Pathogenesis of cytomegalovirus infection after organ transplantation

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Cytomegalovirus (CMV)-associated pneumonitis (CMV-P) is a major complication in organ transplant recipients, although its pathogenesis has been still unclear. This research was organized to solve this problem. In 1998-1999, the following results were obtained.1. (C3HxBALB/c) F1 mice, which had been inoculated with 0.2 LD50 of murine cytomegalovirus (MCMV) at 4 wk before, were injected with parental spleen cells to induce GVH. Thereafter, MCMV-DNA could be detectable in the lungs and hearts in Nitric Oxice (NO)-dependent manner, suggesting that NO played a role in MCMV reactivation. However, such emergent DNA was not transferred to RNA. Thus, other factor(s) may be required for the full reactivation of latent MCMV.2. Four weeks after intraperitoneal inoculating of 0.2 LD50 (50% lethal dose) of (MCMV) in adult BALB/c mice or in (C57BL/6xSv129) F1 mice, CMV-P was evoked by a single injection of anti-CD3 mAb in the lungs free of the virus. In immunohistochemistry, nitrotyrosine was detected in the bronchioepithelial cells, suggesting that the cells were targeted in our model of CMV-P. In contrast, CMV-P could not be induced in inducible Nitric Oxidase Synthetase knock-out (iNOS KO) mice.3. In in vitro assay, T cells from MCMV-infected mice, in which the virus was detected only in the salivary glands, were revealed not to be induced termination signals upon anti-CD3 stimulation. This may be the why MCMV-infected mice produced higher amounts of cytokines upon anti-CD3 stimulation in vivo, than those of uninfected control mice.