Background: Immune responses to cytomegalovirus (CMV) infection may precipitate acute/chronic graft rejection in immunocompromised transplant recipients. CMV infection can be primary or its reactivation from the latently-infected graft. Achieving tolerance could eliminate both the transplant-induced inflammation and need for immunosuppression that are thought to promote CMV reactivation. Currently, studies regarding CMV reactivation in tolerized recipients are lacking. We thus investigated the impact of transplantation tolerance on CMV reactivation and graft-function.

Methods: Balb/c mice were infected with the murine CMV strain [Delta]m157 to develop latency over 3 months. The kidneys from latently infected mice (D+) were transplanted in naïve C57BL/6J recipients (R-). The transplant groups included: 1) Control group (CT; untreated); 2) Immunosuppression group (IS; received antilymphocyte serum on days -1, 1, 3, & 5, tacrolimus, and dexamethasone on days 0-7, then thrice weekly until day 28); 3) Tolerized group (tolerance was induced by infusing donor apoptotic splenocytes pre-treated with the chemical cross-linker ethyl carbodiimide (ECDI-SP) on days -7 & +1).

Results: The kidney allografts from CT group showed distorted architecture with an aggressive infiltration of myeloid and T cells by histology and FACS analysis on day 28 post transplantation which correlated with a high level of blood urea nitrogen (BUN). Inversely, kidney allografts from both IS and ECDI-SP groups showed a much less aggressive intragraft cellular infiltration and a better graft-function (low BUN). However, despite preserved graft function in both groups, only the IS group showed detected levels of MCMV DNA in kidney allografts and in other organs (lung, liver and spleen) suggesting viral dissemination. We further observed that viral dissemination in the IS group correlated with a higher number of intragraft Ly6C^LowF4/80⁺ myeloid cells at an early time point (day 2). This population has been previously shown to be associated MCMV dissemination.

Conclusions: Tolerance induction seems to eliminate MCMV reactivation while preserving kidney allograft function. While this may be mediated by inhibiting intragraft Ly6C^LowF4/80⁺ cells, ongoing studies will further elucidate the preventative mechanisms of MCMV reactivation.

CITATION INFORMATION: Dangi A., Wang J-.J., Burnette M., Zhang Z., Luo X. Transplantation Tolerance Prevents CMV Reactivation and Preserves Kidney Allograft Function in a D+/R- Transplant Setting Am J Transplant. 2017;17 (suppl 3).

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