Non-Hodgkin's B cell lymphoma (AIDS-lymphoma) is seen in greatly-elevated frequency in AIDS and HIV infection. In this proposal, studies to delineate immune system changes in HIV infection that are relevant to the development of AIDS-lymphoma are presented.
The specific aims are: l) to elucidate the mechanism by which IL6 enhances the resistance of lymphoblastoid B cells, or AIDS-lymphoma cells, to cytotoxic T lymphocyte- mediated lysis and apoptosis, by determining if IL6 modulates the expression or activity of cellular receptors (fas, TNF-receptor, CD4O) for apoptotic signals or of proto-oncogenes (p53 or bcl-2) involved in the regulation of apoptosis, 2) to confirm preliminary studies indicating that Hiv-i gp4l can induce monokine (IL6 and IL10) production, to determine if other immune cells bind and respond to gp41, and to identify the molecule on monocytes that interacts with HIV gp4l, and 3) to define immune- stimulatory factors that contribute to the greatly elevated levels of serum sCD23 seen in AIDS-lymphoma and/or to AIDS-lymphoma cell growth. The accomplishment of these specific aims will add valuable new information to our understanding of the role of immune dysfunction in the generation and growth of AIDS-associated lymphoma. While the dominant immune system dysfunction seen in AIDS is a severe functional and numerical CD4 T cell defect, various other immune system changes are seen, including a marked increase in B cell activation. The high frequency of B cell lymphoma seen in HIV infection may result from this chronic polyclonal B cell stimulation, which could increase the frequency of c-myc:Ig gene chromosomal translocations, resulting in B cell tumors. Also, loss of immunoregulatory control of EBV-activated lymphoblastoid B cells could contribute to AIDS-lymphoma: IL6 appears to allow such cells to escape growth control, by enhancing resistance to CTL- mediated killing. Studies described in this proposal will examine how HIV interacts with monocytes, resulting in the induction of IL6 production, the mechanisms by which IL6 acts as a viability-enhancing, apoptosis- inhibiting factor for EBV-transformed lymphoblastoid B cells and AIDS- lymphoma cells, as well as the role of B cell stimulatory factors (cytokines, cytokine receptors, and cell-surface stimulatory molecules), other than IL6, in AIDS-lymphoma cell growth. The realization of the specific aims will provide valuable information on the relationship between HIV-induced immune dysfunction and the development of AIDS-lymphoma. This information could form the foundation for future studies on the role of cytokines in AIDS-lymphoma, or could suggest new forms of treatment for AIDS-related diseases. Also, the realization of these specific aims could lead to new screening techniques able to detect AIDS-lymphoma earlier in the course of tumor development, allowing for earlier clinical intervention.
Showing the most recent 10 out of 49 publications
