Cytokine production in response to Epstein‐Barr virus infection of peripheral blood mononuclear cells in vitro

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Abstract
To obtain a better understanding of the immune response to Epstein-Barr virus (EBV), we measured the cytokines tumour necrosis factor (TNF)-/, interleukin-2 (IL-2), interferon-gamma (IFN-), IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the conditioned medium of peripheral blood mononuclear cells from 10 healthy adults before and at 48 h and at 1, 2, 3 and 4 weeks following infection in vitro with EBV. Cultures were examined for regression of outgrowths of nascent virus-transformed B cells, and populations of cells in the cultures were analysed by flow cytometry. TNF-/ was not detected in infected or non-infected cultures. In infected cultures assayed at the nominated times, the highest levels of IL-2 were detected at 48 hours, IFN- at 1 week, IL-6 at 2 weeks and GM-CSF between 2 and 4 weeks. IL-6 and GM-CSF, but not IL-2 or IFN-, were detected in non-infected cultures but at lower levels than in infected cultures. Nine of the 10 healthy adults showed regression of outgrowths of virus-transformed B cells and, of these, seven had antibodies to the EBV capsid antigen (VCA). Strong regression was associated with sequential increases in IL-2, IFN-, and low levels of IL-6 and GM-CSF. Absent or weak regression was associated with an undetectable level of IL-2, a low level of IFN-, high levels of IL-6 and GM-CSF and an increased frequency of cells bearing the phenotype CD20 and HLA-DR in the final weeks of culture. The percentage of cells with a phenotypic marker for natural killer cells remained constant in all cultures over the 4 week period, and there was a modest decrease in the percentage of T cells in both infected and non-infected cultures. The demonstration of different temporal profiles of cytokines is in accord with a programmed cellular immune response to EBV infection which could serve as a model to study the events that modulate the inflammatory response to EBV.