Tolerance induction of alloreactivity by portal venous inoculation with allogeneic cells followed by the injection of cyclophosphamide. I. Specific suppression of alloreactive cytotoxic and delayed-type hypersensitivity responses as well as allograft rejection.

BALB/c mice receiving allogeneic C3H/He spleen cells via portal venous (p.v.) route or a single administration of cyclophosphamide (Cy) were capable of rejecting allogeneic X5563 tumor cells (C3H/He origin). In contrast, the combined treatment of p.v. inoculation with C3H/He cells and Cy administration abrogated the capability of rejecting allogeneic X5563 tumor cells. The dose of Cy and interval between p.v. presensitization and Cy injection needed to be more than 1.5 mg Cy/mouse and less than 2 days, respectively. Such abrogation of alloreactivity was alloantigen-specific, since p.v. inoculation of C3H/He cells followed by Cy injection resulted in selective inhibition of rejecting allogeneic C3H/He tumor cells (X5563 plasmacytoma) without suppressing the capability of rejecting allogeneic C57BL/6 tumor cells (EL4 leukemia). Most important, the induction of alloantigen-specific unreactivity by p.v. presensitization plus Cy injection contrasted with the failure of intravenous or subcutaneous presensitization plus Cy injection to induce tolerance that permits the growth of allogeneic tumor cells inoculated. This was substantiated by the finding that p.v. presensitization with C3H/He cells prior to Cy injection eliminated anti-C3H/He cytotoxic T lymphocyte (CTL) and delayed-type hypersensitivity (DTH) potentials under conditions in which appreciable CTL and DTH responses are induced in mice inoculated via the i.v. route before Cy injection. These results demonstrate that p.v. inoculation of allogeneic cells followed by a single administration of Cy results in more efficient elimination of antialloantigen CTL and DTH reactivities, leading to the abrogation of potential to reject the allogenic tumor graft.