The rescue effect of 15-deoxyspergualin on intraperitoneal microencapsulated xenoislets

Abstract

Because the development of surface neogrowth composed mainly of macrophages and fibroblasts precedes the recurrence of hyperglycemia in treated diabetic animals, the pericapsular macrophages may adversely affect the graft function of i.p. alginate-poly-L-lysine-alginate (A-P-A) microencapsulated islets. In order to clarify the role of pericapsular macrophages on late islet xenograft dysfunction, we investigated whether 15-deoxyspergualin (15-DSG), a macrophage inhibitor, has a rescue effect on the recurrent hyperglycemia in streptozotocin-induced diabetic mice that had been treated with i.p. transplantation of A-P-A microencapsulated rat islets. The mean duration of normoglycemia (whole blood glucose level below 8.3 mmol/l) in streptozotocin-induced diabetic mice treated with implantation of about 2200-2400 of A-P-A microencapsulated rat islets was 75 days. When the blood glucose levels were higher than 11.1 mmol/l for two consecutive determinations, 15-DSG at a dose of 0.625 mg/kg body weight or isotonic sodium chloride solution (control group) was given daily s.c.. The blood glucose levels decreased significantly from 13.9 +/- 0.5 mmol/l to 11.0 +/- 1.3 mmol/l (n = 18, p < 0.05) at the fourth day and to 7.6 +/- 1.0 mmol/l (n = 18) at the 14th day of 15-DSG administration. That was not significantly different from the mean glycemic level during the normoglycemic period (7.6 +/- 1.0 vs. 7.0 +/- 1.7 mmol/l, n = 18, p = NS). Isotonic sodium chloride solution injections did not reduce glycemic levels of mice in the control group. As another control, 10 streptozotocin-induced diabetic mice were given the same daily doses of 15-DSG for 14 days. 15-DSG did not decrease the blood glucose levels of diabetic mice in the control group. We further studied the effect of 15-DSG on the expression of interleukin-1beta (IL-1beta) in peritoneal exudate mononuclear cells (PEMCs) using reverse transcription-polymerase chain reaction. It was found that the mRNA of IL-1beta was undetectable in PEMCs of 15-DSG-treated diabetic mice even after those cells were stimulated by lipopolysaccharides in vitro. Administration of 15-DSG at a daily dose of 0.625 mg/kg body weight from the 22nd to the 28th day after transplantation and 7 consecutive days every 3 weeks thereafter did not prolong graft survival of i.p. microencapsulated rat islets. Our data suggest that 15-DSG has a rescue effect when A-P-A microencapsulated islets have induced cellular overgrowth that threatens the survival of the graft. It is possible that the surface overgrowth composed of macrophages is involved in the pathophysiology of late failure of A-P-A microencapsulated xenogeneic islets.