Effect of combined Cyclosporine A and liposome encapsulated dichloromethylene diphosphonate on the organisation of the rat thymus: evidence for a role of macrophages in guiding the post Cyclosporine A thymic reorganisation.

Cyclosporine A (CsA) is a powerful immunosuppressant inducing marked involution of the thymic medulla, and disappearance of interdigitating cells (IDCs) and reducing the number of macrophages (Mphi). Usually, while the thymus of rats receiving a short course of CsA promptly recovers after stopping CsA treatment, long term CsA treatment, like mediastinal irradiation, impairs the normal thymic recovery and is thought to be responsible for the development of autoimmune diseases. In the present study we evaluated the role played by the IDCs and Mphi in the normal recovery of the thymic histology at light and ultrastructural level. Besides CsA administration, we also used liposome-encapsulated dichloro-methylene-diphosphonate (lip-CL2MDP), that induces a total depletion of the Mphi resistant to CsA. After a short (21 days) course of CsA and lip-CL2MDP administration, we did not observe the normal recovery of the thymic parenchyma but only cortical zones consisting of lymphoblasts, epithelial cells and Mphi. The CsA/lip-CL2MDP treatment determining the loss of IDCs and Mphi and consequently the loss of the normal thymic histology seems to simulate in the rats, the long term CsA treatment or the mediastinal irradiation. The results obtained suggest that the loss of IDCs and the depletion of Mphi interfere with the normal thymic recovery. The delay in the recovery of I DCs could be a consequence of the absence of macrophages. These findings would indicate that the IDCs, determining the negative selection of T-lymphocytes, are the main cells responsible for the thymic microenvironment.