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)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA021112-09
Application #
3092929
Study Section
Clinical Cancer Program Project Review Committee (CCP)
Project Start
1979-05-01
Project End
1987-04-30
Budget Start
1985-05-01
Budget End
1986-04-30
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
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Kabat, E A (1988) Antibody combining sites: how much of the antibody repertoire are we seeing? How does it influence our understanding of the structural and genetic basis of antibody complimentarity? Adv Exp Med Biol 228:1-45
Berman, J E; Mellis, S J; Pollock, R et al. (1988) Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus. EMBO J 7:727-38
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Kabat, E A; Nickerson, K G; Liao, J et al. (1986) A human monoclonal macroglobulin with specificity for alpha(2----8)-linked poly-N-acetyl neuraminic acid, the capsular polysaccharide of group B meningococci and Escherichia coli K1, which crossreacts with polynucleotides and with denatured DNA. J Exp Med 164:642-54
Merlini, G; Farhangi, M; Osserman, E F (1986) Monoclonal immunoglobulins with antibody activity in myeloma, macroglobulinemia and related plasma cell dyscrasias. Semin Oncol 13:350-65
Bonagura, V R; Agostino, N; Crow, M K et al. (1985) Anti-immunoglobulin stimulation of human B lymphocytes is inhibited by anti-class II major histocompatibility complex antibodies. Cell Immunol 96:442-7

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