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Immune Modulation for Prevention of Type 1 Diabetes

Immune Modulation for Prevention of Type 1 Diabetes. Peter A. Gottlieb, MD Barbara Davis Center University of Colorado Health Sciences Center Denver, CO. Main Points. Type 1 diabetes is an autoimmune disease It is a predictable disease with different phases

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Immune Modulation for Prevention of Type 1 Diabetes

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  1. Immune Modulation for Prevention of Type 1 Diabetes Peter A. Gottlieb, MD Barbara Davis Center University of Colorado Health Sciences Center Denver, CO

  2. Main Points • Type 1 diabetes is an autoimmune disease • It is a predictable disease with different phases • Approaches to prevention and cure are possible. • New insulins, medications and devices will improve therapy in the coming decade.

  3. Cellular Mechanics of Autoimmune Type 1 Diabetes Target b NK b b Tc1 CD4CD25 b Effector Cells b b b B MO Tr1 Th1 Th2 Th3 Regulatory Cells NKT

  4. 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

  5. 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

  6. Prevention of Type 1 diabetesPrimary: 1autoimmunity 1b-cell loss 1clinical diabetes Complications Tertiary 1c 1b Clinical diabetes Autoimmunity -cell loss 1a Secondary Genetic susceptibility Clinical remission No autoimmunity ?

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

  8. 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.

  9. 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.

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

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

  12. Past Trials in New Onset Type 1 DM • Cyclosporine A - no lasting effect • Imuran - no lasting effect • Corticosteroids - no lasting effect • Plasmapheresis - no lasting effect • BCG (Denver) - no effect • Nicotinamide (DENIS) - no effect (At risk) • Gluten-free diet (Italy) - no effect • Q fever vaccine s.c. - no effect • Nicotinamide and Vitamin E - no effect

  13. Metabolic Effects of AZA and Prednisone at 1 year in New Onset T1DM - Silverstein, et al. NEJM 1988, 319:599-604

  14. Accelerated Loss of C-Peptide with BCG Vaccination at Onset Fasting C-Peptide Stimulated C-Peptide Age < 12 >=12 Adapted from Allen, et al, Diabetes Care 1999, 22:1703-07

  15. MMF and DZB - Peter Gottlieb, TrialNet Multidose anti-CD3 hOKT3 - Kevan Herold, NY; Lucienne Chatenoud, France HSP 65 p277 s.c. - (Peptor) – Jerry Palmer, Seattle Multi-dose DZB - Henry Rodriguez, Indiana Exanitide and Rapamycin – David Harlan, NIH Oral hIFN-alpha - Staley Brod, Texas Anti-CD20 – Mark Peskovitz, Indiana, TrialNet ATG (Sandostat) – Steve Gitelman, UCSF, ITN, TrialNet Rapamycin and IL-2, Alex Rabinovitch, Canada Fish oil - A-G Ziegler, Germany Diazoxide - E Bjork+A Karlsson, Sweden Lisofylline i.v. - S Kirk, Virginia Vitamin E+nicotinamide - P Pozzilli, Italy Ongoing and Proposed Non-antigen Specific Immunotherapy Trials in New Onset Type 1 DM

  16. The Barbara Davis Center Indiana University Stanford University University of Florida University of Minnesota Virginia Mason (Washington) Joslin Diabetes Center Columbia University UCSF Children’s Hospital of Los Angeles Toronto, Canada Milan, Italy and Munich, Germany Preservation of Pancreatic Production of Insulin (POPPI) Participating Centers Existing Centers New Centers

  17. Preservation of Pancreatic Production of Insulin (POPPI) study(Mycophenolate Mofetil and Zenapax) • MMF protects BB rats from developing DM and is effective in islet allograft transplantation in mice • MMF effective in a number of autoimmune conditions and in transplantation • DZB effective as part of Edmonton protocol and in other transplantation regimens • Anti-IL2R Ab protects BB rat, but not NOD islet grafts • IL2-Receptor + Cells increased at diagnosis of DM • IL-2R+, CD4hi population harbors autoreactive T cells (mouse and man) • Relative known toxicities of drugs are low

  18. Mycophenolate Mofetil (MMF) • Inhibits inosine monophosphate dehydrogenase (IMPDH) • Inhibits de novo pathway of guanosine nucleotide synthesis • T and B cells need de novo pathway (other cell types use salvage pathway)

  19. APC MHC T cell TCR MMF: Mode of action • Blocking of activated T and B cell proliferation and antibody formation • Does not block IL-1, IL-2 production IL-2 Greenbaum, C Benaroya Research Institute Seattle, WA

  20. MMF (CellCept) • An immunosuppressive medication that is most commonly used to prevent transplant rejection. • Capsules, taken by mouth, twice a day for two years. • Most common side effects: Diarrhea, vomiting, nausea, decreased white blood cells.

  21. MMF Toxicities • Leukopenia • Gastrointestinal • Increased rate of viral infections • Lymphoproliferative disorder? No increase in multidrug regimens. No increase in single drug use (Psoriasis). • Cancer? (Psoriasis data – No).

