Cyclosporin A-Induced Autoimmunity in the Rat: Central versus Peripheral Tolerance

Abstract

Cyclosporin A-induced autoimmunity (CsA-AI) is a thymus dependent and T cell-mediated autoimmune disease that is readily induced in rodents (1, 2) and also occurs in humans (3). Induction of CsA-AI requires total body X-irradiation, rescue with syngeneic or autologous bone marrow, and subsequent cyclosporin A (CsA) administration for about 4 weeks (4). Because the induction protocol involves bone marrow transplantation (BMT), CsA-AI is also referred to as syngeneic or autoimmune graft-versus-host disease (GvHD) (5). The CsA-AI model is being studied for three reasons. Firstly, the animal model, and in particular the chronic phase of the disease, has been reported to have several macroscopic and histopathologic similarities with human scleroderma (6,7). Secondly, CsA-AI is clinically and experimentally examined for its graft- versus-tumour potential against lympho-hematopoietic malignancies as well as metastatic breast cancer (8). And thirdly, CsA-AI has been very informative in terms of T cell development and tolerance induction, including central as well as peripheral control of autoreactivity (9, 10). In the present review, a summary of the characteristics of CsA-AI will be given. Next, the supposed mechanism of CsA for interference with central tolerance induction will be presented. Finally, the role of peripheral tolerance, and in particular dominant T cell tolerance as mediated by regulatory T cells, will be discussed in relation to induction of CsA-AI as well as to strain-related resistance to CsA-AI.