The long-term objective of the proposed research is to understand the basis and significance of the pathologic alterations in lymphocyte IgM-Fc receptor expression that are triggered in mice bearing IgM-secreting tumors. These studies address an interesting but poorly understood facet of tumor immunology, but at the same time they are focused on fundamental aspects of immunoregulatory mechanisms.
The specific aims are to investigate the: a) occurrence, b) specificity, c) regulation, d) structure, e) physiological significance and f) mechanisms of action of IgM-specific Fc receptors on murine T and B lymphocytes. The impetus for the studies comes from: a) initial studies that are published, b) preliminary findings presented in the proposal, and c) the absence of information on lymphocytes. Igm Fc receptors in spite of the substantial evidence in the literature that express Fc receptors specific for IgE, IgA, IgG and IgD appear to play important immunoregulatory roles. The experimental approach to address these questions will utilize: a) multiparameter flow cytometry to measure the developmental expression and regulation of IgM Fc receptors on normal and neoplastic T and B lymphocytes, b) constant region domain deletional mutant IgM molecules to identify the site(s) on IgM molecules recognized by the IgM receptor(s), c) recombinant and purified lymphokines, and normal and mutant proteins to investigate their influence on IgM Fc receptor expression, d) monoclonal and polyclonal antibodies specific for IgM Fc receptors to isolate and chemically characterize the receptors, e) recombinant DNA techniques to isolate and characterize the gene(s) that encodes IgM Fc receptors, and f) immunological and biochemical techniques to identify and dissect the physiological significance of lymphocyte IgM Fc receptors. We expect that these studies will provide new information about IgM Fc receptors on lymphocytes, the mechanisms by which they influence immunologic processes, and the relationship of IgM FcR to receptors for other classes of immunoglobulin in heavy chains. These studies will also further dissect the immunologic relationship between the immune system of the host and the malignant IgM-producing lymphoid cells growing in the host. An improved understanding of these issues could provide useful in understanding and influencing pathologic alterations of immune function that occur in humans with immunoglobulin-secreting neoplasms as well as provide insight into the immunologic alterations triggered in the host by cells and secreted products of malignant lymphoid tumors.
