Protective effect of CTLA4Ig secreted by transgenic fetal pancreas allografts

Background. Pancreas allotransplantation offers a cure for insulin-dependen t diabetes mellitus, Systemic immunosuppression used to prevent immune dest ruction of the graft has side-effects, including increased susceptibility t o infection and neoplasia. These unwanted effects may be limited by enginee ring the graft to secrete immunomodulatory molecules, to achieve local immu nosuppression, Several studies have shown that transient local CTLA4Ig resu lts in partial protection of allogeneic grafts. Our intent has been to dete rmine whether sustained secretion of transgenic CTLA4Ig from pancreatic isl ets is able to protect against allograft rejection. Methods and Results. Mouse CTLA4 (test = CTLA4Ig) or CD5 leader sequence (c ontrol = CDFLIg) was fused to the Fc of mouse IgG2c, and expressed transgen ically under the control of the rat insulin promoter in C57BL/6 mice carryi ng the bm1 mutation of H-2K(b) (B6.C-H-2(bm1)), This resulted in expression in pancreatic islets, We used ELISA quantification of transgene products s ecreted into the supernatants of cultured fetal pancreata to select high (C TLA4Ig(hi)) and low (CTLA4Ig(Io)) expresser transgenic mice. Cultured fetal pancreata were transplanted under the kidney capsule of wholly allogeneic CBA recipient mice. CTLA4Ig(hi) but not CTLA4Ig(lo) expresser grafts showed enhanced survival compared with control CD5LIg grafts at 6 weeks posttrans plant, provided the recipient mice were transiently depleted of CD4 T cells (by a single low-dose injection of GK1.5) before transplantation. Conclusions. Sustained local secretion of CTLA4Ig from transgenic grafts in combination with transient systemic CD4 T-cell depletion can enhance allog raft acceptance.