B-cell chronic lymphocytic leukemia (B-CLL), the most common non-solid tumor in western societies, currently has no effective treatment. Conventional chemotherapeutic drugs are toxic and not well suited to the biology of the disease. In studies that have begun to elucidate the structural requirements of the induction of in vivo targeted death of primary B lymphocytes, we have shown that the bacterial toxin, Staphylococcus aureus protein A (SPA) forms complexes with membrane B-cell receptors (BCR) that induce programmed cell death. The current studies will characterize the properties of the pro-apoptotic BCR complex, and assess whether co-blocking of other immunological survival signals can enhance this potential therapeutic approach.
SPECIFIC AIMS : These studies will evaluate basic mechanisms, and consider the overall relevance and efficacy of treatment in an in vivo model of human B-CLL deletion.
Aim 1 : To define the nature of the pro-apoptotic ligand-BCR complexes on healthy and leukemic Human B cells. Studies will be carried out to reveal the SpA-BCR complexes formed on healthy and CLL B-cells. Using flow cytometry and de-convoluted con-focal microscopy, we will characterize the pro-apoptotic complexes, and specific constituents required to cause activation and signaling of these B-cells in vitro.
Aim 2 : To evaluate the sensitivity of B-CLL cells to BCR-induced deletion in an in vivo RAG -/- transfer model. We will investigate the deletion of transferred healthy and CLL B-cells in RAG-1 -/- mice and evaluate whether the specific B-CLL subset can be deleted with SpA (VH3-specific) and also investigate the mechanism(s) associated with B-cell deletion.
Aim 3 : To evaluate the enhancement of BCR induced apoptosis in B cells by simultaneously blocking alternative immunological survival signals. To further define how BCR targeting can be utilized as a therapeutic reagent, different pathways of activation-induced cell death will be considered and how they can be enhanced by the addition of various inhibitors for immunological survival signals i.e., TACI-Fc or anti- BAFF antibodies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA104815-02
Application #
6864872
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Howcroft, Thomas K
Project Start
2004-03-09
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2007-02-28
Support Year
2
Fiscal Year
2005
Total Cost
$136,800
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
MacLellan, Lindsay M; Montgomery, Jennifer; Sugiyama, Fujimi et al. (2011) Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum 63:3897-907
Goodyear, Carl S; Corr, Maripat; Sugiyama, Fujimi et al. (2007) Cutting Edge: Bim is required for superantigen-mediated B cell death. J Immunol 178:2636-40
Goodyear, Carl S; Silverman, Gregg J (2005) B cell superantigens: a microbe's answer to innate-like B cells and natural antibodies. Springer Semin Immunopathol 26:463-84
Silverman, Gregg J; Goodyear, Carl S; Siegel, Don L (2005) On the mechanism of staphylococcal protein A immunomodulation. Transfusion 45:274-80
Goodyear, Carl S; Silverman, Gregg J (2004) Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes. Proc Natl Acad Sci U S A 101:11392-7