Although interstitial pneumonitis due to cytomegalovirus (CMV) is a significant source of morbidity for the immunocompromised patient, little is known about the pathogenesis of CMV interstitial pneumonitis and the relative contributions of virus and host factors to the genesis of this process. We previously observed that murine CMV (MCMV) infection significantly augments GVH reaction to major histocompatibility antigens (HA) and leads to severe interstitial pneumonitis, not seen with virus or GVH alone. Preliminary data indicates that pneumonitis seen in combined MCMV/GVH is not the consequence of increased virus replication in the lung due to GVH. The objective of this proposal is to determine the viral and host immune factors important in the pathogenesis of MCMV interstitial pneumonitis associated with GVH. We will examine the role of virus replication in the genesis of pneumonitis and determine the lung structures which support MCMV replication using in situ hybridization methods. We will also examine the quatitative relationship of MCMV lung replication to GVH and interstitial pneumonitis by modulating virus replication in the lungs, using antiviral agents, vaccination, and Ts MCMV mutants. We will also determine if MCMV is present during pneumonitis in which virus cannot be recovered by culture of lung homogenates. The host immune processes operating in the lung during GVH/MCMV interstitial pneumonitis will also be examined. We will characterize the cellular changes which occur in the lungs, determining the lymphocyte phenotypes and the origin (donor/recipient) of the cells present in the lung. We will also examine the functional CMI processes operating in the lung, and determine if these are directed at MCMV or host H2 determinants. By immunohistochemical methods, we will examine the alterations in expression of H2 antigens in the lungs during pneumonitis. We will also determine if modification of the host immune responses will alter interstitial pneumonitis. Finally, we will determine if GVH to minor HA will alter MCMV replication in the lung or lead to interstitial pneumonitis. These studies should substantially increase our understanding of the pathogenesis of CMV pneumonitis and the interactions of viral and host factors which may be involved in the genesis of disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Pathology A Study Section (PTHA)
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University of Connecticut
Schools of Medicine
United States
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Almeida-Porada, G; Porada, C D; Shanley, J D et al. (1997) Altered production of GM-CSF and IL-8 in cytomegalovirus-infected, IL-1-primed umbilical cord endothelial cells. Exp Hematol 25:1278-85
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Shanley, J D; Korngold, R; Forman, S J (1993) The effect of graft-versus-host disease in response to minor histocompatibility antigens on acute murine cytomegalovirus infection. Transplantation 56:487-9
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Shanley, J D (1990) In vivo administration of monoclonal antibody to the NK 1.1 antigen of natural killer cells: effect on acute murine cytomegalovirus infection. J Med Virol 30:58-60
Shanley, J D; Debs, R J (1989) The folate antagonist, methotrexate, is a potent inhibitor of murine and human cytomegalovirus in vitro. Antiviral Res 11:99-106
Erlich, K S; Mills, J; Shanley, J D (1989) Effects of L3T4+ lymphocyte depletion on acute murine cytomegalovirus infection. J Gen Virol 70 ( Pt 7):1765-71
Shanley, J D; Pomeroy, C; Via, C S et al. (1988) Interstitial pneumonitis during murine cytomegalovirus infection and graft-versus-host reaction: effect of ganciclovir therapy. J Infect Dis 158:1391-4

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