Ganciclovir Prophylaxis Improves Late Murine Cytomegalovirus-Induced Renal Allograft Damage

Abstract

BACKGROUND Human cytomegalovirus (CMV) infection is associated with inferior survival in renal transplant patients, and ganciclovir (GCV) prophylaxis is associated with improved survival. In a murine CMV (MCMV) renal transplant model, GCV prophylaxis improved innate infiltrates and allograft damage during the period of prophylaxis. In this study, late effects were examined after discontinuation of prophylaxis. METHODS MCMV D+/R− and D−/R− allogeneic transplants were performed with cyclosporine immunosuppression. One D+/R− cohort received GCV prophylaxis for 14 days post-transplant, followed by 28 days without GCV. At 42 days post-transplant, grafts were analyzed for histologic tissue damage and immune infiltrates. Another D+/R− cohort was treated with anti-NK1.1 antibodies for 14 days post-transplant and compared to animals without NK depletion. RESULTS At day 42, MCMV infected transplants had higher damage scores (15.6+/−0.6) compared to uninfected transplants (8.3+/−0.9) (p<0.01), which improved in GCV treated allografts (9.5+/−1.4). MCMV infected grafts contained greater frequencies of natural killer (NK) cell and myeloid infiltrates compared to uninfected grafts (p<0.05), which decreased in the GCV treated grafts. NK depletion improved allograft histology of MCMV infected grafts. CONCLUSIONS MCMV infection exacerbates late renal allograft damage and is associated with NK and myeloid cell infiltrates. GCV prophylaxis reduces allograft injury, NK cell and myeloid infiltrates even after cessation of prophylaxis. NK depletion in MCMV infected transplants also improves histology. These results suggest that GCV prophylaxis may have a long-term beneficial effect upon CMV infected renal allografts, and suggest a potential role for NK cells in the pathogenesis of CMV associated allograft injury.

NK cell and Th17 responses are differentially induced in murine cytomegalovirus infected renal allografts and vary according to recipient virus dose and strain

“…Using an 8-criteria scale to quantitate allograft damage, at day 14 post-transplant D−/R− allografts had lower damage scores (7.6±1.6) compared to D+/R− grafts (10.57±2.1, p=0.027), consistent with prior studies (36). D+/R+ transplant had higher damage scores (11.9±1.4) than D−/R− grafts (p=0.0022), but were similar to D+/R− grafts.…”

“…Sections were evaluated by a veterinary pathologist (T.R.S.) blinded to sample identity using a previously published 8-criteria scale (Table 1) with a maximum damage score of 24 (36). …”

“…In a murine allogeneic renal transplant model, MCMV D+/R− transplants had increased intragraft CD45+ infiltrates compared to D−/R− transplants, including NK cells, CD4+ and CD8+ T cells (35). MCMV-infected allografts with acute rejection demonstrated more severe late fibrosis compared to MCMV-uninfected grafts, suggesting that MCMV-associated early graft injury combined with acute rejection might contribute to late graft fibrosis (36). NK depletion ameliorated MCMV-associated allograft damage, suggesting that virus-directed NK cells mediate allograft injury (36).…”

“…MCMV-infected allografts with acute rejection demonstrated more severe late fibrosis compared to MCMV-uninfected grafts, suggesting that MCMV-associated early graft injury combined with acute rejection might contribute to late graft fibrosis (36). NK depletion ameliorated MCMV-associated allograft damage, suggesting that virus-directed NK cells mediate allograft injury (36). In this study, we investigated the impact of antiviral memory NK and CD8+ T cells upon MCMV-associated allograft injury by varying the recipient’s infecting virus dose to generate differential memory CD8+ T cell responses (T CM vs. T EM ), or by infecting the recipient with a different MCMV strain from the donor organ.…”

The Cell Biology of Cytomegalovirus: Implications for Transplantation

“…In part, this is mediated by cytokine-mediated stimulation of alloreactive T cells and by direct alloimmune injury (156). The contribution of MCMV to NK-mediated late renal allograft damage is reversed by antiviral therapy (ganciclovir) or NK cell depletion (189).…”