The development of a means for inducing immunological tolerance may have a dramatic impact not only on the way autoimmune disorders such as type 1 diabetes (T1D) are treated, but, in addition, towards therapeutic applications related to allergy, transplantation, and oncology. The focus of this application is to identify the therapeutic potential of umbilical cord blood as a means for inducing tolerance in an autoimmune setting and to define the role for a class of so-called regulatory T cells (Treg; identified by their coexpression of CD4 and CD25 molecules) in imparting immune regulation. We recently received FDA approval for a highly innovative study aimed at the reversal of recent onset T1D involving autologous umbilical cord blood transfusion (obtained from banked material). This current application seeks to test the hypothesis that T1D can be reversed or the rate of metabolic loss slowed by autologous umbilical cord transfusion. In addition to evaluating therapeutic efficacy, the project's specific aims are designed to provide a mechanistic understanding for the ability of cord blood to modulate immune reactivities and induce tolerance. 1) Determine whether autologous umbilical cord blood administered to children with recently diagnosed T1D will lead to the preservation and/or regeneration of insulin-producing beta cells. This notion will be assessed by longitudinal evaluation of metabolic function (e.g., blood glucose control, insulin usage, mixed-meal stimulated C-peptide production) from protocol subjects versus an age/gender/HLA-matched population of T1D patients. 2) Determine the influence of this therapy on immune responsiveness including tolerance induction. Specifically, whether alterations in the frequency and/or functional capacity of Treg in peripheral blood occur, the course of anti-islet cell immunity (production of T1D associated islet cell autoantibodies), and humoral and cellular immune response against immunization based, environmental, or insulin antigens. 3) Evaluate the frequency and function of Treg in cord blood from persons with T1D and by comparison to healthy, non-diabetic controls (age and gender matched), and identify their potential contributions to the risk of developing this disorder. The successful completion of these pilot studies could uncover an innovative method for tolerance induction and understand the contributions of Treg to both the process of tolerance induction as well as the pathogenic defects underlying the formation of T1 D. ? ? ? ?
