513 Introduction. Delayed xenograft rejection (DXR) is a vascular type of rejection that can occur in a T cell-independent manner. The immunological mechanisms leading to DXR, however, remain unclear. In this study we tested whether the pathogenesis of DXR was initiated by the generation of elicited anti-graft IgM xenoreactive antibodies (Xabs) following transplantation. While generally assumed to be the case, this has never been shown. Methods. Hamster hearts were transplanted into adult rats depleted of circulating IgM by the administration of an anti-μ monoclonal antibody (Mab) 1 day prior to transplantation (30 mg/kg), and 1 and 3 days after transplantation (15 mg/kg). Cyclosporin A (CyA) was administered at the time of transplantation and daily thereafter (15 mg/kg). Results. Anti-μ administration, without further treatment, resulted in depletion of circulating IgM to undetectable levels, and had no effect on complement, NK cells or monocyte/macrophages. Depletion of IgM suppressed DXR, leading to rejection 5-7 days post-transplantation (Table) Rejection was associated with the generation of T cell-dependent IgG antibodies. When IgM depletion was combined with CyA treatment, anti-graft circulating IgG antibodies where no longer detected and xenografts survived long-term (> 50 days). IgM Xabs returned to the circulation 20-30 days after transplantation, which correlated with the clearance of circulating anti-μ Mab, but was not associated with xenograft rejection. Continued survival of the xenograft in the presence of IgM and complement indicated that the xenograft had accommodated. Accommodation was associated with the expression in the xenograft of the protective genes A20, Heme oxygenase-1 and bcl-xL as early as 3 days after transplantation.TableConclusion. DXR of hamster to rat cardiac xenografts can occur through the rapid generation of T cell-independent elicited Xabs of the IgM isotype. Temporary depletion of IgM antibodies and continuing T cell immunosuppression leads to xenograft accommodation. Expression of the protective genes does not require the presence of anti-graft IgM antibodies. Xenograft accommodation is associated with the expression of heme oxygenase-1, which we have previously shown to be functionally associated with xenograft survival.