Down regulation of T-cell-derived IL-10 production by low-dose cyclophosphamide treatment in tumor-bearing rats restores in vitro normal lymphoproliferative response

In previous reports, we demonstrated an inhibitory effect of a single low-d ose of cyclophosphamide (Cy) on spontaneous and experimental metastasis of a rat lymphoma (L-TACB). This antimetastatic effect could be adoptively tra nsferred by immune spleen cells from Cy-treated turner-bearing rats and it was abrogated by the use of immunosuppressed hosts, suggesting an immunomod ulatory effect. Subsequently, we found that increased levels of TGF-beta, I L-10 and NO were involved in tumor-induced immunosupression by inhibiting l ymphocyte proliferation. The treatment of tumor-bearing rats with low-dose Cy reduced the splenic production of these suppressive cytokines, restoring the lymphoproliferative capacity otherwise diminished during tumor growth; th. Here, we investigated the changes of the cytokines modulated by the Cy therapy that are responsible for the restoration of the lymphoproliferative response and determined the spleen cell type producing TGF-beta, IL-10 and NO in our experimental model. Our current results show that IL-10 and NO a re produced exclusively by T lymphocytes and macrophages, respectively, whe reas TGF-beta is produced by both cell types. The high level of IL-10 produ ced by T-cells from tumor-bearing rats is responsible for the inhibition of lymphocyte proliferation. Moreover, our results suggest that the shift fro m immunosuppression to immunopotentiation induced by treatment of tumor-bea ring rats with a single low-dose of Cy is mediated by a reduction in T-cell derived IL-10 production, which would account, to same extent, for the ant imetastatic effect of Cy treatment. (C) 2001 Elsevier Science B.V. All righ ts reserved.