S. Saiagh et al., INDUCTION OF APOPTOSIS IN MOUSE THYMOCYTES BY CYCLOSPORINE-A - IN-VIVO STUDY, Immunopharmacology and immunotoxicology, 16(3), 1994, pp. 359-388
We investigated the in vivo effect of cyclosporin A (CsA) on mouse thy
mus and thymocytes. Administration Of CsA (10 mg/kg of body weight) wa
s found to induce a marked reduction in the size, weight and consisten
cy of the thymus. These modifications were associated with thymic reti
culo-epithelial cells (TREC) and thymocyte damage. Some of the damaged
thymocytes displayed characteristic of cells undergoing apoptosis. Ul
trastructural study of thymocytes and thymic tissue, as well as DNA el
ectrophoresis of thymocytes, showed chromatin condensation, cellular s
hrinkage, and nuclear fragmentation in oligonucleosomal fragments. DNA
labeling with propidium iodide (PI) of thymocytes from CsA treated mi
ce cultured for 24 hrs showed an increased number of apoptotic nuclei.
Furthermore, flow cytometric analysis using monoclonal antibodies (mA
bs) specific for thymocyte subsets confirmed that CsA induces a large
decrease in the relative number of mature single positive (SP) CD4+CD8
- and CD8+CD4- thymocytes expressing high densities of CD3 and T cell
receptor ab (TCR alpha beta) surface molecules, but also a decrease in
the absolute number of the other thymocyte subsets. These results sug
gest that CsA causes macroscopic and ultrastructural modifications of
the thymus, associated with an active process of cell death in mouse t
hymocytes in vivo. In line with these results we formulate a hypothesi
s concerning the stage of T-cell development at which CsA induces apop
tosis.