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Background: The combination of two immunosuppressants, leflunomide (Lef) and cyclosporine (CsA), completely inhibits immune xenoreactions in the hamster-to-Lewis rat xenotransplantation model. In addition, a transient treatment with Lef and CsA subdues early T- independent xenoreactivity and uncovers a late immune response that can be controlled by CsA alone. We attribute this acquired-sensitivity to CsA to a medication in the recipient's humoral response to the xenograft and refer to this change as host accommodation. This study further characterizes the induction of host accommodation in this rodent model of concordant xenotransplantation. Methods: Accommodation was induced in Lewis rats transplanted with hearts from Golden Syrian hamster with the combination of Lef (5 mg/kkg/d) and CsA (20 mg/kg/d) for 7-21 days and maintained on CsA (20 mg/kg/d) for the duration of the experiment. The specificity of the accommodated state was defined by transplanting additional hamster or mouse hearts into the accommodated Lewis recipients. The titers of xenoreactive antibodies were determined by flow cytometry. Results: Host accommodation was induced in Lewis rats receiving hamster hearts and the combination of Lef and CsA, but not with either of these agents alone. A >/-7 day treatment of Lef and CsA was able to convert xenoreactivity from one that was resistant to CsA treatment into one that was completely controlled by CsA. The presence of the hamster xenograft was critical for the induction of host accommodation since the immunosuppressive regimen alone, or in combination with donor-specific transfusion with spleen cells, were unable to modify the anti-hamster reactivity in Lewis cats. Finally we report that when accommodation was induced in the presence of hamster hearts, these accommodated Lewis rats were able to acutely reject third-party mouse hearts while under CsA therapy. Conclusions: Induction of host accommodation requires the combination of Lef and CsA as well as the presence of the xenograft, and is associated with a loss in the ability to mount a T-independent xenoantibody response. The ability of the accommodated host to respond with a T-dependent xenoantibody response is retained and is controllable with CsA alone. Finally, the species-specificity of host- accommodation suggests that xenoreactive T-independent humoral responses can be selectively deleted without significant loss of other innate, antigen-specific T-independent humoral responses.