Enhancing engraftment of neonatal porcine xenoislet with CTLA4Ig and nordihydroguaiaretic acid.

ABSTRACT

This study examined the combinatory effect on graft survival of neonatal pig pancreatic cell clusters (NPCC) with nordihydroguaiaretic acid (NDGA), a 5-lipoxygenase inhibitor, with systemic CTLA4Ig expression, with local CTLA4Ig and with interleukin-1 (IL-1) receptor antagonist (IL-1ra) expression using a pig to mouse model. About 2000 NPCCs, which were infected with both adenoviruses carrying CTLA4Ig and IL1-1ra genes (each 500 pfu/NPCC), were transplanted beneath the kidney capsule of diabetic BALB/c mice. Two days before transplantation, the recipient mice were either injected with (group C, n = 4; group D, n = 6) or without (group A, n = 7; group B, n = 9) 1 x 10(13) pfu/kg body weight of adenovirus carrying the CTLA4Ig gene. Mice in groups B and D received daily injections of NDGA (20 mg/kg body weight) subcutaneously for 4 weeks. Blood glucose levels less than 200 mg/dL were defined to be normoglycemic and the transplant termed as a functioning graft for the purpose of calculating mean graft function time (MFT). Four weeks posttransplantation, an intraperitoneal glucose tolerance test (IPGTT) was performed to calculate the area under the curve (AUC). Blood glucose levels in groups C and D were significantly lower than groups A and B at 1, 2, and 3 weeks after transplantation. Graft MFT and AUC of IPGTT in group D were significantly different from those in groups A and B. Our data suggested that a high dosage of systemic expression of CTLA4Ig was effective to enhance xenograft survival and that in it was reinforced by a combination with the macrophage inhibitor NDGA.