The Efficacy of CD40 Ligand Blockade in Discordant Pig-to-Rat Islet Xenotransplantation Is Correlated with an Immunosuppressive Effect of Immunoglobulin

Abstract

The authors' aim was to evaluate the efficacy of immunosuppression with monoclonal anti-CD40 ligand antibodies (aCD40L) or nonspecific polyclonal intravenous immunoglobulin (IVIG) in the pig-to-rat islet xenotransplantation model. Fetal porcine islet-like cell clusters were transplanted under the kidney capsule of nondiabetic rats. All antibodies were administered alone or in combination with cyclosporine A (CsA). In addition, some animals were administered antibodies plus tacrolimus (TAC) or sirolimus (SIR). Twelve days after transplantation, islet xenograft survival and rejection were evaluated using immunohistochemistry. aCD40L plus CsA had a pronounced inhibitory effect on islet xenograft rejection for up to 12 days after transplantation. Unexpectedly, treatment with a monoclonal control antibody (anti-keyhole limpet hemocyanin [aKLH]) plus CsA had a similar inhibitory effect. Furthermore, a similar inhibition of islet xenograft rejection was observed also in animals administered IVIG plus CsA. Monotherapy with aCD40L, aKLH, IVIG, or CsA had no effect on the rejection process. Also, when aCD40L or aKLH was administered together with TAC, islet xenograft rejection was inhibited. There was no marked difference compared with rats treated with aCD40L or aKLH and CsA. Immunosuppression with aCD40L or aKLH in combination with SIR also inhibited pig-to-rat islet xenograft rejection, but the protective effect was not as pronounced. Immunosuppression with high doses of antibodies, monoclonal or polyclonal, in combination with CsA or TAC inhibits pig-to-rat islet xenograft rejection. No specific effect of co-stimulatory blockade with aCD40L could be observed. Instead, the results indicate a nonspecific immunosuppressive effect of high doses of antibodies in this model.