Human cytomegalovirus (HCMV) infection is an important clinical problem for patients undergoing allogeneic transplantation. The most important manifestation of infection is interstitial pneumonitis, an often fatal complication occurring during the first 100 days after transplantation. Although the pathogenesis of infection is not understood, there is substantial evidence from both murine and human studies to indicate that the disease may be mediated immunologically rather than by direct viral damage. We hypothesize that the interstitial pneumonitis associated with HCMV in the allogeneic setting is an immunopathologic process that is mediated by cytokines, e.g., TNF-alpha, TNF-beta, IL-1, IL-2 and interferon-gamma. HCMV in this setting leads to stimulation of immune cells of the lung which induces local production of cytokines which mediate tissue injury. In this proposal, we will investigate the role of these cytokines in the tissue injury of the lungs of mice during interstitial pneumonitis associated with HCMV infection and GVHD and in patients with HCMV infection of the lung before and during the course of interstitial pneumonitis. This will be accomplished by direct measurements of specific cytokines from blood and cells obtained by bronchoalveolar lavage and by molecular methods to assess production of these cytokines. In the murine model we will determine the effect of monoclonal or polyclonal antibody to these cytokines on the course of pneumonitis. Finally, we will also examine the effect of HCMV and MCMV on cytokine secretion and whether these cytokines alter the cellular susceptibility to infection by HCMV or MCMV. These investigations should allow us to determine the role of cytokines in the pathophysiology of pneumonitis following allogeneic transplantation.
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