Immunomodulation of fetal pig islet-like cell clusters by gamma-irradiation.
Pretreatment of tissues to reduce their immunogenicity is an attractive option, 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 potential xenogeneic tissue for the treatment of type 1 diabetes. The purpose of this study was to examine in vivo and in vitro the immunomodulatory effects of gamma-irradiation on ICCs in a xenogeneic situation. The immunogenicity of gamma-irradiated ICCs was determined in a mixed islet lymphocyte culture (MILC), in which fetal pigs ICCs were able to stimulate human peripheral blood mononuclear cells (PBMCs). Exposure of the ICCs to gamma-irradiation 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 experiments in which the stimulation index was relatively low. Gamma-irradiation was toxic to ICCs in vitro, causing a reduction in the [3H]-thymidine incorporation 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 capsule 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/kg per day) did not prevent the rejection of ICCs transplanted beneath the renal 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 combination with cyclosporine, and was unable to prolong discordant islet xenograft survival in mice.
Deol
H S
HS
Department of Endocrinology, Prince of Wales Hospital, Sydney, New South Wales, Australia. h.deol@unsw.edu.au
Tuch
B E
BE
D000818:Animals; D015478:Antigens, Heterophile / Q000528:radiation effects*; D005720:Gamma Rays; D006084:Graft Rejection / Q000276:immunology*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology* / Q000528:radiation effects*; D016381:Islets of Langerhans Transplantation; D051379:Mice; D013552:Swine; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous
D015478:Antigens, Heterophile