A murine paratopic model of intestinal transplantation was developed and used to study the immune response to allografts in normal C57BL/6 recipients (H2(b)) and C57BL/6 recipients treated with tacrolimus (1 mg/kg, Days 0-7). B6C3F1 mice (C57BL/6 x C3H/HeJ, H2(bxk)) were used as donors. The paratopic model differed from the standard heterotopic model in that continuity of the intestine graft with the recipient intestine was established by anastomosing the graft ileum to the side of the recipient jejunum. The success rate of this modified procedure was 82% (94/114). Major complications included hypovolemic shock and/or anesthetic-related deaths (8%), infection (8%), and vascular thrombosis (2%). Rejection was assessed using both clinical features (i.e., edema and closure of the stoma, mucous discharge, and a palpable mass) and histologic features (apoptosis of crypt cells, crypt destruction, lymphocytic infiltrate, and mucosal ulceration). Syngeneic grafts appeared clinically and histologically normal throughout the study period. Untreated recipients of allografts developed clinical and histologic evidence of rejection by Day 4 which progressed to severe rejection and graft destruction by Day 18. After initially developing evidence of mild to moderate graft rejection on Day 8, the severity of allograft rejection decreased significantly by Days 10 to 14 in tacrolimus-treated mice. By Day 28 evidence of moderate rejection had recurred in mice treated with an 8-day course of tacrolimus. Consistent with these observations, graft function, as assessed by maltose absorption, was impaired in rejecting allografts when compared with syngeneic grafts. Allografts in mice treated with tacrolimus demonstrated improved maltose absorption relative to allografts from untreated mice. These studies describe a modified technique for intestinal transplantation in mice and provide a detailed analysis of complications as well as an assessment of rejection and its functional consequences. Based on these results, we conclude that the paratopic model of intestinal transplantation in mice is a useful tool for studying the host immune response to intestinal allografts.
Copyright 1998 Academic Press.