IMMUNOBIOLOGY OF AIDS--LARGE CELL LYMPHOMA

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/947/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health: $266,017.00
  • National Institutes of Health: $291,917.00
  • National Institutes of Health

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Human Herpesvirus 4
Lymphoma
Acquired Immunodeficiency Syndrome
Virus Latency
Large-Cell Immunoblastic Lymphoma
Interleukin-5
Cytotoxic T-Lymphocytes
Cytokines
Non-Hodgkin's Lymphoma
Lymphocytes
Antigens
AIDS-Related Lymphoma
Neoplasms
HIV
B-Lymphocytes
K562 Cells
Immunologic Factors
Natural Killer Cells
Interleukin-4
Interleukin-10

ASJC

  • Medicine(all)