Long-term Heart Allograft Survival Research Articles

A short-term combination therapy with cyclosporine and rapamycin or leflunomide induces long-term heart allograft survival in a strongly immunogenic strain combination in rats.

Synergism between cyclosporine (CsA) and rapamycin (RAPA) or leflunomide (LF) was studied in a strongly immunogenic cardiac allograft model in rats. In the absence of immunosuppression, PVG recipients rejected WKAH heart grafts after a mean survival time (MST) of 5.2 +/- 1.1 days. A dose of 7.5 mg/kg per day CsA did not prolong graft survival (MST 5.6 +/- 1.2 days). CsA given at 10 mg/kg per day for 30 days extended MST of the grafts to 48 +/- 7 days. A short course of combination therapy consisting of adding a non-therapeutic dose of RAPA or a subtherapeutic dose of LF to a 1-month course of CsA resulted in permanent graft survival. These data suggest that RAPA and LF synergize with CsA enabling not only the lowering of the dose of CsA, but also inducing transplantation tolerance.

Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats.

Rapamycin (RAPA) induces unresponsiveness toward heart allografts by at least two mechanisms: selective production of noncytotoxic IgG2c-blocking Ab and preferential activation of Th2 cells. RAPA (0.8 mg/kg/day) delivered via a 14-day osmotic pump to Wistar Furth (WF; RT-1u) recipients prolongs Buffalo (BUF; RT-1b) heart allograft survival from a mean survival time (MST) of 6.5 +/- 0.5 days to 75.0 +/- 18.9 days (n = 18; p < 0.001), with 6 of 18 grafts beating for more than 100 days. Recipient sera or their IgG but not IgM fraction, obtained after postgrafting day 40, passively transfer the unresponsive state to sublethally irradiated secondary recipients in a dose-dependent and immunologically-specific fashion. Sera obtained after untreated WF hosts rejected BUF hearts contained IgG moieties of all subclasses that bound to class I MHC BUF epitopes. In contrast, the unresponsive sera contained predominantly non-C'-fixing IgG2c and only marginal amounts of activated (C') fixing IgG1, IgG2a, and IgG2b Ab. The transcription of IL-2, IL-4, and IL-10 mRNAs was assessed using a PCR method. There were similar increases in the levels of IL-2, IL-4, and IL-10 mRNA in heart allografts from both untreated and RAPA-treated recipients on day 5 postgrafting. In contrast, on days 60 and 300 postgrafting heart allografts from RAPA-treated unresponsive recipients showed increased levels of IL-10 and IL-4 but not of IL-2 mRNA, suggesting preferential activation of Th2 cells. Thus, RAPA treatment selectively inhibits the synthesis of C'-binding of IgG subclasses, spares the non C-binding blocking IgG2c Ab, and preferentially activates Th2 cells.

Induction of long-term heart allograft survival in the rat by rabbit ATG.

A rat model for induction of transplantation tolerance, by antithymocyte globulin (ATG) as sole immunosuppressive agent, was studied. Vascularized heart allografts were employed. The conditions for establishment of long-term surviving (LTS) grafts were investigated as well as some of the characteristics of the tolerant state. The tolerance-inducing effect of ATG was found to be reproducible and dose-dependent. Treatment before grafting was essential. Preimmunization of the recipient inhibited the tolerance induction, while thymectomy seemed to have the opposite effect. The differences in survival of second allografts, third party or syngeneic to the first, indicated a largely strain-specific tolerance that most probably was the result of a changed host reactivity and for its induction strictly depended on presence of the graft. There were microscopical signs of rejection in the LTS grafts, while almost no such changes could be found in second allografts from the same donor strain, transplanted to the LTS-bearing recipients.

Serum-blocking factors versus specific cellular tolerance in long-term survival of rat heart allografts.

Long-term survival of Ag-B compatible rat heart allografts was obtained by short-term treatment of the recipients with antilymphocytic serum (ALS). Graft survival apparently was based on a specific change in the hosts rather than on persistent nonspecific effects of ALS. The hosts were not fully tolerant in that they were able to reject secondary skin allografts from the heart donor strain, although in a delayed fashion. The long-surviving heart allografts retained their immunogenicity as they were rejected when retransplanted to new hosts. The passive transfer of serum from long-term heart graft acceptors to new hosts receiving fresh allografts delayed rejection by several days. This effect was seen only with the serum from long-term acceptors suggesting that serum-blocking factors were involved in long-term survival of the heart allografts. However, the ability of adoptively transferred lymphoid cells to break tolerance to a heart allograft residing in a classically tolerant host was tested. In contrast to normal lymphoid cells, cells from the long-term acceptors were unable to break tolerance, suggesting that a specific cellular tolerance had been induced in this cell population. Moreover, a serum from the long-term acceptors failed to block the breakage of tolerance by normal lymphoid cells.