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Prevention Of Type 1 Diabetes Mellitus: Current Status And Future Directions

Prevention Of Type 1 Diabetes Mellitus: Current Status And Future Directions. ITAMAR RAZ. Hadassah University Hospital Jerusalem Israel. Foreward on Type 1A Diabetes Mellitus …. A chronic progressive autoimmune disease

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Prevention Of Type 1 Diabetes Mellitus: Current Status And Future Directions

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  1. Prevention Of Type 1 Diabetes Mellitus:Current Status And Future Directions ITAMAR RAZ Hadassah University HospitalJerusalem Israel

  2. Foreward on Type 1A Diabetes Mellitus … • A chronic progressive autoimmune disease • Inflammatory response targeted specifically at beta cells in the islets of Langerhans

  3. Preventing the Progression of Diabetes in Its Early Stages = Interfering with the autoimmune disease

  4. Stages in Development of Type 1 Diabetes GENETICALLY AT RISK MULTIPLE ANTIBODY POSITIVE LOSS OF FIRST PHASE INSULIN RESPONSE BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES TIME NEWLY DIAGNOSED DIABETES Modified from G. Eisenbarth, NEJM, 1986

  5. Initial Trials… • Prednisone • Prednisone with Azathioprine • Anti Thymocyte Globulin • Cyclosporine A FAILED Elliot et alSchernthaner et alBougneres et al

  6. Treatment of Autoimmune Diabetes: Rationale • Autoimmune diabetes results from destruction of the insulin-producing pancreatic beta-cells. • Beta-cell destruction is mediated by cellular immunity. • Autoimmune diabetes can be stopped by immunological intervention (NOD mice, BB rats, Cys-a clinical studies) • The immunological intervention should be: • Effective • Safe • Disease-specific

  7. AUTOANTIGEN T CELL INNATE SYSTEM VACCINATION MODULATORY MODULATION APPROACH a Galactosylceramide Insulin Cyclosporin A GAD Peptide 277 ( Diapep 277 ) Prednisone Diapep 277 NKT Azathioprine Cytokines (IL - 4 , IL - 10 ) a galactosy Anti CD 3 Ab l - ceramide Peptide MHC dimers Diapep 277 p 277 p 277 Anti - CD 3 Ab p 277 TLR - 2 Al T Al GAD GAD APC GAD vaccine MHC dimers TCR GAD Pro - inflammatory TLR - 2 effect T Anti - inflammatory effect b Insulin Immune TCR Insulin modulatory agent B 9 - 23

  8. Immune Modulation in Type 1 Diabetes More questions than answers…

  9. Proliferative T-cell Responses 100 10 Stimulation index (log) 1 Age of mice (weeks)

  10. The Search for the Autoantigen... • Gad? • Heat shock protein 60 (HSP60)? • Insulin B9-23 peptide ?

  11. DPT-1 - Kaplan-Meier Curves according to Treatment-Group Assignment NEJM 346:1685, 2002

  12. Diabetes Prevention Trial-type 1(CONT) • CONCLUSION: IN PERSONS AT HIGH RISK, INSULIN AT THE DOSES AND DELIVERY USED IN THIS TRIAL DOES NOT DELAY OR PREVENT TYPE1 DIABETES.

  13. Insulin B9-23 • Diabetes Prevention Trial-11 • Sub cutaneous Insulin B chain peptide B:9-232(in NOD mice) • vaccination with DNA encoding peptide B:9-233(in NOD mice) 1. Pozzilli et al2. Liu et al; Ramiya et al3. Urbanek-Ruiz et al

  14. Glutamic Acid decarboxylase • reduction of severity of insulitis and prevention of onset of diabetes in NOD mice was achieved with: • Injection of GAD651 • Injection of GAD 67 (isoform) 2 • Anti GAD monoclonal antibodies 3 • GAD-plasmid DNA/DNA vaccine/GAD antisense4 • A Vaccinia virus expressing GAD5 • GAD derived peptides6 1. Ramiya et al; Pleau et al; Petersen et al; Tisch et al 2. Elliott et al3. Menard et al4. Yoon et al;Balasa et al; Li et al5. Jun et al6. Tisch et al;Sai et al

  15. Transgenic plants expressing autoantigens fed to mice to induce oral immune tolerance. “a GAD-expressing transgenic plant, given as a dietary supplement, inhibits the development of diabetes in the NOD mouse…” Ma et al. Nat Med. 1997

  16. Low dose linomide in Type I juvenile diabetes of recent onset: a randomised placebo-controlled double blind trial. • 42 patients with recent onset diabetes received low dose Linomide for a year. • After 1 year • HbA1C was significantly lower • Insulin requierments where significantly lower • A higher C peptide value after 6 months (in patients with residual C peptide at trial entry) Coutant R Saint-Vincent-de-Paul Hospital, Paris,France. Diabetologia. 1998

  17. IL-4 IL-10 IL-4 IL-10 IL-10 IL-4 TH-2 cell TH-1 cell P 277 GAD65 hOKT31 linomide An immunomodulatory effect?

  18. T cell Proliferative Responses to hsp60 P<0.01 P<0.001 Proliferation Index

  19. IFN ; TNFa hsp60 hsp60 hsp60 hsp60 hsp60 hsp60 Cell lysis Hsp60 Promotes Inflammation in b-cell Autoimmunity Th1 Stressed b-cell IL-12 GAD TNFa NO Macrophage Destruction of b-cells by autoimmune responses Autoimmunedisease Stressed b-cell insulin IL-12 CTL

