The cellular basis of cardiac allograft rejection VIII. Mechanisms underlying delayed allograft rejection in PVG C6-deficient rats

Background. The delayed allograft rejection in C6-deficient PVG C6 - rats compared with normal PVG rats- has been attributed to the lack of alloantibody activation of the membrane attack complex of complement. As T cells alone have been shown to effect graft rejection, we examined T-cell responses in PVG C6 - rats. Methods. The cellular infiltrate and its mRNA for cytokines and effector molecules in DA heart allografts to PVG and PVG C6 - rats was compared by immunoperoxidase staining and semiquantitative reverse transcriptase polymerase chain reaction. The ability of pure populations of T cells or alloantibody to mediate DA heart graft rejection in irradiated (750 rads) PVG and PVG C6 - rats was also compared. Results. The median rejection time of DA heart allografts was 8 days in PVG rats and 17.5 days in PVG C6 - . PVG C6 - rats sensitized to DA by two skin grafts rejected DA heart grafts in 5-6 days. CD3 + , CD4 + , CD8 + , interleukin-2 receptor-positive T cell, macrophage, and natural killer cell infiltration, as well as class II major histocompatibility complex and intercellular adhesion molecule-1 up-regulation, in grafts was similar in naive PVG and PVG C6 - rats. mRNA for T helper 1 cytokine interleukin-2, interferon-γ, tumor necrosis factor-β, macrophage molecules tumor necrosis factor-α, and inducible nitric oxide synthase, as well as cytotoxic T-cell effector molecules perforin and granzyme A and B, were found to be the same in the grafts from both naive PVG and naive PVG C6 - rats. Thus, there appeared to be no difference in the T-cell effector response between the PVG and PVG C6 - groups. There were higher alloantibody titers in PVG C6 - rats than in PVG hosts. Irradiation ablated rejection and alloantibody responses and reconstitution with naive T cells alone restored rejection in both PVG and PVG C6 - rats. Irradiated rats given serum from PVG rats that had rejected DA grafts did not effect rejection of DA grafts even if given naive T cells. Sensitized T cells restored second set. Conclusions. PVG C6 - rats have normal T-cell responses and can mediate allograft rejection in the absence of alloantibody. The failure of PVG C6 - to reject allografts rapidly may be a result of the poor clearance of alloantisera leading to enhancement of graft survival rather than a critical role for complement and membrane attack complex in acute rejection.