Background: The incidence of cytomegalovirus (CMV) disease is higher in lung transplants, than in other SOT recipients, especially in high-risk D+/R- recipients. Using a murine CMV (MCMV) model, we have identified that donor alveolar macrophages (AMs) are sites of latency. However, whether latently infected donor AMs contribute to the viral reactivation and dissemination following lung transplant remains unclear. We hypothesize that inflammatory events triggered activation of donor AMs following transplantation are essential for MCMV reactivation and dissemination in the immunosuppressed recipients.

Methods: To test our hypothesis, we have developed a model that closely mimics the clinical transplant setting: an immune competent murine recipient that receives a clinically relevant immunosuppression (IS) regimen (ALS, FK506 & steroids). We utilized a mouse model the orthotopic left lung transplantation in which latently infected lungs (D+) were transplanted into syngeneic BALB/c mice without or with concomitant IS. To deplete the AMs from the donor lungs, donor mice were treated either with Clodronate liposomes or PBS-liposomes via intra-tracheal instillation at 24h and 12 hr prior to the lung transplantation. Viral RNA/DNA analyses were performed by qPCR.

Results: We observed a significant increase in MCMV DNA copies in the IS treated lung grafts compared with both day 0 controls and the IS groups (P<0.01), as well as evidence of dissemination to other organs, on the 14th and 28^th post-operative day (POD) in IS groups. Treatment with Clodranate-liposomes depleted >90 % AMs in the lungs and bronchoalveolar lavage fluid from the donors. Little changes were seen in the number of lung interstitial macrophages. Interestingly, depletion of AMs resulted in marked reduction of the viral DNA abundance of in both transplanted lung and recipient's salivary gland in the IS treated allografts at POD 14, compared to PBS controls. Consistently, expression of MCMV immediate early genes (e.g. IE-1) were also significantly reduced.

Conclusion: Transplantation of D+ lungs with IS promotes MCMV reactivation and systemic dissemination. AMs derived from D+ donors are sources of MCMV reactivation, responsible for the subsequent lyrical replication and dissemination following the D+/R- lung transplantation in mice.

CITATION INFORMATION: Han S., Zheng Z., He M., Wang J-.J., Yan S., Abecassis M., Zhang Z. Alveolar Macrophages Derived from MCMV Latently Infected Donors Drives the Viral Reactivation and Dissemination Following the Orthotopic Left Lung Transplantation in Mice Am J Transplant. 2017;17 (suppl 3).

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