DONOR-SPECIFIC PROLONGATION OF RAT SKIN-GRAFT SURVIVAL INDUCED BY RAT-DONOR CELLS AND CYCLOPHOSPHAMIDE UNDER COADMINISTRATION OF MONOCLONAL-ANTIBODIES AGAINST T-CELL RECEPTOR-ALPHA-BETA AND NATURAL-KILLER-CELLS IN MICE

Because of the recent interest in human xenotransplantation, we invest igated the possibility of inducing tolerance in a xenogeneic combinati on using cyclo-phosphamide (CP), Donor-specific prolongation of xenoge neic Fisher 344 (F344) rat skin graft survival for up to 60 days was i nduced in C57BL/6 (B6) mice by giving F344 bone marrow cells and splee n cells on day 0, CP on day 2, and monoclonal antibodies against murin e TCR-alpha beta and NK1.1 on days -1 and 3. The inoculation of the xe nogeneic cells brought accelerated repopulation of TCR-alpha beta(+) T cells, even under the administration of anti-TCR-alpha beta mAb. The quick increase of the host TCR-alpha beta(+) T cells caused by the xen ogeneic cell injection was deeply suppressed by CP. Mixed lymphocyte r eaction, CTE activity, and antibody production against donor F344 were profoundly suppressed for 50 days. Mixed xenogeneic chimerism was obs erved for 1 month after the inoculation of donor cells in the spleen a nd peripheral blood of the recipient Be mice, but was never observed i n the thymus, Moreover, when irradiated F344 cells were used in place of viable cells, chimerism was never detected and graft survival was o nly slightly prolonged, Clonal deletion of V beta 5- or V beta 11-bear ing murine T cells was not observed on day 50 in the thymus or spleen of the recipient B6 mice. These results suggest that treatment with vi able xenogeneic donor cells, CP, and mAbs against T and NK cells can i nduce a temporary peripheral mixed chimerism and donor-specific prolon gation of xenogeneic skin graft survival, The destruction with CP of T and B cells that are xenoreactive and thus proliferating after antige n stimulation, followed by mechanisms other than intrathymic clonal de letion, may be the mechanism of the hyporesponsiveness in the present system.