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Can Type 1 Diabetes Be Prevented?

Can Type 1 Diabetes Be Prevented?. Della Matheson, RN, CDE Research Coordinator, Type 1 Diabetes TrialNet University of Miami, Diabetes Research Institute. Type 1 Diabetes Prevention in NOD Mice. 200+. Mycobacterium avium Mycobacterium leprae Natural antibodies

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Can Type 1 Diabetes Be Prevented?

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  1. Can Type 1 Diabetes Be Prevented? Della Matheson, RN, CDE Research Coordinator, Type 1 Diabetes TrialNet University of Miami, Diabetes Research Institute

  2. Type 1 Diabetes Prevention in NODMice 200+ Mycobacterium avium Mycobacterium leprae Natural antibodies Natural polyreactive autoantibodies Neuropeptide calcitonin gene-related peptide Nicotinamide Nicotine Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation NKT cells NY4.2 cells OK432 Overcrowding Pancreatectomy Pentoxifylline Pertussigen Poly [I:C] Pregestimil diet Prenatal stress Preproinsulin DNA Probucol Prolactin Rampamycin Recombinant vaccinia virus expressing GAD Reg protein Reg protein Rolipram Saline (repeated injection) Schistosoma mansoni Semi-purified diet (e.g., AIN-76) Short term chronic stress Silica Sirolimus/tacrolimus Sodium fusidate Soluble interferon-gamma receptor Somatostatin Non-specific pathogen free conditions Streptococcal enterotoxins Streptozotocin Sulfatide (3’sulfogalactosylceramide) Superantigens Superoxide dismutase-desferrioxamine Anti-T cell receptor TGF-beta 1 somatic gene therapy Th1 clone specific for hsp60 peptide Anti-thy-1 Thymectomy (neonatal) Tolbutamide Tolerogenic dendritic cells induced by vitamin D receptor ligands Top of the rack Treatment combined with a 10% w/v sucrose-supplemented drinking water Tumor necrosis factor-alpha TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) Vitamin E Anti-VLA-4 AAV murine IL-10 AAV rat preproinsulin gene (vLP-1) Adenovirus expressing mIL-4 Aerosol insulin Allogenic thymic macrophages Alpha Galactosylceramide Alpha-interferon (rIFN-alpha) Alpha/beta T cell receptor thymocytes Aminoguanidine Androgens Anesthesia Antioxidant MDL 29,311 Antisense GAD mRNA Azathioprine Anti-B7-1 Bacille Calmette Gue’rin (BCG) Baclofen Bee venom Biolistic-mediated IL-4 Blocking peptide of MHC class II Bone marrow transplantation Castration Anti-CD3 Anti-CD4 CD4+CD25+regulatory T cells Anti-CD8 Anti-CD28 MAb Cholera toxin B subunit-insulin protein Class I derived self-I-A beta(g7) (54-76) peptide Cold exposure Anti-complement receptor Complete Freund’s adjuvant Anti-CTLA-4 Cyclic nucleotide phosphodiesterases (PDEs) Cyclosporin Cyclosporin A DC deficient in NF-kappaB DC from pancreatic lymph node DC with IL-4 Deflazacort Deoxysperogualin Dexamethasone/progesterone/growth hormone/estradiol Diazoxide 1,25 dihydroxy Vitamin D3, KH1060 1,25 dihydroxycholecalciferol 1,25 dihydroxyl Vitamin D3 Elevated temperature Emotionality Encephalomyocarditis virus (ECMV) Essential fatty acid deficient diets FK506 FTY720 (myriocin) GAD 65 peptides in utero Anti-GAD monoclonal antibody Galactosylceramide Glucose (neonatal) Glutamic acid decarboxylase (intraperitoneal, intrathymic, intravenous, oral) Glutamic acid decarboxylase 65 Th2 cell clone Glutamic acid decarboxylase peptides (intraperitoneal, intrathymic, intravenous, oral) Gonadectomy Guanidinoethyldisulphide Heat shock protein 65 Heat shock protein peptide (p277) Hematopoietic stem cells encoding proinsulin Housing alone Human IGF-1 I-A beta g7(54-76) peptide Anti-I-A monoclonal antibodies Anti-ICAM-1 IgG2a antibodies Immobilization Inomide Anti-integrin alpha 4 Insulin (intraperitoneal, oral, subcutaneous, nasal) Insulin B chain (plasmid) Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal) Insulin-like growth factor I (IGF-I) Anti-intercellular adhesion molecule-1 (ICAM-1) Interferon-alpha (oral) Interferon-gamma Anti-interferon-gamma Interferon-gamma receptor/IgG1 fusion protein Interleukin-1 Interleukin-4 Interleukin-4-Ig fusion protein Interleukin-4-plasmid Interleukin-10 Interleukin-10-plasmid DNA Interleukin-10-viral Interleukin 11-human Interleukin-12 Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic administration of mycobacterial heat shock peptide p277 Islet cells-intrathymic L-Selectin (MEL-14) Lactate dehydogenase virus (LDH) Large multilamellar liposome Lazaroid Anti-leukocyte function associated antigen (LFA-1) Anti-LFA-1 Linomide (quinoline-3-carboxamide) Lipopolysaccharide-activated B cells Lisofylline Lymphocyte choriomeningitis virus (LCMV) Anti-lymphocyte serum Lymphoctyte vaccination Lymphocytic choriomeningitis virus Anti-L-selectin Lymphotoxin LZ8 MC1288 (20-epi-1,25-dihydroxyvitamin D3) MDL 29311 Metabolically inactive insulin analog Anti-MHC class I Anti-MHC class II MHC class II derived cyclic peptide Mixed allogeneic chimerism Mixed bone marrow chimeras Monosodium glutamate Murine hepatitis virus (MHV)

