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 beause of T1DM's known intrinsic nephrotoxic effects. In 1993, however, investigators reported that the majority of non-obese diabetic (NOD) mice with recently diagnosed diabetes could have normal blood sugar control restored by administering an immunomodulatory agent called anti-CD3. These data generated great interest because the NOD mouse is the best-studied model for T1DM in man. 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 diseases in the RIP-CD80 transgenic mouse model. We are extending these studies in an effort to identify the mechanism underlying the anti-CD3 effect. Experiments just now underway are designed to test whether anti-CD3 therapy induces specific immune regulatory cells as the mechanism underlying the therapy's efficacy. 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. Trials were not instituted however because of toxicities associatd with the anti-human CD3 antibody. One problem was that the anti-huamn CD3 antibody then available (called OKT3) was a mouse anti-human antibody. When administered to humans, as is done in patients rejecting a life-critical organ transplant, an anti-mouse antibody response is invariably induced. Thos anti-mouse antibodies markedly decrease OKT3's serum half-life and clinical efficacy. As important, OKT3 therapy was associated with occasional severe toxicity. OKT3 markedly decreases T lymphocyte counts (at least temporarily), but during the T cell depletion process, many of the T lymphocytes are activated and product inflammatory cytokines. Thus, a patient given OKT3 could experience a systemic inflammatory response syndrome (SIRS) acutely, and be profoundly immunosuppressed for some time following the drug administration. In view of these toxicities, researchers worked to modify OKT3 so as to improve its safety and efficacy profile. Two changes were made. One, the mouse anti-human CD3 antibody was humanized in order to decrease the chance of an anti-mouse antibody response. Two, the OKT3 antibody was further genetically modified so as to impair its ability to bind Fc receptors on antigen presenting cells. This latter modification was predicted to decrease the antibody's T cell activating effect, and to limit its T cell depleting effect. Limited clinical experience with the modified agent in the transplant setting supported these predictions. Therefore, in 1999, Dr. Kevan Herold at Columbia University initiated a controlled clinical trial testing whether the modified OKT3 antibody (called OKT3 gamme, 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. Plans are underway to extend and expand this protocol, and to test other immunomodulatory agents in other individuals with recently diagnosed T1DM.
