SYNERGY BETWEEN SUBTHERAPEUTIC DOSES OF CYCLOSPORINE AND IMMUNOLOGIC ENHANCEMENT IN RAT RECIPIENTS OF CARDIAC ALLOGRAFTS1

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Abstract
We have analyzed the adjunctive effect of subtherapeutic doses of cyclosporine (CsA, 1.5 mg/kg/day * 7 or 14 days) on cardiac allograft survival in actively and passively enhanced rats. This CsA dose, one tenth of the effective dose, when administered after, but not before, transplantation into enhanced hosts produced permanent graft acceptance; cardiac allografts survive c. 25 days in recipients enhanced only and 1 week in untreated animals. Adoptive transfer of spleen T cells of OX8+ or W3/25+ phenotype from long-term (>200 days) graft recipients prolonged donor-specific test graft survival in naive rats (c. 16 days and c. 14 days, respectively, P<0.001) and delayed rejection in reconstituted B rats from 7 days to 21–23 days (P<0.001). Indeed, both T subsets were separetely equally potent and with no overlap responsible for the suppressor activity. The phenotypic profile of the immune cells in the maintenance phase of enhanced or enhanced + CsA-treated recipients was comparable to naive or isografted controls as demonstrated by flow cytometry and immunohistologic studies. Furthermore, the activation status of the graft infiltrate in long-term survivors was similar regardless of the initial immunosuppressive protocol. CsA contributed selectively to the enhancing regimen in the induction phase of unresponsiveness, diminishing the cellularity of graft infiltrate and preventing intragraft T cell activation. These studies stress synergy between subtherapeutic doses of CsA and immunologic active/passive enhancement, 2 immunosuppressive modalities that spare T cells with suppressor capabilities byt differ in the inhibition of T helper cell activation.

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