*Purpose: We have previously shown that transplant of kidneys from donor mice latently infected with murine cytomegalovirus (CMV) into naïve recipients treated with clinically relevant immunosuppression results in CMV reactivation and systemic dissemination. Our study is to determine the cellular and molecular mechanisms underlying CMV dissemination following kidney transplantation in immunocompromised recipients by blocking inflammatory mediators associated with transplant injury.

*Methods: Kidneys from BALB/c mice latently infected with Smith murine CMV were transplanted to binephrectomized naïve immunodeficient NSG mice deficient of T cells, B cells and NK cell function. Recipients were treated with various extracellular mediator blockers, including anti-IL-1β, anti-IL-6 receptor, anti-IL-18 receptor, anti-CD40L, anti-TNFα, or a cocktail mixed with the above antibodies. At endpoints, kidney grafts, spleens, salivary glands and lungs were collected for CMV immediate early (IE) gene copy analysis and/or flow cytometry analysis.

*Results: We observed that treatment with the cocktail antibodies resulted in a dramatic increase in viral DNA copies in the kidney grafts as measured on post-transplant day (POD) 28 and POD42, compared with the transplants treated with isotype controls. To determine the role of each individual inflammatory mediator in controlling post-transplant reactivation, the recipients were treated with a single monoclonal antibody against CD40L, IL-6, TNFα, IL-1β or IL-18. Interestingly, recipients received anti-CD40L treatment accelerated CMV reactivation and dissemination as a significant increase in DNA replication was observed in the kidney grafts as early as POD14, compared with recipients untreated or treated with the other antibodies. The increased DNA copies were also observed in distal organs such as salivary glands and lungs, indicating that blockade of CD40/CD40L signaling promoted CMV reactivation and dissemination at early stage after transplantation. Flow cytometry analysis exhibited that anti-CD40L treatment dramatically increased myeloid cells infiltration in kidney grafts, including both Ly6C⁺CX3CR1⁺ inflammatory macrophages and Ly6C^–CX3CR1⁺ patrolling monocytes which are key vehicles of murine CMV dissemination, suggesting that blocking CD40/CD40L signaling enhanced influx of monocyte and macrophages, leading to accelerated CMV transition.

*Conclusions: We conclude that CD40/40L signaling plays a pivotal role in controlling CMV transmission following kidney transplantation in immunocompromised recipients.

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