  3. Azathioprine & Steroids Discovery of Insulin Auto-Antibodies Canadian-European Cyclosporin Study Remissions Skyler, Diabetes 1988; 37:1574-1582 Silverstein et al NEJM 1988;319:599-604

  4. PUTATIVE ENVIRONMENTAL TRIGGER HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD65, IA2Ab, ZnT8 ) CLINICAL ONSET Natural History of Type 1 Diabetes CELLULAR (T CELL) AUTOIMMUNITY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) GENETIC PREDISPOSITION BETA CELL MASS GLUCOSE INTOLERANCE (OGTT) INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES TIME

  5. ADA Position Statement: 1990 • Sufficient data exist to warrant intervention studies for prevention of T1D • Intervention for prevention should be attempted only in the context of • defined clinical trials • Intervention studies are best accomplished by randomized controlled studies • A registry of intervention studies should be maintained, and all planned • studies should be reported to a coordinating body • Screening of high risk populations is encouraged • Risk assessment, counseling, and follow-up must be offered. • Studies must be evaluated on the basis of potential risks vs. benefits; children should not be excluded, on the basis of age alone, from a therapeutic study that may benefit them by preventing diabetes

  6. How Risk is Determined • Step 1: Screening antibody testing • Step 2: Monitoring OGTT HbA1c HLA (DQA0102, DQB0602) Risk Score (age, BMI, C-peptide)

  7. DPT-1 – Time to Diabetes By Number of Antibodies 1.0 0.9 0.8 0.7 0.6 Survival Distribution Function 0.5 P- Value< 0.001 (Log Rank Test) 0.4 Number at Risk 0.3 24151 1718 405 378 147 22297 1401 297 255 95 17049 1045 229 192 61 11807 743 163 130 40 9052 557 118 78 30 7439 457 91 49 22 6198 371 66 31 16 0 1 2 3 4 3524 199 35 14 8 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 Years Followed n = 26799 1 2 4 0 3 STRATA:

  8. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 Combined DPT-1 Parenteral & Oral Insulin Trials Indeterminate: BG > 200 mg/dl at 30, 60, or 90 min Normal Glucose Tolerance Survival Distribution Function P- Value< 0.001 (Log Rank Test) Indeterminate only 1 Comb IFG+(IGTorIndet) IGT Only Indet Only NGT Number at Risk Combined 1 1 2 57 64 26 536 42 51 20 499 23 35 16 410 16 19 9 308 9 6 7 220 3 2 3 110 1 1 43 IGT only Years Followed Indet Only STRATA: Comb IFG + (IGT or Indet) NGT IGT Only

  9. DPT-1 Objective • To determine of antigen based therapy (specifically insulin) could prevent or delay onset of T1D • Parenteral Insulin In Subjects with High Risk: > 50% 5 year risk • Oral Insulin In Subjects with Moderate Risk: 25-50% risk

  10. The DPT·1 Funnel • 103,391 Relatives Screened • 97,635 Eligible Samples • 97,273 Samples Analyzed • 3483 Samples ICA+ (3.58%) • 711 Subjects Randomized

  11. 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:

