Department of Pathology & Laboratory Medicine
Elizabeth S. Raveche, Ph.D.
Ph.D., 1977, George Washington University
|McCarthy, B., Mansour, A., Lin, Y., Kotenko, S., Raveche, E. (2004) Analysis of autocrine IL-10 in leukemic B-1 cells after treatement with RNAi and antisense. Cancer Immun (in press)|
|Czarneski, J., Lin,Y., Chong,S., McCarthy,B., Parker, G., Fernandes. H., DeCotiis, C, Huppi, K, Marti, G, Mansour, A., Raveche, E. (2004) Studies in NZB IL-10 Knockout Mice of the Requirement of IL-10 for Progression of B Cell Lymphoma. Leukemia 18: 597-606|
|Fernandes, H, Koneru, B, Fernandes, N, Hameed, M, Cohen, M, Raveche, E., Cohen, S. (2002) Investigation of promoter polymorphisms in the TNF alpha and IL-10 genes in the liver of transplant patients. Transplantation 83: 1886-1891|
|Chong, SY, Lin, Y, Czarneski, J, Zhang, M, Coffman, F, Kashanchi, F, Ravech?, E. S. (2001) Cell Cycle Effects of IL-10 on Malignant B-1 Cells. Genes and Immunity 2:239-247|
|Zhang, M., Chong, SY, Ravech?, E. S.(2001) The Role of B-Cell specific activator Protein (BSAP) in the response of malignant B-1 cells to LPS. Experimental Cell Research 264:233-243|
|Chong, SY, Zhang, M, Lin, Y, Coffman, F, Garcia, Z. Ponzio, N., Ravech?, E. S. (2001) The growth regulatory role of BSAP in NZB malignant B-1 cells. Cancer Immunology Immunotherapy. 50:41-50|
|Parker G, Fernandes H, Chong S, Czarneski, J, Hong, R, Lin, Y,Ravech?. E. (2000). Antisense IL-10 abrogrates the inhibitory effect of IL-10 production by transfected tumor cells. Cytokines Cellular and Molecular Therapy 6: 113-119|
|Parker, G., Peng, B, He M, Gould-Fogerite, S, Chou C and Ravech? E. (2000) In vivo use of antisense IL-10. Antisense Technology in Methods in Enzymology, Vol 314 411-429|
|Morse, R.,Bidwell, J. Ravech?, E. 1999. Poly (C ) repeat polymorphism in the promoter of the IL-10 gene in NZB mice. Eur J. Immunogenetics 26: 377-8|
|Ravech?, E.S., Fernandes, H. Ong, H. Peng, B. 1998. Regulatory role of T cells in a murine model of lymphoproliferative disease. Cell Immunol 187: 67-75|
The main focus of the research is aimed at developing novel methods to induce apoptosis in B-1 malignancies. This work employs human patient samples predominantly from chronic lymphocytic leukemia (CLL) patients, human cell lines and mouse models of CLL. Early work studied the immunomodulatory effects of the interleukin 10 (IL-10) family of cytokines. IL-10 is an important anti-inflammatory cytokine which also acts as a growth factor for B cells. We have found that in the malignant disease, CLL, IL-10 is an important growth factor and prevents cell death, apoptosis. We have used both in vitro analysis of cell cultures, mouse models and samples from patients with CLL to further understand the cell cycle regulation induced by IL-10. We have developed several strategies to decrease IL-10 signaling including: antisense IL-10 (US Patent # 6,184,372 B1 (Feb 6,2001), "Antisense Interleukin 10 and Method of Use"), RNA interferences for IL-10, and soluble IL-10 receptor. We have also genetically engineered a mouse model of CLL, NZB, such that these mice no longer produce IL-10 (NZB IL-10KO see Figure below). This strain does not develop the leukemia and is now on the NCI database for mouse models of cancer. Since we found that IL-10 was an important survival factor in the mouse models of CLL we tested this in human CLL cells and found that antisense IL-10 and soluble IL-10 receptor (which binds IL-10 and prevents it from binding to the IL-10 receptor normally expressed on B cells) both induce cell death in malignant B cells. We searched for other agents that might block IL-10 and found that a soy isoflavone, Genistein, was able to decrease IL-10 and induce apoptosis. Genistein and agents that reduce IL-10, both induce a G2M arrest and reduce cdc25C and the bcl-2 family expression. Recently, microarray analysis of the expression profiles in B cell malignancies demonstrated that CLL patients with a rapidly advancing disease are zap70 positive (the expression of zap70 as a signaling molecule is normally restricted to T cells). In our study, CLL patients with increased zap70 expression were sensitive to genistein. The present work continues to identify agents which act by decreasing IL-10 and apoptosis induction in malignant B cells.