The influence of FK-506 on the thymus: an immunophenotypic and structural analysis.

The influence of the powerful new immunosuppressant FK-506 on the thymus was investigated in Sprague Dawley rats that were immunized with sheep erythrocytes and treated with FK-506 (1 mg/ kg/day i.m.) for 7 days. Suppression of humoral immunity in drug-treated animals was accompanied by reductions in circulating lymphocytes bearing activation markers (interleukin-2 receptor β-chain and OX40, activated CD4 cells) and by striking thymic medullary atrophy. There were, however, no significant differences in thymic weights or in thymocyte numbers between experimental and control groups during the period of FK-506 administration. Reduction of the medullary compartment was visualized immunohistochemically, by decreases in major histocompatibility complex (MHC) class 1- and MHC class II-positive cells and in CD37 (mature medullary) thymocytes. Flow cytometric analysis of thymocytes showed that EK-506 induced increases in bright, Thy 1.1 cells and in numbers of CD4+ and CD8+ thymocytes, whilst CD37 cells were less numerous than in controls. Percentages of MHC class 1- and MHC class II-positive cells varied little throughout the course of FK-506 administration. Evidence of selective damage to medullary epithelial cells, attributable to FK-506, was found at both the light and electron microscopic levels, whilst thymic macrophages in drug-treated rats displayed features of enhanced phagocytic activity, including ingestion of damaged epithelial cells. These FK-506-induced abnormalities were reversed within 14 days of drug withdrawal. These findings suggest that, like cyclosporin A. FK-506 reversibly disrupts the thymic microenvironment and may interfere with the junction/maturation of T lymphocytes. [ABSTRACT FROM AUTHOR]