Linomide induces apoptotic death of cortical CD4/CD8 double positive thymocytes and thymic atrophy by a corticosteroid-independent pathway

Linomide is a synthetic immunomodulator which was shown to protect animals against a wide range of experimental autoimmune diseases. In this study we have investigated the effects of Linomide on the thymus in an effort to elu cidate the mechanisms by which this immunomodulator suppresses autoimmune r eactivity. Normal or adrenalectomized SJL/J mice were treated orally for 10 days with linomide (80 mg/kg/day). Thymocytes were tested by FACS for the analysis of the CD4 and CD8 markers and TCR expression on their surface. Th ymuses from these animals were examined for size and cellularity and immuno histopathologically for the detection of apoptosis and for the expression o f the markers CD4 and CD8. A significant reduction in the thymus size and c ellularity was observed in mice treated with Linomide, starting from day 3 after treatment, accompanied by an enhanced apoptotic death of cortical thy mocytes, which was first noted on day I of treatment and peaked on day 3. F ACS analysis and immunohistochemistry revealed a significant depletion of t he CD4(+)/CD8(+) (double positive) cells with a parallel relative increase of the more mature, medullar, single positive, lymphocytes. These effects o n the thymus were not mediated through a corticosteroid-dependent pathway, and were also observed in adrenalectomized and Linomide-treated animals. Th ese observations may be of importance for the clarification of the role of thymus in autoimmunity and the possible ways for immune intervention with i mmunomodulators like Linomide at this level. (C) 1999 Academic Press.