  12. DPT-1 Oral Insulin Trial Time to Diabetes By Treatment 1.0 0.9 Treated 0.8 0.7 Control 0.6 Survival Distribution Function 0.5 0.4 P- Value= 0.188 (Log Rank Test) 0.3 Number at Risk 0.2 186 186 174 170 146 137 110 102 85 71 40 37 23 12 Oral Insulin Oral Placebo 0.1 0.0 0 1 2 3 4 5 6 7 YearsFollowed Oral Placebo OralInsulin STRATA:

  13. DPT-1 Oral Study - Time to Diabetes - By Treatment Subset: IAA Confirmed > 80 nU/ml 1.0 Projected 4.5 – 5 year delay 0.9 0.8 Treated 0.7 0.6 Survival Distribution Function 0.5 Control 0.4 P- Value= 0.015 (Log Rank Test) 0.3 Number at Risk 0.2 130 133 122 121 104 96 86 69 66 46 40 32 23 12 Oral Insulin Oral Placebo 0.1 0.0 0 1 2 3 4 5 6 7 Years Followed Oral Placebo Oral Insulin STRATA: Diabetes Care 2005; 28:1068-76

  14. Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300 Projected 10 year delay N=63 (Ins.) and 69 (Plac.)

  15. endit European Nicotinamide Diabetes Intervention Trial

  16. 50 40 Nicotinamide Percentage developing diabetes 30 Placebo 20 10 0 2 3 4 1 5 0 Years since randomisation Placebo Nicotinamide 275 274 245 260 205 208 184 171 232 232 Overall Treatment Effect:Intention To Treat Analysis N = 549

  17. NIDDK NIAID NICHD NCRR ADA JDRF

  18. TrialNet Sites in North America 14 Clinical Centers + 200 North American Affiliates

  19. TrialNet International Sites + 25 International Affiliates Turku, Finland Malmo, Swedem Bristol, UK Melbourne, Australia Milan, Italy Munich, Germany

  20. Other NIH Funded Consortiums Immune Tolerance Network TRIGR Study (Trial to Reduce IDDM in the Genetically At Risk) breastfeeding/hydrolyzed formula vs standard formula; 2,160 babies to be followed x 10 years; results expected in 2017 TEDDY(Environmental Triggers and Determinants of Type 1 Diabetes) 7,801 babies: 788 first degree relatives with genetic risk (10% risk), 7013 non- relatives with genetic risk (3%) 2836 families (11,626) sib pairs 493 families (1479): trio’s 968 Controls

  21. Natural History of Progression to Type 1 Diabetes • New Onset Studies: • MMF/DZB • AntiCD20 • CTLA-4 Ig • GAD-alum • Anti-IL1β • Metabolic Control (DirectNet) • Thymo (ITN) • IL-2/Rapa (ITN) • AntiCD3 (ITN) • Alefacept (ITN) not yet • completed C • Risk: Low • To Moderate • (antibodies present • Normal OGTT) • Natural History • (Monitoring) • Risk: Low • (no antibodies) • Natural History • (Screening 113,000) • Genetic & Mechanistic Studies ANTI-CD3 Risk: High (multiple antibodies &/or abnormal OGTT) BETA CELL MASS ORAL INSULIN NIP Pilot CTLA-4IG Helminths Diabetes Diagnosed

  22. Strategies for Interdicting Type 1 Diabetes Immunosuppressive Agents: Inhibit or Prevent Activity of the Immune System: Cyclosporin √ Anti-CD20 (Rituximab) √ Azathiaprine √ CTLA-4Ig (Abatacept) √ MMF/DZB Anti-CD3 (Teplizumab) √ Thymoglobulin (ATG) IL2/Rapamycin Not yet reported: Alefacept (anti-CD2)

  23. APC TH 2 TH 0 cell ß cell Protective Cytokines IL-4, IL-4, IL10 Beta cell survival

  24. How Immunosuppressive Agents Work APC TH 1 TH 0 cell TH 2 ß cell Cytotoxic MØ & T Cells Death IL-1, TNF-ą, TN-ß, IFN-y Destructive Cytokines 02, H202, NO

  25. Other Strategies for Interdicting Type 1 Diabetes • Antigen-Specific Therapies • rhGAD65 with Alum (Diamyd) • Oral Insulin √ Probiotic Therapy Helminths (TSO)

  26. Protective T cells APC TH2 TH 1 TH 0 cell ß cell Destructive Cytokines IFN-y, IL-2 Cytotoxic MØ & T Cells Death IL-1, TNF-ą, TN-ß, IFN-y 02, H202, NO

  27. The Benefit vs. Risk Ratio must be appropriate to the degree of risk for development of type 1 diabetes Must have proven efficacy Must be able to include children Choosing the Right Therapy

