Program Directors: Peter Stock and Jeffrey Bluestone

Recent advances in basic islet biology, immunology, islet isolation and preservation techniques, organ transplantation and immune tolerance offer the hope that the outlook for the person with Type 1 diabetes in the near future will be vastly improved compared with the present.  We now understand that even after clinical presentation of disease, a continued decline in beta cell function occurs that, if treated, could preserve islet function.  Therefore, early rescue or transplantation of a sufficient functional mass of islets could theoretically prevent or reverse the development of many diabetic complications.  The mission of the UCSF DERC Program in Islet Transplantation is to promote the basic and clinical research that will lead to successful islet transplantation in patients with ongoing autoaggressive Type 1 diabetes.  The approach will be multi-faceted taking advantage of the wealth of faculty with strong research projects in both basic and clinical immunology.  Efforts are focused towards identifying novel immunosuppressive therapies pioneered at this Diabetes Center and elsewhere, pre-clinical and clinical efforts in rodents, non-human primates and humans in our state-of-the-art cGMP facility.

Optimization of islet transplantation
A substantial proportion of transplanted islet beta cells are therefore destroyed by early innate immune responses involving primarily macrophages, NK cells and their by-products, even before classic T-cell mediated rejection may ensue. Thus, if we are to achieve insulin independence in patients receiving only marginal islet mass, adaptive immune-independent islet losses early after transplantation must be minimized. Investigators in the program will study the cell biology of isolated islets, early T cell independent inflammatory responses, and novel islet implantation techniques to effect optimal conditions for achieving successful engraftment of limited numbers of healthy islets. We hypothesize that by inhibiting non-specific inflammation and the generation of oxidative radicals, while inhibiting the increased expression of cellular adhesion molecules induced by the process, the cascade of events leading to dysfunction and destruction of transplanted islet cells will diminish non-specific cell loss and lessen the incidence and severity of acute cellular rejection.

Develop and test novel tolerogenic protocols for islet transplantation
A series of novel approaches using genetically engineered monoclonal antibodies (mAbs), altered antigen and gene therapy will be used in a combined allotransplant/autoimmune setting. The protocols developed will be targeted towards the inhibition of co-stimulation, clonal inactivation, and the study of altered T cell receptor-mediated signaling in the NOD autoimmune model, non human primates and patients with Type 1 diabetes undergoing islet transplantation. Emphasis will be placed on overcoming the unique problems associated with transplantation into autoimmune animals, targeting co-stimulatory molecules and TCR antagonists known to act in the autoimmune setting and further, analyzing the basic regulatory mechanisms that modulate the development of diabetes.

Clinical application of developmental biology/islet stem cell biology/ immunology program advances
A major goal of this program is to facilitate translational research in islet transplantation, as described in the Translational Research portion of this application. Basic scientific advances created from other UCSF DERC programs have the potential to dramatically impact the clinical application of islet transplantation and success in this regard will depend on a clear, integrative organizational approach within the program. Thus, tolerogenic strategies (i.e. CD28 blockade, anti-CD3, and adaptive regulatory T cells) as well as the new approaches (e.g. anti-CTLA-4) will be combined with alloantigen/ and autoantigen-expressing cells to generate a “tolerogenic vaccine” to promote tolerance in the autoimmune prone recipients. Ultimately, this approach will rely on genetically manipulated allogeneic or autologous cells expressing autostimulatory antigens (i.e. GAD and insulin) as the source of tolerogen or cytokines.

Program members:

Abul Abbas 
Jeffrey Bluestone 
Garrison Fathman 
Stephen Gitelman  
Gerald Grodsky 
Doug Hanahan  
Max Krummel 
Sang-Mo Kang
Lewis Lanier
Umesh Masharani
Martha Nolte
Peter Stock
Greg Szot
Flavio Vincenti