Pathogenesis and treatment of cytomegalovirus infection after organ transplantation

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Cytomegalovirus (CMV) causes various types of diseases such as retinitis, hepatitis, pneumonitis, gastritis and colitis. Among them, CMV-associated pneumonitis is a major complication in organ transplant recipients, as the pathogenesis and therapy for the disease is still unclear. This research was organized to solve this problem.Four weeks after intraperitoneal inoculating of 0.2 LD_<50> (50% lethal dose) of murine cytomegalovirus (MCMV) in adult BALB/c mice, MCMV remained detectable in the salivary glands, but not in the lungs or other organs. When the T cells of these mice were activated in vivo by a single injection of anti-CD3 monoclonal antibody (mAb), interstitial pneumonitis was thus induced in the lungs that were free of the virus. Using this animal model of CMV-pneumonitis, we observed the followings.1. In the lungs of such mice persistently infected with MCMV,the cytokines such as IL-2, IL-6, TNF-alpha and IFN-gamma were excessively produced after the injection of mAb.2. Then, Cytokines as TNF-alpha and IFN-gamma produced excessively in the lungs induced inducible nitric oxide synthetase (iNOS).3. A significant elevation of the serum levels of nitrate and nitrite, which are the metabolic products of nitric oxide in the serum, was also observed.4. The administration of a nitric oxide antagonist alleviated the interstitial pneumonitis provoked by anti-CD3 mAb.Based on these findings, we concluded that MCMV-associated pneumonitis is mediated by cytokine-induced nitric oxide.