We will continue our research efforts to chemically and biologically characterize the thymosins, a family of hormonal like peptides isolated from bovine thymus. Two thymosin preparations, thymosin fraction 5(TF5) and thymosin yield1 (Tyield1), are active biological response modifiers (BRM's) and have been shown to reconstitute immune function in patients with primary and secondary immunodeficiency diseases. In Phase II trials, Tyield1 was found effective in restoring helper T-cell function and prolonging survival in patients with non-oat lung cancer following radiotherapy (RT). Tyield1 is the first of the BRM's to enter Phase III trials in non-oat cell lung cancer in conjunction with RT. These trials are currently underway at 25 medical centers under the auspices of the RTOG and MAOP cooperative programs of the NCI. During the course of the current grant period, we have identified a number of other thymic peptides which influence neuroendocrine as well as immune circuits and stimulate the release of peptides, such as ACTH, LHRH, GH, prolactin and Beta-endorphin. We have also demonstrated that TF5 and Tyield1 act to modulate production of lymphokines, such as interleukin-2 (IL-2), and upsilon-interferon in peripheral blood lymphocytes. These studies provide the first evidence of a mechanism whereby thymosin may influence post-thymic lymphocytes. The research has the following objectives: -- Chemical characterization of novel thymosins responsible for the range of biological activities in TF5 and TF5A. -- Further definition of the biological properties of these thymic peptides on modulation of immune and neuroendocrine circuits. --Development of monoclonal antibodies and immunoassays for monitoring physiological changes in these peptides with age and/or disease states. --Development of in vitro and in vivo assays for establishing the mechanism(s) of action and physiological roles of these thymic peptides including receptor studies. It is anticipated that these studies will result in the characterization of several new thymic hormones, lymphokines and/or cytokines, which like Tyield1, may help in the development of new treatments for cancer and other diseases associated with a malfunctioning thymus and/or immunosuppression of the host.
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