Immunomodulation of fetal pig islet-like cell clusters by gamma-irradiation

Pretreatment of tissues to reduce their immunogenicity is an attractive opt ion, and exposure of donor islets to gamma-irradiation has previously been shown to result in their prolonged survival when transplanted into rodents. Fetal pig islet-like cell clusters (ICCs) are currently under trial as a p otential xenogeneic tissue for the treatment of type 1 diabetes. The purpos e of this study was to examine in vivo acid in vitro the immunomodulatory e ffects of gamma-irradiation on ICCs in a xenogeneic situation. The immunoge nicity of gamma-irradiated ICCs was determined in a mixed islet lymphocyte culture (MILC), in which fetal pigs ICCs were able to stimulate human perip heral blood mononuclear cells (PBMCs). Exposure of the ICCs to gammairradia tion significantly reduced their ability to stimulate PBMCs in a MILC when 10 Gy but not lower doses of irradiation were applied. However, this effect of gamma-irradiation was variable and was present only in those experiment s in which the stimulation index was relatively low. Gamma-irradiation was toxic to ICCs in vitro, causing a reduction in the [H-3]-thymidine incorpor ation of 82-94% at 5-20 Gy. This toxic effect of gamma-irradiation was also demonstrated in vivo: the insulin content of ICCs beneath the renal capsul e in SCID mice treated with 5-20 Gy significantly was reduced (P < 0.05) 6 weeks after transplantation. Exposure of ICCs to gamma-irradiation (2.5 Gy) alone in vitro or in combination with injection of cyclosporine (12.5 mg/k g per day) did not prevent the rejection of ICCs transplanted beneath the r enal capsule of BALB/c mice. We conclude that gamma-irradiation is toxic to fetal pig ICCs at a higher dose and at a lower dose, alone or in combinati on with cyclosporine, and was unable to prolong discordant islet xenograft survival in mice.