Patients with chronic infectious diseases and cancer have an impaired immune response characterized by an absent delayed type hypersensitivity (DTH), a decreased cytotoxic function and a diminished proliferation to antigenic stimuli. The basis for this immune dysfunction has been poorly understood, however, it could present a barrier in the development of new therapeutic cancer vaccines and immunotherapy protocols. Multiple reports have demonstrated alterations in signal transduction molecules of T cells, suggesting that these could in part explain the immune dysfunction in these patients. Recent reports have also shown an impaired expression of costimulatory molecules in tumor associated antigen presenting cells which could lead to T cell anergy. Therefore, we hypothesize that chronic stimulation by tumor antigens, in the absence of adequate costimulation can induce T cell anergy and lead to an impaired expression of signal transduction molecules. Preliminary data from our laboratory demonstrates that in vitro chronic stimulation of the T cell receptor in the absence of costimulatory signals, results in altered expression of signal transduction molecules, similar to those described in patients with cancer, leprosy and other chronic inflammatory diseases. The present proposal will use this in vitro model to carry out the following Specific Aims: 1) to characterize the alterations in signal transduction molecules in T cells and in CD4 and CD8 T cell subsets, induced by chronic stimulation; 2) to study the kinetics of these changes and identify the intracellular mechanisms leading to such alterations; and 3) to test whether chronic stimulation of tumor specific T cell clones, with tumor specific antigens, can result in the induction of anergy and T cell signal transduction alterations.
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