LYMPHOID NONLYMPHOID COMPARTMENTALIZATION OF DONOR LEUKOCYTE CHIMERISM IN RAT RECIPIENTS OF HEART ALLOGRAFTS, WITH OR WITHOUT ADJUNCT BONE-MARROW/

Background. The role of leukocyte migration and chimerism in organ all ograft acceptance has been obscured by the lack of information about t he late localization of the donor cells. Methods. Male Lewis rat-->fem ale Brown Norway abdominal heart transplantation was performed under t acrolimus immunosuppression (days 0-13, 20, and 27) with or without do nor bone marrow and (in bone marrow subgroups) a 1-week postoperative course of a possibly chimerism-enhancing drug. Using rat sex-determini ng region-Y-specific oligonucleotide primers, we determined the donor DNA concentration by polymerase chain reaction in serial venous blood samples for 100 days and in tissue specimens when animals were killed. Results. Chimerism was detected out to 56 days in 89% of the blood sa mples but in none of the samples at 100 days. However, donor DNA was d etected when animals were killed in 95% of the native hearts, 80% of t he skin biopsy specimens, and 23% of the spleens. The presence and qua ntity of early and late chimerism were strongly correlated the adminis tration of adjunct bone marrow and with a reduction in the vasculopath y and inflammation index in the cardiac allografts. Marginally signifi cant further increases in chimerism and/or reductions in chronic heart rejection beyond those achieved with adjunct bone marrow alone were a ssociated with additional treatment with the growth factors Flt-3 liga nd, granulocyte colony-stimulating factor, and a recombinant molecular variant of interleukin-6 (interleukin-6 mutein) but not with hepatocy te growth factor or lisofylline. Conclusions. The previously suspected shift of early chimerism in the blood and lymphoid organs to dominanc e in host nonlymphoid tissues is consistent with the dual mechanisms o f clonal exhaustion and immune indifference, governed by antigen migra tion and localization, that have been postulated elsewhere to account for organ allograft acceptance.