- SLE is characterized by excessive activation of both B and T lymphocytes. Recent therapeutic approaches have involved the use of anti-CD40 ligand and CTLA4Ig, agents that antagonize the costimulatory pathways of B and T cell activation. The goals of these investigators are 1) to determine the mechanisms by which CTLA4Ig and anti-CD40L therapy inhibit the development and regulation of pathogenic B cells that secrete the autoantibodies responsible for tissue damage in SLE and 2) to identify the mechanism responsible for the powerful synergy between these two agents.
In Specific Aims I and II the applicant will determine whether the regulatory effects of anti-CD40L and CTLA4Ig are mediated via naive hyper-reactive germ line encoded B cells that develop outside the germinal centers, somatically mutated and class switched B cells that arise within the germinal centers, and/or plasma cells within the long lived bone marrow compartment. They will do this by analyzing monoclonal anti-DNA antibodies generated from treated B/WF1 mice, and studying the expression of a particular autoreactive antibody gene that is highly restricted to anti-DNA antibodies in these mice. Subpopulations of autoreactive B cells bearing the R4A Tg anti-DNA HC will also be examined. T and B cell co-cultures will be used to determine whether the effects of these agents on B cells are mediated by modulation of the T cell compartment or whether B cell nonresponsiveness has been induced. Finally it will be determined whether these agents alter B cell responses to an exogenous antigen. The experimental tools the applicants developed will allow an examination of central and peripheral regulation of autoreactive B cells. These findings should help determine optimal regimens for delivery of CTLA4Ig and anti-CD40L to humans and help predict their safety profiles in the autoimmune host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047291-05
Application #
6739700
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Johnson, David R
Project Start
2000-05-01
Project End
2005-03-18
Budget Start
2004-05-01
Budget End
2005-03-18
Support Year
5
Fiscal Year
2004
Total Cost
$167,000
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Schiffer, Lena; Sinha, Jayashree; Wang, Xiaobo et al. (2003) Short term administration of costimulatory blockade and cyclophosphamide induces remission of systemic lupus erythematosus nephritis in NZB/W F1 mice by a mechanism downstream of renal immune complex deposition. J Immunol 171:489-97
Wang, Xiaobo; Huang, Weiqing; Mihara, Masahiko et al. (2002) Mechanism of action of combined short-term CTLA4Ig and anti-CD40 ligand in murine systemic lupus erythematosus. J Immunol 168:2046-53