INDUCTION OF SPECIES-SPECIFIC HOST ACCOMMODATION IN THE HAMSTER-TO-RAT XENOTRANSPLANTATION MODEL

The combination of two immunosuppressants, leflunomide and cyclosporin A (CsA), completely inhibits immune xenoreactions in the hamster-to-L ewis rat xenotransplantation model. In addition, the control of acute xenograft rejection with this combination of immunosuppressants subdue s early T-independent xenoreactivity and uncovers a late immune respon se that can be controlled by CsA alone. We attribute this acquired res ponsiveness to CsA to a modification in the recipient's humoral respon se to the xenograft, and refer to this change as host accommodation. H ost accommodation can be induced in Lewis rats receiving hamster heart s by the combination of leflunomide and CsA. A 7-day treatment with le flunomide and CsA was able to convert xenoreactivity from one that was resistant to CsA treatment into one that was controlled by CsA. The p resence of the hamster xenograft was critical for the induction of hos t accommodation since the immunosuppressive regimen, either alone or i n combination with a transfusion with donor-specific spleen cells, was unable to modify the anti-hamster reactivity in Lewis rats. When acco mmodation was induced in the presence of hamster hearts, these accommo dated rats were able to acutely reject third-party mouse hearts while under CsA therapy, thus indicating that the host accommodation is spec ies specific. Finally, we demonstrate that host accommodation is assoc iated with a loss in the ability to produce species-specific, T-indepe ndent xenoantibodies. These novel observations suggest that xenoreacti ve T-independent humoral responses can be deleted selectively without significant loss of other innate, Ag-specific T-independent humoral re sponses.