Validation of Donor-Specific Tolerance of Intestinal Transplant by a Secondary Heart Transplantation Model

摘要

Objectives: It is well accepted that survival after a second organ transplant without immunosuppressive agents indicates tolerance for the first transplant. To validate donor-specific tolerance, we established arat model with a secondary heart transplant after intestinal transplant, which has so far not been described in the literature. Materials and Methods: We transplanted intestine from Fischer F344 rats to Lewis rats orthotopically. Lewis rats received tacrolimus pretreatment before trans-plant and a 14-day course of rapamycin 1 month after transplant. At 120 days after primary intestinal transplant, hearts from 6 F344 rats (group A) or 6 Brown Norway rats (group B) were transplanted to Lewis rats that had survived intestinal transplant and without additional immunosuppressive agents. We analyzed survival data, histologic changes, cells positive for the ED1 macrophage marker in trans-planted hearts, and 3 lymphocyte levels in both groups. Results: Thirty days after secondary heart transplant, group A hearts were continuously beating; however, group B hearts stopped beating at around 10 days after transplant (8.5 ± 1.5 d; P .05). Fluorescence-activated cell sorting showed that CD4/CD25-positive regulatory T cell, CTLA4/CD4/CD25-positive regulatory T cell, and Natural killer T-cell levels were significantly higher level in group A versus B ( P < .05). Conclusions: The donor-specific tolerance that we observed was possibly a state of “clinical tolerance” rather than “immunologic tolerance.” Our rat model is a feasible and reliable model to study donor-specific tolerance. The higher levels of lymphocytic T cells shown in intestinal transplant recipients were associated with longer allograft survival, possibly contributing to donor-specific tolerance.