  28. Anti-CD3 (Teplizumab) • High Risk: > 75% Risk for development of type 1 diabetes over the next 5 years • 140-170 participants ; follow-up 4-6 years • 1:1 randomization; Teplizumab: Control • 14 Day Infusion (51mcg/m2 -826mcg/m2 day 4-13) • Ages: 8-45 • of 633 participants in studies using AntiCD3, 378 were children

  29. Risk: AntiCD3 • Lymphopenia (low WBC): 15% with 2% graded as severe • Infections 49.5% with 48.6% mild to moderate • Cytokine Release Syndrome: 5.7% with 85% mild moderate - chills, fever, headache, nausea, vomiting, achiness • Rash 42-62%

  30. hOKT3g1(Ala-Ala) in new onset Type 1 diabetes C-peptide Hemoglobin A1c Insulin use

  31. Therapies for Moderate Risk: CTLA 4Ig (Abatacept) Moderate risk: >32% 5 year risk • 2 antibodies (but not mIAA) • Normal OGTT • Ages 6-45 • 1:1 randomization, 206 participants • 14 infusions over 1 year (2 in the first month, then 1 monthly) • Follow: primary outcome: abnormal GTT secondary outcome: diabetes

  32. CTLA-4Ig (Abatacept) Risks Infusion and Hypersensitivity Reactions: 2% (47 of 2,514) Infectious Adverse Events: 54% in Abatacept and 48% Control; most upper respiratory infections with no increase in neutropenia or EBV

  33. Therapies for Moderate Risk: Oral Insulin Oral Insulin: >32% 5 year risk • 2 antibodies, one of which is “insulin autoantibody (mIAA)” • Normal Oral Glucose Tolerance Test • Ages 4-45 • Risk – no adverse events or side effects observed in DPT-1 • 1 capsule per day (7.5mg) • 1:1 randomization

  34. Antigen Based Therapy/Oral Tolerance: Mode of Action Protective Cytokines Oral Antigen Regulatory (Th2 / Th3) Lymphocytes Producing Protective Cytokines Inhibition of -Cell Autoimmunity and Prevention of Diabetes InsulinProducing -cells Autoimmune Lymphocytes

  35. Therapy for Low to Moderate Risk Helminths: Trichuris suis ova (Porcine whipworm ova) • Proof of principle established in inflammatory bowel disease and MS • Oral bi-weekly administration • Well tolerated • Use of therapeutic helminth therapy based on the “Hygiene Hypothesis”

  36. Hygiene Hypothesis 1910 = 65% helminthic infections; current = < 2% 1901 Paul Ehrlich dictum: “autotoxicus”: body’s immune system would never attack host tissue to cause disease 20th Century brought an end to this theory with the identification of > 80 autoimmune diseases.

  37. Enhance expression Of Protective T Regulatory Cells

  38. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial Summers, et.al., Gastroenterology 2005

  39. Benefits of Trichuris suis ova (TSO) • Does not multiply in human host • Colonization is self-limited in humans • No systemic phase • No direct transmission • Ova stable Side Effects limited to GI symptoms: nausea, upper abdominal cramping, Diarrhea, flatulence occurring during the first few weeks of treatment and then subsiding

  40. Effect of Helminths on the Prevention of Insulin Dependent Diabetes Mellitus in Non-obese Mice Cooke, et.al., Parasite Immunology 1999

  41. Inhibition of Diabetes by Helminth Infection Saunders, et.al, Infect. Immunol 2007

  42. CLINICAL ONSET Can Type 1 Diabetes be Prevented? • Combination Therapies may need to be employed • primary prevention • anti-inflammatory agents • beta cell expansion therapies • antigen-specific therapies • immunosuppressive agents GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY ORAL INSULIN BETA CELL MASS “PRE”-DIABETES CTLA-4IG ANTI-CD3 Helminths DIABETES TIME

  43. New Onset Studies Underway: • UCSF, Phase 1 Study: Infusion of T regulatory cells; 14 participants, ages 18-45 • Albert Einstein College of Medicine, Bronx NY, Phase 4: Exenatide; 20 patients, ages 12-18 • University Sao Paulo General Hospital, Phase 1: • High Dose Immunosuppression and Autologous • Hematopoeitic Stem Cells; 30 participants, ages 16-35

  44. Why is Prevention Important? Without prevention there is no Cure!!!! Evidence of reactivated autoimmunity after whole organ and islet cell transplantation Get Involved – participate in Research www.clinicaltrials.gov www.diabetestrialnet.org www.immunetolerance.org

  45. Debt of Gratitude

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