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Rejection of Cardiac Xenografts by CD4⁺ or CD8⁺ T Cells

Immunobiology Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

We recently showed that brief complement inhibition induces accommodation of hamster cardiac transplants in nude rats. We have reconstituted nude rats carrying an accommodated xenograft with syngeneic CD4⁺ or CD8⁺ T cells to investigate the cellular mechanism of xenograft rejection. We show that CD4⁺ T cells can initiate xenograft rejection (10 ± 1.7 days) by promoting production of IgG xenoreactive Abs (XAb). These XAb are able to activate complement as well as to mediate Ab-dependent cell-mediated cytotoxicity. Adoptive transfer of these XAb into naive nude rats provoked hyperacute xenograft rejection (38 ± 13 min). The rejection was significantly (p < 0.001) delayed by cobra venom factor (CVF; 11 ± 8 h in four of five cases) but was still more rapid than in control nude rats (3.3 ± 0.5 days). CVF plus NK cell depletion further prolonged survival (>7 days in four of five cases; p < 0.01 vs CVF only). CD8⁺ T cell-reconstituted nude rats rejected their grafts later (19.4 ± 5.8 days) and required a larger number of cells for transfer as compared with CD4⁺ T cell-reconstituted nude rats. However, second xenografts were rejected more rapidly than first xenografts in CD8⁺ T cell-reconstituted nude rats (9 ± 2 days), indicating that the CD8⁺ T cells had been activated. This study demonstrates that CD4⁺ and CD8⁺ T cells can both reject xenografts. The CD4⁺ cells do so at least in part by generation of helper-dependent XAb that act by both complement-dependent and Ab-dependent cell-mediated cytotoxicity mechanisms; the CD8⁺ cells do so as helper-independent cytotoxic T cells.

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