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 beta-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 I- and MHC class II-positive cells and in CD37+ (mature medullary) thymocytes. Flow cytometric analysis of thymocytes showed that FK-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 I- 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 function/maturation of T lymphocytes.
Pugh-Humphreys
R G
RG
Department of Pathology, University of Aberdeen, U.K.
Ross
C S
CS
Thomson
A W
AW
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004848:Epithelium / Q000187:drug effects / Q000648:ultrastructure; D005434:Flow Cytometry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007958:Leukocyte Count / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects; D016559:Tacrolimus; D013950:Thymus Gland / Q000187:drug effects* / Q000648:ultrastructure
D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents; D016559:Tacrolimus