The AIDS associated, non Hodgkin's lymphomas (NHL) are aggressive B-cell malignancies. Large cell lymphoma (LCL) and large cell immunoblastic lymphoma (IBL) occur predominately in a setting of severe immunodeficiency. A high proportion of IBL and of immunoblast-rich LCL have been found to be Epstein Barr Virus (EBV)-associated. We propose to study the process of lymphomagenesis in relation to immune surveillance; factors modifying immune surveillance and the role of the EB virus in the large cell category of AIDS associated lymphomas. The working hypothesis of this proposal is that lymphomagenesis in AIDS-NHL, classified LCL or IBL, is associated with defective cytotoxic T lymphocyte (CTL) mediated immune surveillance and that this is a primary determinant of occurrence, regression or lack thereof under therapy and recurrence. A shift in production by stimulated CD4 cells of II-2 and IFN-gamma (Th1-like response) to production of IL-4, IL-5, IL-6, IL-10 (Th2-like status) as HIV disease progresses has been described. It is proposed that a Th1-like response of CD4 cells is associated with resistant to lymphomagenesis and that the ultimate consequence of a shift to a predominance of a Th2-like response is enhanced lymphomagenesis both due to impaired CTL and the predominance of B cell proliferative cytokines. This will be tested in the context of an ongoing clinical trial of the value of combined antiretroviral and anti-lymphoma chemotherapy. Parameters of immune surveillance at critical time points in the process of lymphomagenesis; initial presentation, lymphoma regression, recurrent lymphomagenesis and progression or sustained remission will be defines. Patients will be staged by Th status based on the amount of cytokine that their peripheral blood lymphocytes (PBL) produce. Specifically, proliferation and in vitro production of cytokines (Il-2, 4,5,6,10, 12, and IFN-gamma following stimulation of PBL with anti-CD3; the amount of CTL activity against HIV-1 infected targets; the amount of natural killer cell activity against K562 cells; the circulating levels of cytokines (IL-2, 5, 6,10,12 and IFN-gamma); the number of CD4, CD8, CD56, CD8+DR+,CD8+CD25+ lymphocytes will be measured. The status of EB virus latency and the immune response to EBV latency antigens will be defined and correlated with clinical events and other immune parameters. The hypothesis that HIV-infected patients with EBV- associated tumors, or a history of EBV-associated tumors, demonstrate a selective defect in the CTL response to EBV latency antigens expressed in the patient's tumor will be tested. The related hypothesis that patients with lymphomas without EBV will show intact responses to the full spectrum of EBV latency antigens will also be tested.
| Patarca, R; Freidlander, A; Harrington, W J et al. (1996) Peripheral blood T cell subsets as prognostic indicators of chemotherapy outcome in AIDS patients with large cell lymphoma. AIDS Res Hum Retroviruses 12:645-9 |
