Immunomodulation with SA-FasL protein as an effective means of preventing islet allograft rejection in chemically diabetic NOD mice.

Allogeneic islet grafts are subject to rejection by both auto- and alloimmune responses when transplanted into diabetic individuals. T cells play a critical role in the initiation and perpetuation of both autoimmunity and allograft rejection. T cells up-regulate Fas and become sensitive to FasL-mediated killing following antigenic stimulation. Therefore, we tested if immunomodulation with an apoptotic form of FasL chimeric with streptavidin (SA-FasL) is effective in preventing the rejection of allogeneic C57BL/6 islet grafts in chemically diabetic NOD mice. C57BL/6 splenocytes and pancreatic islets were biotinylated and engineered to display the SA-FasL protein on their surface. Female NOD mice (6-7 weeks old) were treated with streptozotocin to induce diabetes and transplanted 5 days later with C57BL/6 islets engineered with SA-FasL in conjunction with transient treatment with rapamycin (3.0 mg/kg daily for days 0-19). Graft recipients were also systemically immunomodulated by intraperitoneal injection of 5 × 10(6) donor SA-FasL-engineered splenocytes on days 1, 3, and 5 after islet transplantation. This regimen resulted in the survival of all allogeneic islet grafts for the 250-day observation period, compared with a mean survival time (MST) of 14.2 ± 3.9 days for the control group. The survival effect was SA-FasL specific, with all NOD mice transplanted with control streptavidin protein-engineered islet grafts and treated with SA-engineered splenocytes under transient cover of rapamycin rejecting their grafts with an MST of 39.8 ± 8.5 days (P < .01). Taken together, these data demonstrate that immunomodulation with SA-FasL-engineered allogeneic islet grafts and splenocytes is effective in overcoming rejection in female NOD mice with preexisting autoimmunity with important clinical implications.