo & Doniach 1974, Lancet Kulmala et al. 1998, J Clin Invest TYPE 1 DIABETES MELLITUS • increasing incidence [+ 3-4%/year] • up to 50/105/year, earlier age at onset • multifactorial, polygenic disease anti-GAD anti-IA2 anti-insulin

  2. 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 1- prediction autoantibodies genetic puzzle

  3. 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

  4. POSITIVITY THRESHOLD % individuals 0 50 90 95 97 99 autoantibody titer (percentiles) AUTOANTIBODY DETECTION: LIMITS  predictive positive value in atypical forms of type 1  delay to diabetes onset in prediabetes  other assays ?

  5. T T CD3 CD3 CYTOKINES ANTIGEN RECOGNITION BY T CELLS T cell receptor MHC class II

  6. Patient A2/A3 B18/B38 34-42 tetramet nb spots/106 cells 34-42 tetramet CD8 Pinske et al. PNAS, 2005 CD8+ T CELL RESPONSE [ELISPOT assay] Toma et al. PNAS, 2005

  7. 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

  8. ROLE OF PROINSULIN IN TYPE 1 DIABETES • PROINS 1-/-NOD MICE: • absence of diabetes PROINS 2-/-NOD MICE acceleration of diabetes  anti-insulin Abs ~ anti-GAD Abs ~ sialitis Ins1-/- Moriyama H et et al. Proc Natl Acad Sci USA 2003 Thebault-Baumont, Tardivel et al. 2003, 2005

  9. AUTOANTIBODY IN OFFSPRING OF DIABETIC PARENTS anti-insulin autoantibodies Ziegler et al, Diabetes, 1999

  10. 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

  11. IMMUNE REGULATION IN TYPE 1 DIABETES EFFECTOR T CELL REGULATORY CELLS EFFECTOR T CELL REGULATORY CELLS T CD4+ CD25+ T CD4+ CD62L+ T CD8+ Th2 IL-4,5 Th3 IL-10 b CELL - Th3 TGFb T CD4+ Th1 cytokines T NK ISLET INFa TLRs

  12. DETECTION IN HUMAN EXPANSION NOD • number ? • function ? protection Krukeja et al. 2002, J Clin Invest Tang Q et al. 2004, J Exp Med Kretschmer K et al. Nat Immunol 2005 Lindley S et al. 2005, Diabetes 10 2 small size CD25 FoxP3 GITR CTLA4 10 1 10 0 10 1 10 0 10 2 CD4 Shimon Sakaguchi 1995

  13. 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

  14. 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

  15. 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

  16. 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

  17. DIFFERENCIATION OF b CELLS FROM ES CELLS pancreatic endoderm primitive gut tube insulin cells definitive endoderm posterior foregut D’Amour et al. Nat Biotechnol, 2006

  18. DIFFERENCIATION OF b CELLS FROM ES CELLS C-PEPTIDE HUMAN ISLETS ESC-DERIVED CELLS D’Amour et al. 2006, Nart Biotech

More Related