Islet cell transplantation tolerance

Curative islet transplantation for type 1 diabetes currently requires lifel ong systemic immunosuppression. Induction of islet transplantation toleranc e would be far preferable. We have previously demonstrated that blockade of costimulation by the administration of a donor-specific transfusion in com bination with anti-CD154 monoclonal antibody leads to permanent islet and p rolonged skin allograft survival in mice. The protocol requires the presenc e of CD4(+) T cells, interferon-gamma, and CTLA4, and involves the deletion of CDS' alloreactive T cells. Translation of this strategy into clinical p ractice will, however, require attention to at least two issues. First, we have observed that the presence of viral infection during tolerance interfe res with tolerance induction. Second, we have observed that our tolerance i nduction protocol is ineffective in autoimmune nonobese diabetic mice. We h ypothesize that resistance to tolerance induction in nonobese diabetic mice is due to the presence of memory autoreactive cells. To overcome the delet erious effects of viral infection and of primed memory responses, it may be necessary to modify current tolerance induction strategies based on costim ulatory blockade. These modifications may require patient isolation, the ge neration of hematopoietic chimerism, or treatments that target the specific T-cell populations, cytokines, and/or costimulatory factors responsible fo r resistance. Such modifications may make it possible to extend tolerance i nduction to the " real world " situation of individuals with type 1 diabete s who are likely to harbor both memory allo-and autoreactive immune cells.