M. Homma et al., DEFECTIVE DE-NOVO THYMOCYTE MATURATION IN CYCLOSPORINE-A (CSA)-INDUCED AUTOIMMUNITY - EXPRESSION OF COSTIMULATORY AND ACTIVATION MOLECULES, Clinical and experimental immunology, 110(1), 1997, pp. 79-85
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.