Suppression of delayed xenograft rejection by specific depletion of elicited antibodies of the IgM isotype

Background, Hamster hearts transplanted into untreated rats undergo delayed xenograft rejection (DXR). This acute inflammatory response is associated with the deposition of anti-graft antibodies of the immunoglobulin (Ig)M is otype in the vasculature. We have previously shown that these antibodies ar e generated in a T cell-independent manner. In this study, we tested whethe r the generation of anti-graft IgM antibodies is involved in the pathogenes is of DXR. in addition, we tested whether the suppression of this antibody response mould overcome DXR. Methods. Hamster hearts were transplanted into rats treated with an anti-mu monoclonal antibodies (mAb) to deplete circulating IgM or with an isotype- matched control mAb recognizing the dinitrophenyl epitope. T cell immunosup pression was achieved with cyclosporin A (CsA). Results. Depletion of circulating IgM by anti-mu mAb inhibited DXR, whereas the control mAb had no effect on DXR. In anti-mu-treated rats, xenografts were rejected 5-7 days after transplantation through a T cell-dependent mec hanism associated with the generation of antibodies of the IgG isotype. Com bination of anti-mu with CsA suppressed the anti-graft IgM and IgG response and resulted in long-term xenograft survival (> 50 days). Xenograft long t erm survival occurred despite the return of anti-graft IgM antibodies to th e circulation, a phenomenon referred to as accommodation. Conclusion. This study demonstrates that the pathogenesis of DXR can be ini tiated by anti-graft antibodies of the IgM isotype, which are generated in a T-cell independent manner. In addition, we show that under T cell immunos uppression, specific depletion of this IgM response by anti-mu mAb administ ration results in xenograft long-term survival and accommodation.