Apoptotic Regulation of Lymphocyte Responses

DESCRIPTION (provided by applicant): The response of lymphocytes to antigen stimulation is characterized by proliferation of an antigen-sensitive lymphocyte population, subsequent differentiation to subsets with effector cell function, and ultimately the retention of antigen-responsive lymphocytes with a memory cell phenotype. The initial increase of responsive lymphocytes is followed by an equally dramatic contraction of the responding population. The characteristic contraction of the number of responding lymphocytes that occurs following the antigen-driven expansion phase is caused, at the molecular level, by a change in the balance of intracellular proteins that are responsible for inhibiting or committing a cell to apoptosis via a programmed cell death pathway. Thus, during the initial antigen-driven expansion phase the level of anti-apoptotic protein(s) is increased and the cell is resistant to programmed cell death. Subsequently the level of these anti-apoptotic proteins declines placing the cell at risk for subsequent events conventionally termed activation-induced cell death. It is the hypothesis of this study that specific immune responses can be inhibited or destroyed at the clonal response level, by preventing the development of the increased level of anti-apoptotic protein(s) that develop during the initial response at the stage of antigen stimulation. Prevention of the production of the antigen response-induced anti-apoptotic proteins will place these cells at immediate risk for activation-induced cell death resulting in a selective deletion of the subset of antigen-responding lymphocytes. Such intervention will result in immunosuppression that is specific rather than global and will only affect those lymphocytes responding to antigen at the time anti-apoptotic protein production is prevented.