Sequential analyses of the development of lymphoproliferative disorders in rats receiving cyclosporine.

Cyclosporine (Cys)-associated, atypical lymphoproliferation in gut-associated lymphoid tissue (GALT) was reproducibly observed in male Sprague Dawley rats by feeding a diet containing 0.015% Cys. Sequential morphological changes occurring in the lymphoid organs of the rats on a Cys diet for 8-10 weeks were examined, and these changes were correlated with those observed in electrophoretic patterns of serum proteins. Proliferative lymphoid alterations were detected in the GALT after 2 weeks of feeding, and these progressed through 8 weeks. Atypical lymphoid proliferation was also seen in lymph nodes after 8 weeks of feeding; thymuses showed marked medullary atrophy, and spleens had a diminution of their periarterial lymphoid sheaths. Elevated levels of gamma-globulin were detected after 4 weeks of Cys administration, and became more pronounced by 8 weeks. The lymphoid lesions induced in rats bear striking similarities to the post transplant lymphoproliferative lesions in patients receiving Cys and in patients with the acquired immune deficiency syndrome.