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SUMMARYLethally irradiated Lewis (LEW) rats reconstituted with syngeneic bone marrow and given CsA for a 4-week period, develop, upon withdrawal of CsA, a graft-versus-host-like disease, so-called CsA-induced autoimmunity (CsA-AI). This T cell-mediated autoimmune disease is thymus-dependent; it is generally held that this disease is a consequence of aberrant T cell recovery brought about by CsA. In this study we determined mononuclear cell subsets phenotypically by tri-colour flow cytometry. A strong decrease in recent thymic emigrants (Thy1.1 + , TCR ® ¯ + ) was observed as a consequence of CsA treatment, eventually resulting in decreased absolute peripheral T cell numbers. In these rats no altered CD4:CD8 T cell ratio was observed before onset of CsA-AI; CD4 + and CD8 + cells consisted predominantly of monocytes (CD4 dim+ , TCR ® ¯ -) and natural killer cells (CD8 + , TCR ® ¯ -), respectively. LEW rats, xirradiated, syngeneic bone marrow-reconstituted and treated with CsA, showed a marked and persistent, relative expansion of mature CD45RC + , RT6 -Th cells. In contrast, Brown-Norway rats treated in a similar fashion, or LEW rats subjected to either CsA treatment or x-irradiation, did not show a comparable expansion of mature CD45RC + , RT6 -Th cells, nor did these animals develop CsA-AI. The CD45RC + , RT6 -Th cells produced IL-2, and moreover constituted the only Th subset producing IFN-°u pon stimulation, and therefore were considered as Th1-like effector cells. These results are consistent with the view that a persistent preponderance of Th1 cells and not the mere presence of autoreactive cells determines whether or not clinically manifest CsA-AI will occur.

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Cyclosporin A (CsA), a potent inhibitor of T-cell activation, has been shown to have several effects on thymocyte maturation, thymic stromal cells, and the generation of autoreactive T cells. In Lewis rats, the combination of lethal irradiation, syngeneic bone marrow transplantation, and a 4-week course of CsA administration causes the development of an autoimmune disease (CsA-AI) resembling allogeneic graft-versus-host disease. This occurs upon withdrawal of CsA, provided the thymus receives irradiation and is present during CsA treatment. In this study, the separate effects of irradiation or CsA treatment on thymic stromal cells and thymocytes, compared to the combinatory effects, were examined using immunohistochemistry and tricolor flow cytometric analysis. CsA treatment causes an involution of the thymic medulla and a strong reduction of the cell number of thymocytes and stromal cells residing in the medulla. However, within the remaining medullary area, changes in cell distribution and antigen density on these cells were not observed. Irradiation on the other hand causes a strong depletion of thymocytes. The thymocyte population is recovered within 2 weeks and a cortical and medullary region can be distinguished. CsA treatment in combination with irradiation results in a strongly inhibited recovery of the medulla during CsA treatment, whereas the cortex recovers to normal size and morphology. The presence of the medullary IDC and epithelial cells is reduced proportionally to the small size of the medulla. However, the distribution of these stromal cells is normal. During the CsA administration, the thymuses from irradiated and CsA-treated rats are very similar to thymuses from CsA-treated rats. In conclusion, no changes specific for irradiation plus CsA treatment have been observed. Regarding the distribution and size of medullary stromal cells and residing thymocytes, thymuses from irradiated and CsA-treated rats hardly differ from the thymuses from rats treated only with CsA. Therefore, irradiation seems essential in the generation of CsA-AI by eliminating suppressor-cell circuits in the periphery.

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