Effect of 15-Deoxyspergualin on Immediate Function and Long-Term Survival of Transplanted Islets in Murine Recipients of a Marginal Islet Mass

Abstract

15-Deoxyspergualin (DSG), a macrophage immunomodulatory agent, was used as a probe in a murine model of islet transplantation to examine 1) the significance of the nonspecific, macrophage-mediated effector arm of beta-cell injury in recipients of a marginal mass of isologous islets by analyzing the duration of temporary posttransplant hyperglycemia, a parameter of immediate beta-cell function; and 2) whether long-term (> 100 days) functional survival could be achieved in recipients of a marginal mass of allogeneic islets. A dose-response study of the number of islets required to ameliorate diabetes showed that 150 isologous islets per recipient resulted in a 75% incidence of cure at a mean of 39.2 +/- 5.8 days posttransplant. DSG-treated (0.625 mg.kg-1.day-1 intraperitoneally) recipients of isologous islets demonstrated a significant (P < 0.01) reduction in the duration of temporary posttransplant hyperglycemia (16.8 +/- 3.2 vs. 39.2 +/- 5.8 days), and DSG-treated recipients of allogeneic islets demonstrated a significant (P < 0.03) improvement in the rate of achieving long-term functional survival (75 vs. 22% in untreated control animals). Finally, identical rates of islet engraftment were found among control animals and DSG-treated animals by measurement of tissue insulin content in transplanted specimens. The results are consistent with the hypothesis that DSG alters the duration of temporary posttransplant hyperglycemia and extends long-term functional survival in murine recipients of a marginal mass of islets, not by affecting the efficiency of islet engraftment, but by suppression of the inhibitory effects on beta-cell function by nonspecific, macrophage mediators.

Conditional and specific inhibition of NF-κB in mouse pancreatic β cells prevents cytokine-induced deleterious effects and improves islet survival posttransplant

“…32 In those experiments, DSG treatment decreased the number of days post islet transplant of hyperglycemia and increased the percentage of allogeneic recipients that reverted to euglycemia after receiving a marginal islet mass transplant. It was concluded that DSG acted by blunting the nonspecific injury to β cells mediated by macrophage-derived proinflammatory cytokine release.…”

The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model

“…The role of macrophages in early engraftment was examined by both gene expression analysis and immunohistochemistry, as these cells are critical players in modulating early inflammation, engraftment, and beta cell replication [63], as well as in T cell-mediated and antibody-mediated rejection [64, 65]. For qPCR analysis, all treatment groups demonstrated increased macrophage presence within the graft, while image analysis of explanted grafts indicated minimal differences and even suppression for the anti-LFA-1 group.…”

Vasculogenic hydrogel enhances islet survival, engraftment, and function in leading extrahepatic sites

“…Although clinically accessible for islet delivery, the hepatic vasculature is an inhospitable transplant site, as evidenced by suboptimal performance of grafts in islet autotransplantation after total pancreatectomy ( 5 , 6 ). Instant blood-mediated inflammatory responses to intraportally infused islets contribute to rapid graft destruction ( 7 – 9 ), resulting in an immediate loss of 50 to 60% of the graft ( 10 ), a substantial barrier to the translation of this therapy. Further graft destruction is mediated by both innate and acquired immune responses, even with chronic immunosuppressive regimens ( 11 ).…”