Abstract
Graft rejection can be initiated by two primary pathways of antigen presentation: (a) direct activation of host T cells by donor-derived antigen presenting cells (APC) and (b) indirect presentation of processed graft antigens by host APC. We investigated the differential roles for direct and indirect antigen presentation by preventing the CD28 costimulatory pathway with monoclonal antibodies to rat or mouse CD80 and CD86 in a rat-to-mouse cardiac transplantation model. Although the mouse anti-rat monoclonal antibodies to CD80 and CD86 did not significantly prolong the survival of rat cardiac xenografts in mice, the rat anti-mouse monoclonal antibodies to CD80 and CD86 did prolong the survival. Development of the anti-donor antibodies was inhibited, and the deposition of C3, IgM, and IgG on endothelium in the xenografts was mild in the anti-mouse CD80/CD86-treated mice. Infiltration of macrophages, neutrophils, and lymphocytes expressing perforin and interferon-gamma was decreased by the anti-mouse CD80/CD86 treatment. These findings suggest that the indirect antigen presentation, which is mediated by CD80 and CD86 pathway on host APC, plays a crucial role in concordant cardiac xenograft rejection.
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