Recent studies in the applicant's laboratory have demonstrated an important role for CD4+ T lymphocytes in downmodulation of the humoral immune response and control of aberrant B cell proliferation's. Specifically, CD40 ligand positive (CD40L+) T lymphocytes can upregulate Fas expressed by B cells. In the research proposed, the applicant will characterize this process as it may be applied to human B cell neoplasms: 1. To examine more precisely the extracellular factors that effect Fas- mediated signaling, with particular emphasis on CD4+ T-cells, Fas ligand, and monoclonal antibody to Fas; 2. To analyze parameters that render malignant B cells susceptible or resistant to CD4+ Th1-induced Fas expression and apoptosis. The focus will be on the following possible mechanisms of resistance: (a) expression of EBV genes; (b) surface immunoglobulin crosslinking; (c) defects in the Fas receptor; 3. To extend their initial studies, which are based on Burkitt's lymphoma B cell line cells, to cells from a variety of leukemias and lymphomas, including fresh tumor specimens; 4. To examine how CD40L-induced Fas expression and apoptosis in malignant B cells can be applied in vivo, using adoptive transfer of human tumor cells into SCID (severe combined immunodeficiency) mice.
| Schattner, E J; Mascarenhas, J; Reyfman, I et al. (1998) Chronic lymphocytic leukemia B cells can express CD40 ligand and demonstrate T-cell type costimulatory capacity. Blood 91:2689-97 |
| Bishop, J Y; Schattner, E J; Friedman, S M (1998) CD40 ligation impedes lymphoblastoid B cell proliferation and S-phase entry. Leuk Res 22:319-27 |
