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Immunopathogenesis of Type 1 Diabetes: Approaches to Prevention and Cure

Immunopathogenesis of Type 1 Diabetes: Approaches to Prevention and Cure. Peter A. Gottlieb, MD George S. Eisenbarth, MD, PhD Jay Skyler, MD + Barbara Davis Center University of Colorado Health Sciences Center + Diabetes Research Institute University of Miami Medical School.

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Immunopathogenesis of Type 1 Diabetes: Approaches to Prevention and Cure

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  1. Immunopathogenesis of Type 1 Diabetes:Approaches to Prevention and Cure Peter A. Gottlieb, MD George S. Eisenbarth, MD, PhD Jay Skyler, MD+ Barbara Davis Center University of Colorado Health Sciences Center +Diabetes Research Institute University of Miami Medical School

  2. Magnitude of Diabetes Worldwide USA • Approximately 6% are diagnosed (90%Type2) • All with Type 1 and 1/3 of Type 2 will require insulin (Expected to Rise significantly) • Cost $100-$140 billion annually Diabetes in Rest of the World • 2 - 25% in different Countries (average 10%) • Incidence rising every year everywhere, especially for Type 2 Diabetes • Disease is still under-diagnosed and delayed in diagnosis • Prevention of pre- type 1 and type 2 diabetes

  3. Incidence Type 1 Diabetesper 100,000 per year Children <=14 Karvonnen et al., Diabetes Care, 23:1516, 2000

  4. Type 1 DM incidence is rising 3-5% /year 1.4 million patients in the U.S. Incidence /100,000/ yr children age 0-14 Rewers

  5. Finland Incidence Type 1 DM/100K 1965-1996 Diabetes Care: 22:1066-1070

  6. Main Points • Type 1 diabetes is an autoimmune disease • It is a predictable disease with different phases • Approaches to prevention and cure are possible. • Combination therapy targeting multiple pathways may hold the greatest hope for prevention and cure.

  7. Progression to Diabetes vs Number of Autoantibodies (GAD, ICA512, Insulin) Percent not Diabetic Years of Follow-up 3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 1 1 Abs n = 93 23 14 10 6 4 Verge et al, Diabetes 45:926-933, 1996 BDC

  8. DQB1*0402  -chain Leu56 -chain Asp57 BDC

  9. HLA-Defined T1 DM Risk GroupsDAISY, Denver Population, n=21,713

  10. Different haplotypes are associated with T1D in Japanese and Caucasian populations Japanese Caucasian DRB1-DQB1Type 1 diabetes HF1)Type 1 diabetes HF haplotypesusceptibilitysusceptibility DRB1*0405-DQB1*0401 susceptible presentunknown rare DRB1*0901-DQB1*0303 susceptible presentunknown rare DRB1*0301-DQB1*0201 unknown rare susceptible present DRB1*0401-DQB1*0302 unknown rare susceptible present DRB1*1501-DQB1*0602protective present protective present • HF: Haplotype frequency, http://square.umin.ac.jp/JSHI/frame.html

  11. 100 80 60 % 40 20 0 I/I I/III III/III IDDM Controls VNTR Class IDDM2 Genotypes in U.S. Caucasians Pugliese et al., J. Autoimm 7: 687- 694, 1994

  12. VNTR alleles affect INS transcription in thymus Thymus INS Transcription cDNA cDNA DNA DNA Predisposing Class I VNTR Protective Class III VNTR Class I VNTR Pancreas INS Transcription Class III VNTR Pugliese et al. Nature Genetics 15:293-297, 1997 Predisposing Class I VNTR Protective Class III VNTR

  13. No Evidence: IDDM 4,6,9,11,16,17,18 (O.R. MHC, DR3/4-DQ8) Adapted from Concannon et al, Diabetes: 54:2995-3001, 2005 BDC

  14. Proportion of Twins Without Diagnosis of DM 1.0 0.8 0.6 0.4 0.2 0.0 0 10 20 30 40 50 6 and younger n= 38 7-10 n= 33 11-14 n= 42 15-24 n= 37 25 and older n= 37 Difference significant (log-rank and gen'ld wilcoxon p= 0.001 , 0.001 ) Years Since DM Diagnosis in Index Twin Redondo, Diabetologia

  15. Type 1a Diabetes: An Autoimmune Disorder • Autoantibodies to islet proteins: insulin, GAD 65, IA-2 (ICA512) • T cell responses to islet proteins • HLA association • Immunosuppressive drugs can ameliorate the disorder – ex. Cyclosporine • Recurrence of autoimmunity in pancreas transplants between monozygotic twins

  16. Autoreactivity: CD4 and CD8 T cell responses

  17. Prediabetic T cell responses to CD4 epitopes from IA-2b Keleman, Gottlieb et al. 2004. Journal of Immunology.15;172(6):3955-62.