  20. And to complicate things… • T cells reactive to HSP60 have been shown to be of the immunomodulatory type TH2 • T cells that recognize HSP confer immunity in rat models of arthritis and mouse models of diabetes1 1. Anderton et al; van Haltren et al; van Eden et al

  21. 60 kDa Heat Shock Protein (HSP60) HSP60 p277 Peptide p277: HSP60 positions 437-460 VLGGGVALLRVIPALDSLTPANED • Targeted by T-cells from diabetic NOD mice and Type I IDDM patients. • Vaccination with p277 arrests NOD diabetes

  22. HSP60 effects macrophages and T cells: Pro- vs Anti-inflammation HSP60 p277 macrophages endothelial cells T cells Activates pro-inflammatory cytokines and matrix metalloproteinase Up-regulates expression of adhesion molecules TLR-4 dependent signaling Activates adhesion to FN and intracellular signaling Down-regulates chemokine receptors and chemotaxis Inhibits IFNg TLR-2 dependent signaling

  23. Innate Regulation of Inflammation by HSP60 and p277

  24. Effects of p277 on p277-specific T-cells T-cell receptor p277 • Promotion of cell adhesion • Inhibition of migration • Modulation of cytokine secretion upon activation P277-specific clone P277-specific clone IL4 TLR2 IL10 Th2 IL13 Activated cells are more sensitive Long term effect

  25. DiaPep277 Immunomodulation P277 Th2 T-cell IL-4 IL-10 Th1 T-cell MF MF IFNg IL-1, NO b-cell

  26. 600 Death Death Death 400 600 600 200 400 400 Blood glucose (µmol/L) 0 10 20 30 40 200 200 0 0 10 30 20 30 20 40 40 10 Age (weeks) Treatment (arrow) of NOD mice with DiaPep277 or Control DiaPep277 treatment prevents the progression of diabetes in NOD mice

  27. Insulin Secreting Cells Preserved by Treatment with DiaPep277 The pancreata of 20 weeks old NOD mice were stained with anti-insulin antibodies (8 weeks after administration of treatment). Control Treatment

  28. None  p278 DiaPep277 Vehicle DiaPep277 reduces IFNg secretionby islet infiltrating T-lymphocytes

  29. Dosing Scheme for Studies 420 and 431

  30. Full Preservation of Endogenous Insulin Secretion in DiaPep277 Treated Patients (study 420) • Endogenous insulin secretion tested by I.V. 1mg glucagon stimulation. • AUC calculated for time points 0-20min. • Two-tailed unpaired t-test. * P<0.05 * * * *

  31. Change in Daily Insulin Dose

  32. Percentage of patients with %HbA1c < 7.5

  33. Partial Preservation in Extension Study: Need for Continuous Treatment • After a 6-18 no treatment period, patients were re-randomized • Patients on continued DiaPep277 treatment showed the least drop in beta-cell function.

  34. Change in %HbA1c

  35. Change in Daily Insulin Dose

  36. Study 441/451 • Same inclusion/exclusion criteria as in study 420 • A total of 64 patients randomized • Female patients included • Dose range: Placebo, 0.04, 0.2, 1 mg DiaPep277. • Low doses were found to be non-effective • The Placebo and 1mg DiaPep277 groups were analyzed in combination with study 420.

  37. Combined Analysis of Israeli Trials:Basal Fasting C-peptide is Significantly Preserved N=52

  38. Combined Analysis of Israeli Trials:Stimulated Endogenous Insulin Secretion is Preserved • DiaPep277-treated patients fully preserve glucagon-stimulated C-peptide secretion (AUC)

  39. Significant Difference in Beta-Cell Functionbetween DiaPep277-Treated and Placebo • The change from baseline in stimulated C-peptide AUC was significant.

  40. Combined Analysis of Adult Phase II Studies: Beta-cell Preservation in upper Thertile p=0.04 p=0.000 p=0.21 p=0.56 p=0.06 p=0.50 High responders: Patienrs with high beta-cell reserve at start of treatment

  41. Opposite Trends in Glycemic Controlof DiaPep277 and Placebo Treated Patients • Overall glycemic control in all patients was good, average Hba1c=7.5% • The trend in DiaPep277-treated patients was for reduced HbA1c, in Placebo-treated for increased HbA1c. N=54

  42. Kinetics of Th2 induced shift inDiaPep277-treated patients

  43. Change in Cytokine Profile in DiaPep277 Treated Newly Diagnosed T1D Adults

  44. Rx DiaPep277 Specific Intervention with DiaPep277TM Re-establishes Balance in the Immune System Health Diabetes + - • Treg Th2 Th1 Th2 Treg Th1

  45. Conclusions • Good safety, not differences between Treatment and Placebo in clinical laboratory parameters, adverse events. • DiaPep277 was well tolerated, most common adverse event was an injection site pain & edema that resolved within 1-2 days. • DiaPep277 treatment preserved both basal and stimulated C-peptide secretion. • DiaPep277 treated patients also showed trend for improved glycemia at similar insulin requirement.

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