MIXED ALLOGENEIC CHIMERISM IN THE RAT - DONOR-SPECIFIC TRANSPLANTATION TOLERANCE WITHOUT CHRONIC REJECTION FOR PRIMARILY VASCULARIZED CARDIAC ALLOGRAFTS

Graft loss secondary to chronic rejection remains a major source of mo rbidity and mortality in solid organ transplantation. Mixed chimerism has been suggested as one potential approach to overcome this limitati on Until now, whether long-term tolerance for primarily vascularized a llografts can be achieved with mixed chimerism has not been adequately assessed due to technical limitations in the mouse and the inability to establish a reliable model of mixed chimerism in the rat. We now re port that stable multilineage mixed hematopoietic chimerism can be ach ieved following the transplantation of a mixture of T cell-depleted sy ngeneic and allogeneic bone marrow cells into myeloablated rat recipie nts using a number of MHC pins minor antigen-disparate donor and recip ient strain combinations (F344+WF-->F344, F344+ACI-->F344, WF+F344-->W F, and WF+ACI--->WF). Ninety-one percent of animals engrafted with a l evel of lymphoid chimerism ranging between 12% and 93% (73.3+/-4.8%). Peripheral blood lymphocyte chimerism remained stable for up to 13 mon ths after reconstitution. Multilineage chimerism for lymphoid (T and B cells) and myeloid (granulocyte and macrophage) Lineages was present, which suggests that engraftment of the pluripotent rat stem cell had occurred. There was no clinical or histologic evidence of graft-versus -host disease. Donor-specific skin (mean survival time [MST] greater t han or equal to 177 days) and primarily vascularized cardiac (MST grea ter than or equal to 213 days) grafts were accepted without evidence f or acute or chronic rejection. In contrast, MHC-disparate third-party skin (MST = 14 days) and cardiac grafts (MST = 13 days) were rapidly r ejected. The tolerance was systemic, since donor-specific tolerance wa s present in vitro as assessed by the mixed lymphocyte proliferation a ssay. These data suggest that mixed chimerism prevents graft loss seco ndary to chronic rejection in skin as well as primarily vascularized g rafts. Furthermore, a rat model for mixed allogeneic chimerism may pro vide insight into the mechanisms involved in tolerance induction for a variety of allografts (lungs, small bowel, Limb, etc.) not readily tr ansplantable in mouse recipients.