The immune system of humans exhibits senescence during the last quarter of the average life span. General features of this descent include thymic involution and changes in the composition and function of B and T lymphocytes. As a consequence, increased dysregulation of the immune system leads to increased incidence of infections, autoimmune disorders and cancer. Research to seek mechanistic connections between immune senescence and age-related dysfunction clearly are necessary. The goal of the studies proposed in this application are to provide insight as to the events that lead to the generation of B cell lymphomas. Further understanding of these mechanisms would lead to new therapies, e.g., vaccination or immune regulation, for age-appropriate intervention. Studies outlined in this application are designed to: 1. Define the immunobiology that leads to B cell lymphoma generation after transplantation of CD4+ T cell-depleted DBA/2J (Mls-1a-bearing (retrovirus-encoded superantigen)) spleen cells into severe-combined immune defective (SCID) mice. 2. Determine the role that cytokine and apoptotic gene expression play in B lymphomagenesis. This will be assessed using sensitive RNase protection assays to quantitate cytokine (e.g., IL-2,IL-4, IL-10, IL-12, IFNgamma, TNF, TGF) and apoptotic (e.g., Bcl-xL, ICE, Fas, FasL) mRNA expression. The long-term goal of this project is to characterize the cellular and molecular events that facilitate B cell lymphomagenesis. The broad purpose of these studies is to generate novel strategies for preventing the B cell lymphoma generation concomitant with senescence.
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