SUCCESSFUL EXPERIMENTAL HEART-TRANSPLANTATION WITHOUT IMMUNOSUPPRESSIVE DRUGS

Donor-specific unresponsiveness is an important goal of heart transpla ntation research. Work by other investigators has shown that intrathym ic transplantation of pancreatic islet cells not only leads to factor permanent acceptance of the intrathymic graft but tolerance to subsequ ent extrathymic islet cell transplants. We applied this concept to a m odel of heart allotransplantation in the rat. Recipient Lewis rats wer e treated with 1 ml of antilymphocyte serum and 5 x 10(7) Lewis-Brown Norway spleen cells injected into the thymus under direct vision. Twen ty-one days later, heterotopic heart transplantation was performed wit h Lewis-Brown Norway (allograft) and Wistar-Furth (third-party allogra ft) donors. Control Lewis recipients received no treatment, antilympho cyte serum alone, or antilymphocyte serum plus intrathymic syngeneic L ewis spleen cells. Another group of animals received intravenous Lewis -Brown Norway cells before transplantation with Lewis-Brown Norway hea rt donors. Untreated control animals had heart graft survival of 6 to 10 days (mean, 7.6 days) and 7 to 9 days (mean, 7.8 days) for Lewis-Br own Norway (n = 5) and Wistar-Furth (n = 5) donors, respectively. Anti lymphocyte serum alone (n = 10) failed to prolong survival of Lewis-Br own Norway grafts (mean, 10.7 days; p = not significant). Antilymphocy te serum plus intrathymic Lewis cells (n = 5) did not prolong survival of a subsequent Lewis-Brown Norway graft (mean, 9.2 days; p = not sig nificant). Survival of Wistar-Furth third-party allografts (n = 10) wa s not prolonged by intrathymic Lewis-Brown Norway cells (mean survival , 13.9 days; p = not significant). Intravenous Lewis-Brown Norway cell s (n = 10) prolonged survival of Lewis-Brown Norway grafts to 10 to 18 days (mean, 14.5 days; p < 0.02). The most pronounced prolongation of Lewis-Brown Norway graft survival occurred in animals pretreated with intrathymic Lewis-Brown Norway cells (n = 10). Mean survival was 66.7 days (p < 0.001), with three of 10 grafts surviving indefinitely. Pro longation of graft survival was seen when cells from a modified recipi ent were passively transferred to a naive animal. These experiments su ggest that manipulation of the thymic milieu with noncardiac allogenei c cells can produce prolongation of graft survival and in some cases c omplete tolerance to a cardiac allograft. Such manipulations may form the basis for improved biologically based treatments of heart transpla nt recipients in the future.