Decomplementation with cobra venom factor prolongs survival of xenograftedislets in a rat to mouse model

Although the involvement of complement in hyperacute rejection of xenotrans plants is well recognized, its role in rejection of devascularized xenograf ts, such as pancreatic islets, is not completely understood. In this study, we investigated whether complement participates in the immunopathology of xeno-islet transplantation in a concordant rat to mouse model. Rat pancreat ic islets were implanted under the kidney capsule of normal and cobra venom factor (CVF)-decomplementized diabetic C57BL/6 mice. Graft survival was mo nitored by blood glucose levels. Deposition of IgM and C3 on grafted islets in vivo or on isolated islets in vitro (after incubation with normal and d ecomplementized mouse serum), as well as CD4- and CD8-positive leucocyte in filtration of grafts, was checked by immunohistochemistry. In addition, com plement-mediated cytotoxicity on rat islet cells was evaluated by a 3-(4,5- dimethylhiazolyl)-2.5-diphenyl-2H-tetrazolium-bromide (MTT) assay. A signif icant C3 deposition was found on grafted islets from the first day after tr ansplantation in vice, as well as on isolated islets after incubation with mouse serum in vitro. By MTT assay, complement-mediated cytotoxicity for is let cells was found. Decomplementation by CVF decreased C3 deposition on ei ther isolated or grafted islets, delayed CD4- and CD8-positive leucocyte in filtration, led to significant inhibition of complement-mediated cytotoxici ty for islet cells, and prolonged graft survival (mean survival lime 21.3 v ersus 8.5 days; P < 0.01). Our results indicate that decomplementation can prolong the survival time of devascularized xenografts across concordant sp ecies. The deposition of complement on transplanted islets may contribute t o xenograft rejection by direct cytotoxicity and by promoting leucocyte inf iltration.