Cyclosporine and the thymus: influence of irradiation and age on thymic immunopathology and recovery.

With the proper experimental conditions, previous studies have demonstrated that syngeneic and autologous radiation chimeras treated with cyclosporine (CsA) routinely develop a syndrome resembling graft-vs-host disease (GVHD) after CsA is discontinued. The thymus is clearly important in the pathogenesis. Thymectomy prior to CsA prevents the development of syngeneic GVHD and the process can be adoptively transferred via thymocytes. The thymus, however, must be within the field of irradiation and the animal must be young. Here we examine how irradiation and advanced age influence the thymic immunopathologic changes induced by CsA and influence the recovery post-CsA. Young LEW rats, with or without pre-CsA mediastinal irradiation, demonstrate a marked involution of the thymic medulla with associated loss of medullary epithelium, Hassall's corpuscles, class II antigen expression, and maturation of thymocytes. While the control group underwent rapid and complete regeneration of the medulla post-CsA, however, the medullary changes in the irradiated group were prolonged or permanent. Most of these animals had changes of chronic GVHD. Older LEW rats had a more prominent medulla prior to CsA. In contrast to younger rats, the medulla did not show significant involution with CsA. While the Hassall's corpuscles disappeared, the medullae still had fusiform epithelium, dendritic cells, and class II antigen expression. Phenotype stains demonstrated many mature-appearing CD4+/CD8- lymphocytes. In light of evidence indicating the importance of the medullary microenvironment to the maintenance of self tolerance, the medullary effects of CsA are most likely essential to the development of autoimmunity. Young rats rapidly lose the ability to maintain tolerance. While unirradiated rats rapidly reestablish the proper microenvironment following CsA, irradiated rats have a prolonged loss. Older rats may resist the development of autoimmunity by retaining the medullary microenvironment.