  18. Cytotoxic T-cells from HLA-A*0201 patients with T1D recognize preproIAPP 5-13 ELISPOT analysis of peripheral blood mononuclear responses to preproIAPP5-13 in patients with the correct HLA to recognize the peptide. Diabetes 2003 52:2649

  19. T cell reactivity to CD8 Epitopes from T1D subjects Ouyang, et al, submitted

  20. Natural History of Type 1 Diabetes PUTATIVE ENVIRONMENTAL TRIGGER HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD65, IA2Ab, etc.) BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY CLINICAL ONSET “PRE”-DIABETES DIABETES TIME CELLULAR (T CELL) AUTOIMMUNITY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GLUCOSE INTOLERANCE (OGTT)

  21. Stochastic Model Non Specific Tx Antigen Specific Tx Immunosuppresive Tx

  22. PREVENTION

  23. Primary Prevention • autoantibodies or diabetes as the endpoint • avoidance of environmental agents ? • induction of autoantigen tolerance ? Rewers-BDC

  24. Early childhood dietand T1 DM ?

  25. TRIGR 3-yr Follow-up Results Seroconversion to 1+ Autoantibody p=0.043 n=173

  26. NutritionalInterventiontoPrevent • Type 1 Diabetes (NIP– Diabetes) • Plan:Use of an omega 3 fatty acid (Docosahexanoic acid or DHA) to preventthe initial autoimmune process. • DHA supplementation will begin in: • the last trimester of pregnancy • the first 6 months after birth • It will be continued in medium or high risk infants for 3 years.

  27. Dietary Intake – Western Diets The Ratio of n-6 to n-3 Fatty Acids in our diet: 1800’s = 1 or 2 (n-6) to 1 (n-3) Present = 20 or 30 (n-6) to 1 (n-3) High n-3: anti-inflammatory anti-thrombotic hypolipidemic vasodilatory (High n-6 has the opposite effect) (Am J. Clin Nutr. 70, 560-569, 1999)

  28. III) Mechanisms of Action of Omega 3 Fatty Acids • Decrease AA in cell membranes  alters PGE 1 and 2 production (inflammatory prostaglandins) • Decrease pro-inflammatory cytokines TNF, IL-1 and IL6 ( efficacy of IL4 and IL10) • Decrease ICAM-1 on monocyte surfaces in humans fed 3g fish oil/dx 21 days ( chronic inflammation) • DHA and /or vit D may haveimportant immune modulating effects in babies at risk for developing T1DM

  29. ENDIT: Kaplan-Meier failure curve - European Nicotinamide Diabetes Intervention Trial (ENDIT) Group Lancet 2004; 363: 925–31

  30. Ongoing or Completed Prevention Trials • TRIGR - Casein Hydrolysate - ongoing (Cow’s Milk Elimination) • NIP - Nutritional Intervention to Prevent T1DM – Starting June, 2006 • DIPP - Nasal Insulin - ongoing • INIT - IntraNasal Insulin Trial • ENDIT - Nicotinamide - Ineffective • DPT-1 - Oral Insulin – May be effective in subgroup - Parenteral - Ineffective • Anti-CD3 and Exanitide- proposed Early stage Late stage

  31. Antigen Specific Therapy • Magic bullet Approach • Targets autoreactive cells • Generates protective cells • Spares rest of immune system • Minimal Toxicity • Timing may be critical to efficacy

  32. Insulin • Beta Cell Specific • Predominant T-cell reactivity islets NOD • Insulin expressed lymphoid tissue by dendritic and macrophage-like cells • Thymic messenger RNA for insulin related to “protective” insulin allele • Proinsulin expression in thymus prevents NOD diabetes

