The major objective of this research is to understand mechanisms of regulation B cell triggering and nonresponsiveness. During the past grant period, the investigators analyzed B cell unresponsiveness induced by exposure to haptenated gamma globulin conjugates. Recently, these workers extended this model to a novel system involving the pretreatment of murine spleen cells with anti-Ig, as surrogate antigen, for 24 hours before challenge with specific antigen or lipopolysaccharide (LPS). This protocol allows the investigators to separate the inductive events from challenge, in analogy to tolerance protocols. Pretreatment led to significant impairment of antibody formation to both specific and polyclonal challenge, with the greatest reduction in the latter. Interestingly, inhibited B cells proliferate normally, suggesting clonal expansion without differentiation may lead to a memory cell population. This system will be analyzed in order to understand the mechanisms for the down regulation of B cell differentiation. The investigators, aims are to establish the basis for the differential reduction in antibody responsiveness to antigen versus LPS, the role of the Fc receptor in this process, and whether membrane IgM and IgD both deliver signals for this downregulation. The necessity for internalization of the Ig:anti-Ig complex and the pathways of intracellular processing will also be examined. In addition, Dr. Scott and coworkers will establish whether clonally expanded B cell lines and Lyl B cells can be regulated in the same manner. The effect of recombinant lymphokines (LK: IL-1 to IL-6, TNF alpha/beta, gamma-IFN), some of which they have shown prevent growth inhibition of B cell lymphomas, will be examined to determine which LK prevent or reverse the negative signal and perhaps lead to memory. These workers will determine the phenotype and subsequent functional activities of these clonally expanded B cells as a model for immunologic memory. These studies interface with their continuing efforts to understand the mechanism of control of B lymphoma growth and the molecular and cell surface events involved in the regulation of the growth and differentiation of normal and transformed lymphocytes. The ultimate goal of this research is to provide the foundation to obviate undesirable humoral responses (such as those that interfere with effective cellular immunity in cancer) or to enhance productive immunity and memory cell development.
