Oral feedings of an antigen can attenuate the subsequent parenteral immunization by that antigen. In experimental autoimmune encephalitis(EAE), the oral administration of myelin basic protein (MBP) can be used to abrogate the severity of disease provoked by encephalogenic peptides of MBP, through a process mediated by tolerance induction. The suppressive effects involve not only the antigen administered, but "bystander" antigens local to areas of inflammation also, as mediated by cytokines, such as TGF-beta. Currently, trials are ongoing to learn the extent to which human multiple sclerosis may be amenable to "oral MBP tolerance" therapy. Insulin-dependent diabetes(IDD) presents often years after the initiation of autoimmune mediated destruction of the pancreatic beta-cells. Target antigens thought to be important in this process include insulin and the 65KDa isoform of the GABA promoting enzyme, glutamic acid decarboxylase (GAD65). Patients with IDD invariably become immunized to their insulin replacement therapy, an effect which may have important long term metabolic and immunologic ramifications. In independent studies, two of us have been able to show that oral administration of porcine insulin to non obese diabetic (NOD) mice can delay the onset and ameliorate the frequency and severity of spontaneous diabetes, an effect which was maximal using the peptide 11-30 of the B chain. Protection against IDD was transferable by splenocytes to NOD recipients, indicating that the effect involved active suppression. Oral feedings of GAD65 gave similar benefits. We therefore propose to administer oral recombinant human insulin in a three dose, placebo controlled trial to groups of 25 newly diagnosed patients, anticipating that the treatment will abrogate their immunization to therapeutic insulin, and improve their metabolic outcomes. Similarly, we will administer two doses of oral insulin in a placebo controlled study to three groups of 130 insulin and/or islet cell autoantibody positive nondiabetic relatives of patients with IDD with normal FPIR to IV glucose, to learn whether antigen specific and/or "bystander" antigen related autoimmunities may be abrogated and their clinical onsets of IDD thereby delayed. After one year, these same relatives will be randomized to receive additional oral GAD65 as well to examine to what extent additive effects can be induced. The three year pilot study will lead to a competitive application for more comprehensive long term intervention trials, if warranted by the results of these studies.