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The effect of cyclosporin A (Cy A) on the host responses to heart allografts have been examined in rats following administration of the drug for 7 days after grafting. All grafts functioned greater than 100 days without rejection episodes in animals of major histocompatibility differences. Thymic or splenic lymphocytes (1 X 10(8) from LEW recipients of (LEW X BN)F1 hearts were transferred at varying periods into untreated LEW rats transplanted with (LEW X BN)F1 test hearts 24 hr later. Test grafts survived 12 to 16 days significantly (P less than 0.001) longer than in untreated animals (MST +/- SD = 7 +/- 0.3 days). Cells from normal LEW animals, Cy A-treated but ungrafted, and grafted but not treated animals, all failed to prolong test graft survival. Specificity of the effect was tested in vivo, using hearts from donor and third-party rats, and in vitro, using the mixed lymphocyte response (MLR). In vivo, thymocytes from treated LEW recipients of (LEW X WF)F1 grafts failed to prolong (LEW X BN)F1 test grafts; conversely, transferred thymocytes from LEW recipients of LEW X BN)F1 grafts failed to prolong (LEW X WF)F1 grafts. The MLR of lymphocytes from Cy A-treated rats was significantly decreased against donor lymphocytes but not against third-party lymphocytes. Additionally, both cellular and humoral immunity mounted by Cy A-treated recipients was depressed throughout the entire follow-up period. Prolonged heart graft survival after 7 days of Cy A treatment suggests emergence of cells with specific suppressor activity, which in turn may cause profound abrogation of host effector responses against vascularized organ allografts.

Untreated LEW rats reject primarily vascularized Ag-B-incompatible LBNF1, BN, and WF cardiac allografts in 6 to 8 days. Cyclosporin A (CyA) administered 15 mg/kg/day i.m. for 7 days after grafting extends graft function greater than 100 days. Histological studies demonstrated that CyA treatment strikingly reduces the size and cellularity of the thymic medulla, splenic marginal zone, and splenic periarterial sheath by 97, 67 and 50%, respectively. These compartments are thought to contain cells of a single T lymphocyte lineage with helper and cytotoxic functions. CyA was less effective against cells in the thymic cortex and splenic red pulp, compartments thought to contain suppressor cells. CyA-induced depletion of lymphoid tissues was maximal 7 to 14 days after completion of treatment. All compartments recovered nearly normal morphology by 50 to 100 days, although hyperplastic nodules were found in spleens of three WF heart graft recipients during the recovery phase. CyA was more effective, histologically, in inhibiting the immune response to heart grafts from WF than from LBNF1 or BN donors. Within 3 days after LBNF1 or BN heart grafting, moderate antibody production occurred in the spleen (as noted by increase in Ig-positive immunoblasts) and vascular damage occurred in the grafts. These signs of rejection were delayed until 14 days in WF heart grafted rats. In none of the strain combinations were these early reactions followed by a vigorous cellular infiltrate. Thus, CyA seems to decrease preferentially cytotoxic and helper T lymphocyte responses to cardiac allografts.