DONOR BONE-MARROW POTENTIATES THE EFFECT OF TACROLIMUS ON NONVASCULARIZED HEART ALLOGRAFT SURVIVAL - ASSOCIATION WITH MICROCHIMERISM AND GROWTH OF DONOR DENDRITIC CELL PROGENITORS FROM RECIPIENT BONE-MARROW

Background. The influence of donor hematopoietic cell microchimerism o n organ allograft survival has been studied largely in vascularized tr ansplant models. Here, we examine the impact of donor bone marrow (BM) cells administered intravenously together with transient systemic tac rolimus therapy on microchimerism, the survival of nonvascularized car diac allografts, and growth of donor antigen-presenting cells (dendrit ic cells [DCs]) from recipient BM. Methods. Adult male C3H (H2(k)) mic e received heterotopic heart transplants from B10 (H2(b)) donors in th e dorsal ear pinna, They were given no further treatment, or either a short course of tacrolimus (FK506; 2 mg/kg i.p. from day 0 to day 13), unmodified donor BM cells (50x10(6) i.v. on day 0) or both treatments . Grafts were examined daily for contractile activity, Anti-donor cyto toxic T lymphocyte responses were determined in recipients' spleens, M icrochimerism (IA(b+) cells) was demonstrated by immunocytochemical st aining of spleens, and of cells expanded from recipient BM using cytok ines and culture conditions that promote the growth of DCs. Results. T acrolimus alone significantly prolonged median heart graft survival ti me from 10 to 22 days (P<0.001). BM alone failed to prolong graft surv ival, By contrast, tacrolimus + donor BM resulted in a mean survival t ime of 42 days (P<0.01 compared with tacrolimus treatment alone), This marked increase in heart allograft survival was associated with reduc ed anti-donor cytotoxic T lymphocyte responses attributable to a nonsp ecific effect of tacrolimus, In addition, however, a link was observed between the beneficial effect of donor BM and comparatively large num bers of donor major histocompatibility complex class II (IA(b+))-posit ive cells in recipients' spleens, and in cultures of granulocyte-macro phage colony-stimulating factor + interleukin-4-stimulated DCs from re cipients' BM, No donor-derived cells were propagated from heart graft recipients given either tacrolimus or donor BM alone. Conclusions. Thi s nonvascularized organ transplant model demonstrates the positive eff ect on allograft survival of donor BM given at the time of transplant to transiently immunosuppressed recipients. The findings also reveal l inks between hematopoietic cell chimerism, the presence of donor DC pr ogenitors in recipient BM, and organ allograft survival.