DIFFERENTIAL-EFFECTS OF X-IRRADIATION AND CYCLOSPORINE-A ADMINISTRATION ON THE THYMUS WITH RESPECT TO THE GENERATION OF CYCLOSPORINE-A-INDUCED AUTOIMMUNITY

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 transplantat ion, and a 4-week course of CsA administration causes the development of an autoimmune disease (CsA-AI) resembling allogeneic graft-versus-h ost disease. This occurs upon withdrawal of CsA, provided the thymus r eceives irradiation and is present during CsA treatment. In this study , the separate effects of irradiation or CsA treatment on thymic strom al cells and thymocytes, compared to the combinatory effects, were exa mined using immunohistochemistry and tricolor flow cytometric analysis . CsA treatment causes an involution of the thymic medulla and a stron g reduction of the cell number of thymocytes and stromal cells residin g in the medulla. However, within the remaining medullary area, change s in cell distribution and antigen density on these cells were not obs erved. Irradiation on the other hand causes a strong depletion of thym ocytes. The thymocyte population is recovered within 2 weeks and a cor tical and medullary region can be distinguished. CsA treatment in comb ination with irradiation results in a strongly inhibited recovery of t he 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. How ever, the distribution of these stromal cells is normal. During the Cs A administration, the thymuses from irradiated and CsA-treated rats ar e very similar to thymuses from CsA-treated rats. In conclusion, no ch anges specific for irradiation plus CsA treatment have been observed. Regarding the distribution and size of medullary stromal cells and res iding 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.