INGESTED IFN-ALPHA IN NEWLY DIAGNOSED TYPE I DIABETES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Type 1 diabetes is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic b-cell. In the United States, the prevalence of type 1 diabetes by age 20 years is 0.26% and lifetime prevalence approaches 0.40%; thus approximately 1 million Americans have IDDM. Histologic studies suggest that an 80% reduction in the volume of b-cells is required to induce symptomatic IDDM. The natural history of type 1 diabetes is unique for a phase frequently referred to as the "honeymoon", a period in which the insulin need becomes minimal and glycemic control improves. It is felt that the b-cell recovers. However, as with all honeymoons, they end and the patient becomes completely insulin deficient. The general consensus of the international diabetes community is to test potential preventive therapies for type 1 diabetes in newly diagnosed patients. Interventions prolonging the "honeymoon", indicative of the reversal of the disease, are considered positive. This study is designed to: 1- Determine the efficacy of 5000 and 30,000 IU ingested human recombinant interferon-alpha (hrIFN-a) in prolonging the 'honeymoon'-like period and preserving b-cell function in type 1 diabetes. We will determine the safety and efficacy of 5000 and 30,000 units ingested hrIFN-a in 120 patients with newly diagnosed type 1 diabetes in a phase II trial of daily ingestion for one year. Primary outcome measures will be a 30% increase in C-peptide levels released after Sustacal stimulation at 3, 6, 9, and 12 months after entry. The increased C-peptide level will be compared to C-peptide levels from the control group and must be significantly higher. 2- Determine if 5000 or 30,000 units ingested hrIFN-a alters surrogate markers of disease. Our laboratory demonstrated that ingested IFN-a increased anti-inflammatory IL-4 and IL-10 in NOD spleen cells and donor cells from IFN-fed mice protected against spontaneous type 1 diabetes in NOD recipients. Preliminary data from our phase I open label clinical trial showed that in four out of the seven type 1 diabetes patients with residual b-cell function ('honeymooners'), anti-GAD antibody titers decreased comparing entry to end of study levels. Examinations of serum cytokine data comparing entry to end of study levels show increased IL-4 or IL-10 levels in six of seven 'honeymooners'. Therefore, we will determine if ingested hrIFN-a increases serum IL-4 or IL-10 cytokines, IL-4 or IL-10 cytokine mRNA transcripts ex vivo in peripheral blood mononuclear cells (PMNC), or decreases titers of anti-GAD and anti-IA-2 antibodies from patients with recent onset type 1 diabetes that retain residual b-cell function after 12 months on the active treatment arm. We will compare the results from the 5000 and 30,000 units dose to see if both are equally effective. Humoral and cyto- immune responses directed at pancreatic b-cells and their antigens. PMNC will be obtained at three monthly interval for ex vivo cytokine mRNA, in particular IL-1, IL-4, IL-6, IL-10, TNF-a, TNF-b, IFN-a and IFN-g. Sera will be obtained at 0, 1, 2, 3, 6, 9, and 12 months for measurement of GAD and IA-2 antibody levels (M. Atkinson Ph.D.) and serum IL-4 and IL-10 levels. Follow-up blood studies to monitor for IFN-a toxicity will be performed on all patients at 1, 2, 3, 6, 9, and 12 months.