  22. Daclizumab (Zenapax) Humanized IgG monoclonal antibody that binds to the alpha subunit (CD25, p55alpha, Tac) of IL-2 receptor on the surface of activated lymphocytes Greenbaum, C Benaroya Research Institute Seattle, WA

  23. DZB: Mode of action Inhibit IL-2 mediated activation of lymphocytes IL-2 DZB IL-2 γ α γ α ß ß Activated T cell Activated T cell Greenbaum, C;Benaroya Research Institute; Seattle, WA

  24. DACLIZUMAB (DZB) • An immunosuppressive medication, commonly used in patients receiving kidney transplants. • IV infusion, twice during the study (Baseline and Week 2). • Most common side effects: Diarrhea, vomiting, nausea, decreased white blood cells.

  25. Placebo (n=293) Zenapax (n=336) Safety Results No increase in most frequently reported AEs in Zenapax-treated patients* Musculoskeletal Pain Insomnia Wound Healing Pain Posttraumatic Headache Tremor 0 20 40 60 80 100 % of Patients with Adverse Event * Pooled data.

  26. POPPI Study • 3 arm study: MMF alone, MMF and 2 doses of DZB and placebo • 60 subjects per arm, 180 total, through TrialNet centers (6 initially) • Type 1 diabetes (autoantibodies) within 12 weeks of diagnosis • Ages 12-35, without significant other disease • Outcomes: HbA1c, C-peptide, hypoglycemia, T cell assays • Start Date: July 27, 2005. 23 patients enrolled.

  27. Potential Benefits of the Study • Patient will be the most important part of a research team that is attempting to learn more about type 1 diabetes. • Diabetes may be easier to manage. • Less chance for long-term complications of diabetes.

  28. Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus Kevan C. Herold, MD; William Hagopian, MD, PhD; Julie A. Auger, BA; Ena Poumian-Ruiz, BS; Lesley Taylor, BA, David Donaldson, MD; Stephen E. Gitelman, MD, David M. Harlan, MD; Danlin Xu, PhD; Robert A. Zivin, PhD; & Jeffrey A. Bluestone, PhD Herold K. et al., N Engl J Med 2002; 346:1692-8.

  29. hOKT3g1(Ala-Ala) Binds to CD3 hOKT3g1(Ala-Ala) is a monoclonal antibody that binds to the CD3 (T cell receptor) on human T cells. The drug is a “humanized” antibody with a mutation in the Fc chain to prevent binding to the Fc receptor. Binding to the Fc receptor and crosslinking of the CD3 molecule is thought to activate T cells, cause release of cytokines, and account for the toxicity of OKT3. Ala-Ala

  30. Changes from Study Entry to 12 Months in the Total C-Peptide Response to Mixed-Meal Tolerance Testing Monoclonal-Antibody Group Control Group Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Total Area under the C-Peptide Response Curve (nmol/l/4 hr) Herold K. et al., N Engl J Med 2002; 346:1692-8.

  31. A single course of hOKT3g1(Ala-Ala) at dx of diabetes improves insulin secretion for over 2 years ** ** ** (p<0.0001 **p<0.02)

  32. Hemoglobin A1c levels in Drug treated and Control Subjects ** * ** * P<0.0001 by RPANOVA ** p<0.01, * p<0.1

  33. Induction of IL-10+CD4+ cells in vivo following Treatment with hOKT3g1(Ala-Ala) Before treatment 1 wk after treatment IL-10+, IFN-g- CD45RO+ CTLA-4- Some TGF-b+ CCR4+

  34. CFSE hOKT3g1(Ala-Ala) induces proliferation of CD8+ T cells in vitro CD8 CD4 hOKT3g1(Ala-Ala) 5 ug/ml PHA

  35. Postulated Induction of CD8+ regulatory T cells by hOKT3γ1(Ala-Ala) CD3 engagement and signaling CD8+ T cell proliferation CD25 Inhibition of antigen-reactive CD4+ cells CD8 CD8 CD8 CD8 CD4 CD25 CD8 CD8

  36. 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

  37. 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

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

  39. 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

  40. APC APC MHC MHC TCR TCR T cell T cell IL-4 IFNγ Altered Peptide Ligand Greenbaum, C;Benaroya Research Institute; Seattle, WA

  41. NBI 6024-003 New Onset TrialAltered Peptide Ligand B:9-23 • Double-blind Phase I/II trial to test safety and efficacy of an altered insulin peptide ligand • Forty Patients (12-40) were randomized to receive 5 doses of NBI-6024 (0.1mg, 1.0 mg, or 5.0mg) or placebo biweekly and monthly. • No side effects. No obvious benefit to subjects, but study was primarily a safety study. • Evidence of immunologic effect on T cells was observed in a dose dependent fashion in adolescent groups particularly.

  42. ELISPOT analysis of Th1 and Th2 Responses to Insulin B(9-23)(▲);NBI-6024 () or Medium only (); 0.1 mg Adolescent Tx’ed Patients from NBI-6024-0003  Patient #O Patient #P IFN-g IFN-g IFNg IFNg IL-5 IL-5 IL-5 IL-5

  43. 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, BDC No effect • B chain – Orban, Joslin ? • hGAD s.c. in alum (Diamyd) 20ug dose only • Peptor Heat Shock Protein ? New Onset

  44. PREVENTION

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

  46. 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)

  47. Primary Prevention Trials • DPT-1 - Parenteral - Ineffective - Oral Insulin – May be effective in subgroup • DIPP - Nasal Insulin • INIT - IntraNasal Insulin Trial • ENDIT - Nicotinamide - Ineffective • TRIGR - Casein Hydrolysate (Cow’s Milk Elimination) • NIP - Nutritional Intervention to Prevent T1DM

  48. 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

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

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