Cyclophosphamide (CY) and 5-Fluorouracil (5-FU) have been shown to spare cytotoxic T-lymphocyte (CTL) precursors while eliminating or inactivating accessory T-helper cells. Interleukin 2 (IL2), in vitro and in vivo, provides the necessary help for expanding specific CTL precursors in spleen cells of mice treated with 5-FU or CY. The 5-Fu, unlike Cy, also spares precursors of antibody-forming cells. The 5-FU does, however, inhibit T- cell-dependent antibody responses which can be restored in full by purified T-cell-replacing factor (TRF).
The aims of this proposal are to determine the optimal conditions for administering purified lymphokines in vivo as adjuncts to chemotherapy. Doses and regimens of CY and 5-FU, which are therapeutic for neoplasia and spare precursors to antibody-forming cells and CTL will be employed. The long-term objective is to develop in vivo models in which immunity in chemotherapy-suppressed mice can be restored by purified soluble helper factors. The in vivo model for restoring immunity will be a viral protection system dependent primarily upon CTL responses. Influenza A, a virus that is eliminated by CTL, is dependent upon upon helper T-cell activity (and T-helper cell-derived lymphokines) which are eliminated by CY and 5-FU. We have chosen CY and 5-FU because in addition to sparing precursors to effector cells, they cause regression of tumor growth in experimental animals bearing syngeneic transplantable tumors or spontaneous tumors. Since immune suppression occurring during administration of these agents occurs at the level of cell-cell interactions dependent upon helper T-cell responses, IL2 and TRF will provide the necessary second signals for precursor differentiation which will ultimately be responsible for elimination of exogenous viral infections in vivo. Rate-controlled systems for the delivery of IL2 and TRF in vivo will be tested and compared to more conventional means of administration. Optimal conditions for the restoration of cellular and humoral immunity will be applied to in vivo protection models for Influenza A viral infections.