  33. Effect of Insulin Injections on Diabetes & Insulitis Female NOD Mice Atkinson, Diabetes 1991

  34. Prevention of Diabetes with B:9-23 Peptide “Immunization” 100 B:9-23 peptide 80 Tetanus control 60 Percent Not Diabetic 40 20 0 0 10 20 30 40 50 60 Age in Weeks D.Daniel ,D.Wegmann . PNAS,1996

  35. Efficacy of NBI-6024 in animal models with ‘new onset’ Type I diabetes. Figure 3. NBI-6024 Treatment of NOD mice Near Onset of Disease Alleva, et al, Diabetes 2002

  36. APL-specific Th2 cell line transfer NBI-6024-specific Th2 cells adoptively transferred protection in NOD mice Figure 4. From Alleva, et al. Diabetes. 2002 51(7):2126-34.

  37. Mouse BHT-3021 provides significant delayof diabetes onset in hyperglycemic mice at all dosing frequencies BHT-3021 QW BHT-3021 Q2W BHT-3021 Q4W

  38. Treatment of hyperglycemic mice with mouse BHT-3021 restores normoglycemia

  39. DPT-1 Parenteral Study – Time to Diabetes By Treatment 1.0 0.9 0.8 0.7 0.6 Treated Survival Distribution Function 0.5 0.4 Control 0.3 P- Value= 0.796 (Log Rank Test) 0.2 Number at Risk 0.1 169 170 144 131 96 101 69 69 39 40 13 14 Intervention Observation 1 0.0 0 1 2 3 4 5 6 7 Years Followed Observation Intervention STRATA: New Engl J Med 2002; 346:1679

  40. TH1 Cells TH2 Cells TH3 Cells IFN-g, IL-2 IL-4, IL-5, IL-10 TGF-b Protective Cytokines Destructive Cytokines Rationale for Oral Insulin

  41. Oral Antigen Protocol • Initial results appeared to suggest no effect of oral insulin • Secondary analysis suggests that for original cohort (IAA>80) there is delay in onset compared to placebo treated patients. • In fact, the higher the titer of IAA, the greater the protective effect that was observed. • A new trial to confirm these observations is being planned by TrialNet (Start Date – Nov, 2006)

  42. Recent and Ongoing Antigen-specific Immunotherapy Trials in T1DM Prediabetes • Joslin Parenteral Insulin: “Delay” • Schwabing Parenteral Insulin: “Delay” • DPT-1 Parenteral: No Effect • DIPP (intranasal): ? • Melbourne (intranasal): ? • DPT-1 Oral Insulin: Possible for subgroup • Italy/France Oral Insulin: No Effect • Maclaren Oral Insulin: ? • NBI 6024-0003 (Neurocrine) – Phase II Spring, 2007 • B chain – Orban, Joslin - Phase I ? • hGAD s.c. in alum (Diamyd) 20ug dose only • Peptor Heat Shock Protein ? • Proinsulin DNA vaccine (Bayhill) Fall, 2006 New Onset

  43. Secondary Prevention • Goal - induction of diabetes remission and preservation of C-peptide • non-antigen-specific interventions • antigen specific interventions

  44. EDIC: Long Term Benefit of Intensive Treatment • The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions • and Complications Research Group. N Engl J Med 2000;342:381-9.

  45. EDIC: Long Term Benefit of Intensive Treatment • The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions • and Complications Research Group. N Engl J Med 2000;342:381-9.

  46. b-Cell Function and Complications in theDiabetes Control and Complications Trial - Steffes MW, et al. Diabetes Care 26:832–836, 2003

  47. b-Cell Function and Hypoglycemia in theDiabetes Control and Complications Trial - Steffes MW, et al. Diabetes Care 26:832–836, 2003

  48. Cellular Mechanics of Autoimmune Type 1 Diabetes Regenerative Therapies Cellular Therapy MMF DZB Anti-CD3 ATG Target b NK b b Tc1 CD4CD25 b Effector Cells b b b B MO Tr1 Rituximab Th1 Th2 Regulatory Cells Th3 Insulin GAD IGRP HSP60 NKT

  49. Lack of Effect of BCG Vaccination in New Onset T1D subjects Fasting C-Peptide Stimulated C-Peptide Age < 12 >=12 Adapted from Allen, et al, Diabetes Care 1999, 22:1703-07

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