DEFECTIVE DE-NOVO THYMOCYTE MATURATION IN CYCLOSPORINE-A (CSA)-INDUCED AUTOIMMUNITY - EXPRESSION OF COSTIMULATORY AND ACTIVATION MOLECULES

Lethally x-irradiated Lewis rats, reconstituted with syngeneic bone ma rrow and transiently treated with CsA for 4 weeks, will develop an aut oimmune disease about 2-3 weeks after cessation of CsA therapy. CsA-in duced autoimmunity is a thymus-dependent and T cell-mediated autoimmun e disease. CsA is thought to generate autoreactive T cells by interfer ence with negative selection in the thymus; x-irradiation is required to eliminate the peripheral autoregulatory T cell circuit. In this stu dy we re-evaluate the effect of CsA on thymic atrophy and thymocyte ma turation. Subsequently we examine the expression of costimulatory and activation molecules (CD2, CD5, CD11a, CD11b, CD25, CD28, CD43, CD54, OX-40, RT-1A, RT-1B and RT-1D) during distinct maturational stages in order to detect possible clues to the observed effects of CsA on thymo cyte maturation and selection. The results revealed that CsA blocks ma turation of double-positive TCRint to double-positive TCRhigh thymocyt es and preferentially inhibits the development of mature CD4 single-po sitive thymocytes. Furthermore, CsA administration resulted in a reduc ed expression of the costimulatory CD2 molecule. Although it is a matt er of debate whether this defective CD2 expression is involved in the aberrant maturation and selection of thymocytes, it is speculated that reduced costimulation via CD2 may influence differentiation into dist inct T cell subsets.