This project represents a continuation of closely coordinated clinical and basic laboratory investigations of multiple myeloma (MM) and related plasma cell dyscrasias (PCD). The specific goals of the five individual projects are as follows: (1) clinical and immunochemical studies of PCD will elucidate the pathogenesis and pathophysiology of PCD, characterize monoclonal immunoglobulins (MIg) with respect to their antibody activities and those properties which relate to specific pathophysiological manifestations in individual cases (e.g., amyloidosis, polyneuropathy, and lipodystrophies), and will investigate new methods of treatment of myeloma, macroglobulinemia, and amyloidosis; (2) studies of the assembly and hapten binding of human myeloma proteins will be undertaken in an effort to determine the primary, secondary, and if possible, tertiary structures, particularly those with known antibody specificities, and to develop mouse hybridomas secreting MIg with the same specificity as the flavin-binding human IgG?GAR? in order to compare their primary and secondary structures and pattern of chain assembly; (3) screening of human myeloma proteins for anticarbohydrate activity in order to perform detailed analyses of primary, secondary, and tertiary structures will be initiated, as will an attempt to relate the defined specificities to possible pathogenic mechanisms in specific patients whose MIg display these antibody activities; (4) determination of patterns of plasma cell and B-cell differentiation in PCD and CLL and definition of the changes in cell markers including Ig and Ia as well as idiotype expression will be investigated, and the study on the dynamics of histocompatibility antigens in B-cell leukemia, lymphomas, and IgM PCD commenced; and (5) the assembly of V?H? genes in human PCD will be studied in order to delineate how rearrangements of human V?H?, D, J?H?, and C?H? gene segments contribute to antibody diversity, including isolation of the heavy chain variable region gene segments from human myeloma tumors and characterization of their composition, organization, and structure; also characterization of myeloma and other tumors with regard to karyotypic abnormalities and oncogene expression will be explored. (CS)
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