Research described in this proposal will enhance our capacity to classify and treat human B cell malignancies. Molecular tools will be generated that permit the rapid isolation and/or identification of the immunoglobulin (Ig) variable region genes (V genes) expressed by clonal populations of malignant B cells. With such tools we may examine the molecular basis for the high frequency expression of particular Ig V genes in CD5 B cell malignancies. In addition, we will immunize mice with either human Igs potentially possessing conserved cross-reactive idiotypes (CRIs), or synthetic peptides, that mimic conserved Ig variable region framework epitopes, to generate anti-idiotype or anti-framework antibody-producing hybridomas that will be selected using the fluorescence activated cell sorter. In total, these tools may allow us to distinguish B cell malignancies with respect to Ig V gene utilization. They also will allow us to examine Ig gene expression by CD5 B cells isolated from normal volunteers and unaffected siblings of patients with CD5 B cell malignancies. Through these studies we may gain insight into physiology of Ig V gene expression and factors contributing to B cell neoplasia. Finally, these reagents will allow us rapidly to characterize clonally distributed antibody variable region determinants that may be targeted for active immunotherapy in a pilot phase I study testing the safety of synthetic peptide vaccines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA049870-04
Application #
3194191
Study Section
Experimental Immunology Study Section (EI)
Project Start
1989-05-01
Project End
1994-04-30
Budget Start
1991-05-01
Budget End
1992-04-30
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Kohsaka, H; Carson, D A; Rassenti, L Z et al. (1996) The human immunoglobulin V(H) gene repertoire is genetically controlled and unaltered by chronic autoimmune stimulation. J Clin Invest 98:2794-800
Ranheim, E A; Cantwell, M J; Kipps, T J (1995) Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells. Blood 85:3556-65
Rassenti, L Z; Kohsaka, H; Kipps, T J (1995) Analysis of immunoglobulin VH gene repertoire by an anchored PCR-ELISA. Ann N Y Acad Sci 764:463-73
Ranheim, E A; Kipps, T J (1995) Tumor necrosis factor-alpha facilitates induction of CD80 (B7-1) and CD54 on human B cells by activated T cells: complex regulation by IL-4, IL-10, and CD40L. Cell Immunol 161:226-35
Martin, T; Crouzier, R; Weber, J C et al. (1994) Structure-function studies on a polyreactive (natural) autoantibody. Polyreactivity is dependent on somatically generated sequences in the third complementarity-determining region of the antibody heavy chain. J Immunol 152:5988-96
Ranheim, E A; Kipps, T J (1993) Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med 177:925-35
Kipps, T J (1993) Immunoglobulin genes in chronic lymphocytic leukemia. Blood Cells 19:615-25;discussion 631-2
Kobayashi, R; Rassenti, L Z; Meisenholder, G et al. (1993) Autoantigen inhibits apoptosis of a human B cell leukemia that produces pathogenic rheumatoid factor. J Immunol 151:7273-83
Kipps, T J; Carson, D A (1993) Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood 81:2475-87

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