B lymphocytes are the central mediators of humoral immunity. Aberrant B cell function contributes to many autoimmune diseases and age-related defects in humoral immunity, with malignant B cells representing the primary cell type in leukemia and lymphoma. B cell function is regulated by cell-surface molecules that generate transmembrane signals, regulate intercellular communication, and direct lymphocyte development.
The aim of these studies is to examine the in vivo function of CD20, a B cell-specific cell-surface protein, and other members of the MS4A gene family that we have recently identified. CD20 is a membrane embedded component of an oligomeric complex that regulates transmembrane Ca2+ transport and cell cycle progression. Anti-CD20 immunotherapy has become a standard treatment for non-Hodgkin's lymphoma, and shows great promise for the treatment of autoimmunity. Despite this, relatively little is known about the function of CD20 in vivo and why it is such an effective target for immunotherapy. Since mechanistic and outcome studies are difficult and expensive in humans and other primates, we have developed mouse models for anti-CD20 mAb therapy that allows us to determine the molecular basis for therapeutic efficacy in vivo. We hypothesize that the molecular structure and function of CD20 and other MS4A family members makes them unique targets for effective therapy. To test this hypothesis, we will determine how CD20-directed therapies regulate B cell function in vivo and determine whether other members of the MS4A gene family are also effective immunotherapy targets.
In Specific Aim 1, the functional significance and consequences of anti-CD20 mAb therapy will be assessed in normal mice.
In Specific Aim 2, the molecular and cellular basis for B cell clearance will be determined.
In Specific Aim 3, the efficacy and mechanism of mAb therapy will be assessed in mouse models of lymphoma.
Specific Aim 4 will focus on the structure and expression of 20 newly-identified members of the MS4A gene family in mouse and man to determine whether they are appropriate targets for immunotherapy. Since CD20 provides an important regulatory checkpoint for ablating or adjusting B cell development and function, a molecular understanding of how it and other MS4A family members function will provide new avenues for modulating humoral immunity and effectively treating human disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA105001-03
Application #
7105656
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Howcroft, Thomas K
Project Start
2004-08-15
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$246,625
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Matsushita, Takashi; Tedder, Thomas F (2011) Identifying regulatory B cells (B10 cells) that produce IL-10 in mice. Methods Mol Biol 677:99-111
Nakashima, Hiroko; Hamaguchi, Yasuhito; Watanabe, Rei et al. (2010) CD22 expression mediates the regulatory functions of peritoneal B-1a cells during the remission phase of contact hypersensitivity reactions. J Immunol 184:4637-45
Yoshizaki, Ayumi; Yanaba, Koichi; Iwata, Yohei et al. (2010) Cell adhesion molecules regulate fibrotic process via Th1/Th2/Th17 cell balance in a bleomycin-induced scleroderma model. J Immunol 185:2502-15
Kuijpers, Taco W; Bende, Richard J; Baars, Paul A et al. (2010) CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 120:214-22
DiLillo, David J; Matsushita, Takashi; Tedder, Thomas F (2010) B10 cells and regulatory B cells balance immune responses during inflammation, autoimmunity, and cancer. Ann N Y Acad Sci 1183:38-57
Ogawa, Asako; Yoshizaki, Ayumi; Yanaba, Koichi et al. (2010) The differential role of L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity. J Invest Dermatol 130:1558-70
Watanabe, Rei; Ishiura, Nobuko; Nakashima, Hiroko et al. (2010) Regulatory B cells (B10 cells) have a suppressive role in murine lupus: CD19 and B10 cell deficiency exacerbates systemic autoimmunity. J Immunol 184:4801-9
DiLillo, David J; Yanaba, Koichi; Tedder, Thomas F (2010) B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice. J Immunol 184:4006-16
Ait-Oufella, Hafid; Herbin, Olivier; Bouaziz, Jean-David et al. (2010) B cell depletion reduces the development of atherosclerosis in mice. J Exp Med 207:1579-87
Haas, Karen M; Watanabe, Rei; Matsushita, Takashi et al. (2010) Protective and pathogenic roles for B cells during systemic autoimmunity in NZB/W F1 mice. J Immunol 184:4789-800

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