T1DM is caused by the incompletely understood immune mediated destruction of the only cells capable of secreting insulin, the pancreatic beta cells. It has been known for some time that most individuals with new onset T1DM have residual beta cell function at the time of their diagnosis, which remain functional for weeks, months, even a few years following diagnosis. Further, it is now recognized that preserving even a marginal beta cell mass has a beneficial effect on a patient's ability to control his/her blood sugar within the normal range. Finally, it has been known for a number of years that instituting immunosuppressive therapy at T1DM diagnosis preserves beta cell mass, at least temporarily. However, for two good reasons instituting immunosupressive therapy at the time T1DM is first diagnosed has not become an accepted practice. One, the beta cell protective effect is only temporary in that all treated patients eventually required full insulin replacement therapy. Two, the immunosuppressive agents available are both toxic to normal beta cell function, and have other undesired toxicities including the impairment of normal renal function. The latter effect has been especially worrisome because of T1DM's known intrinsic nephrotoxic effects. Two alternative approaches to beta cell preservation have been and are under investigation in the Transplant and Autoimmunity Branch: 1) Administration of anti-CD3 antibodies: In 1993, it was first reported that normal blood sugar control was restored in non-obese diabetic (NOD) mice with recently diagnosed diabetes by administering a murine anti-CD3 antibody. The exact mechanism underlying the remarkable effect remains incompletely explored. We have reproduced these previously reported studies. In addition, we have studied whether anti-CD3 could similarly reverse disease in the rat insulin promoter-CD80 (RIP-CD80) transgenic mouse model we developed. Contrary to the experience with the non-obese diabetic (NOD) mice, anti-CD3 treatment only temporarily ameliorated disease in the RIP-CD80 transgenic mouse model. Since the first report that anti-CD3 therapy could stop the ongoing immune-mediated beta cell destruction in the NOD mouse, in fact could restore euglycemia, investigators have desired to test the analogous anti-human CD3 antibody in clinical trials. The original anti-human CD3 antibody was associated with significant toxicity such as marked lymphopenia and cytokine release syndrome. Therefore, the antibody has been modified in order to limit the toxicity. In 1999, Dr. Kevan Herold at Columbia University initiated a controlled clinical trial testing whether the modified OKT3 antibody (called OKT3 gamma, ala-ala) could be safely administered to patients with new onset T1DM (diagnosed within 6 weeks), and to test whether the agent preserved beta cell mass. We applied for permission to enter patients into the protocol under compassionate exemptions. Two patients received the agent and two patients are serving as controls in the NIH clinical center without significant complications. Neither of the two patients treated with the agent experienced any significant toxicity from the drug (except myalgias, temporary fever, and expected transient decreases in T cell counts), and they are being closely followed as part of the cohort at Columbia University to test whether the agent has acted to preserve beta cell mass. Twelve month follow up data have recently been published. 2) Administration of oral interferon-alpha was first found to inhibit chronic relapsing experimental autoimmune encephalomyelitis representing an animal model for multiple sclerosis. In 1998, Brod et al reported that administration of oral interferon-alpha in the non-obese diabetic (NOD) mouse model reduced insulitis and prevented the onset of diabetes. Furthermore, adoptive transfer of unstimulated splenocytes from interferon fed donors suppressed spontaneous diabetes in recipient animals. Consistent with this finding, spleen cells from treated animals when compared with controls produced more interferon-gamma and interleukins 4 and 10. Subsequently, ten patients with new onset type 1 diabetes were included in an open label pilot study at the University of Texas in Houston, in which more than the expected number of individuals remained in the so called honeymoon phase (period of time with continued endogenous insulin production). The exact mechanisms of action of ingested interferon-alpha remain unknown. We recently initiated a multi-center, controlled, double-blinded clinical trial, in which patients with type 1 diabetes of less than six weeks duration are randomized to two different doses of oral interferon-alpha (5,000 or 30,000 Units per day) or placebo. So far, forty three patients between the ages of 3 and 25 years have been included in this trial in all three participating centers (NIH, Bethesda; University of Texas, Houston; and Children's Hospital St. Paul, MN). We investigate and monitor beta cell secretory capacity, metabolic control, insulin requirements, frequency and severity of hypoglycemic events as well as serum cytokine patterns and cytokine mRNA transcript levels in stimulated lymphocytes. All patients have shown excellent compliance with taking the study medication and returning to NIH for the required mixed meal studies performed every 3 months. Due to the blinded nature of the study, it is impossible to tell whether the very different courses observed in this study reguarding the progressive loss of insulin producing beta-cells are related to the ingestion of interferon alpha. Since there are no discernable study drug related side effects, good compliance and enthusiasm for continued participation on the parents' and patients' side as well as clearly different clinical courses, which may or may not be due to the drug treatment, we feel strongly about continued subject accrual on this protocol. However, once we have accrued 50 percent of the planned accrual ceiling, we will perform an interim analysis of efficacy. If this analysis is negative (no drug effect), we plan to terminate the study prematurely. Two serious adverse events (both judged to be unrelated to study drug) have been reported. One child was diagnosed with a malignant brain tumor (NIH). One child was hospitalized with asthma (Houston).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Intramural Research (Z01)
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U.S. National Inst Diabetes/Digst/Kidney
United States
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Brown, Rebecca J; Rother, Kristina I (2008) Effects of beta-cell rest on beta-cell function: a review of clinical and preclinical data. Pediatr Diabetes 9:14-22
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