Cytomegalovirus latency exacerbated small-for-size liver graft injury through activation of CCL19/CCR7 in hepatic stellate cells

Abstract

Background and objective: Cytomegalovirus (CMV) latency is significantlyassociated with graft survival in liver transplantation. Hepatic stellate cells(HSCs) play essential roles in either acute or chronic graft injury. Here, weaimed to investigate the impact of HSCs activation on graft injury during CMVlatency after living donor liver transplantation (LDLT). Materials and methods: The impactof CMV latency on graft injury was investigated in the liver biopsies of LDLT. Anorthotopic liver transplantation model using small-for-size graft wasestablished in CMV latent rats to study the association of intragraft HSCsactivation and CMV latency. The mechanism of HSCs interactionwith CD8+ T cell responses was further examined both in vivo and in vitro co-culturesystem. Results: CMV latency was associated with elevated AST level(clinical biopsies: p=0.025; ratmodel: p=0.026), increased hepatocyteapoptosis/necrosis, prominent activation of HSCs at early stage aftertransplantation in the clinical biopsies as well as in the rat model (Figure 1). Upregulation of CCL19/CCR7 wasidentified through the microarray analysis of stellate cellsco-cultured with primary CD8+T cells isolated from CMV latent rats. The augmentation of intragraft CCL19/CCR7accompanied with more HSCs activation was validated both in clinical and animalstudies (Figure 2). Conclusion: CMV latencypre-transplantation accelerated the activation of HSCs after livertransplantation and resulted in deteriorated graft injury. CCL19/CCR7 axis may be a key mechanism to includethe stellate cell activation in liver graft injury during CMV latency.