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 and lasting for weeks, months, even a few years following diagnosis. Further, it is now recognized that preserving even a marginal beta cell mass has a salutary 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 are currently 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 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, however, such as marked lymphopenia and cytokine release syndrome. Therefore, the antibody has been modified in order to limit the toxicity. Limited clinical experience exits with the modified agent in the transplant setting. 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 three patients into that protocol under compassionate exemptions. Two patients received the agent in the NIH clinical center without significant complications, and one patient is serving as a control. 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 closed followed as part of the cohort at Columbia University to test whether the agent has acted to preserve beta cell mass. 2) Administration of oral interferon-alpha Ingested 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 previously mentioned 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-gamman and interleukins 4 and 10. Subsequently, eleven patients with new onset type 1 diabetes were included in a 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 interferon-alpha (5,000 or 30,000 Units per day) or placebo. So far, fourteen patients between the ages of 3 and 25 years have been included in this trial in both participating centers (NIH, Bethesda and University of Texas, Houston). 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.
