Innate Immunity and Viral Renal Allograft Injury

Shimamura, Masako

Abstract

Despite excellent short-term outcomes in renal transplant recipients resulting from advances in immunosuppression and management, long-term allograft survival has not substantially improved over the past few decades. Viral infections,particularly human cytomegalovirus (HCMV), are associated epidemiologically with inferior transplant outcomes. The pathogenesis behind these observations is not known; however, CMV infection is well recognized to activate innate effectors such as natural killer (NK) cells. The function of NK cells in allograft loss has not been clearly defined: in animal models, NK cells cancontribute to either rejection (by promoting activation and differentiation of dendritic cells and alloreactive T lymphocytes), or tolerance (by killing donor antigen presenting cells). CMV infection in animal models can reverse NK mediated tolerance to allografts by unknown mechanisms. An understanding of the pathogenesis of virus associated allograft injury could lead to new approaches to improve allograft survival and function in CMV-infected transplant recipients. To better understand how CMV infection contributes to renal allograft loss, we have developed a murine transplant model in which murine CMV (MCMV) infected donor kidneys are transplanted into MCMV native recipient mice, resembling the mode of viral transmission in transplant patients. MCMV infected allografts demonstrated accelerated and intensified tissue damage compared to uninfected grafts, and this damage was associated with increased intragraft NK cell infiltration. Pharmacologic inhibition of viral replication resulted in decrease NK infiltration and improvement in allograft histology. In this application, we will use this modelto determine whether NK cells in MCMV infected allografts induce direct antiviral-directed graft damage, or whether virus-induced NK activity might exacerbate allogeneic responses. Findings from the animal model will then be used to guide and focus analysis of archival human renal transplant biopsies to identify likely pathogenic mechanisms and predictors of virus-associated graft dysfunction. Since not all patients with CMV infection experience allograft loss, it is likel that many factors contribute to allograft outcome. It is intended that the work in the animal model will identify potential factors of relevance to outcome in CMV infected transplant patients, so that analysis of the patient samples can be directed toward likely parameters that may be correlated with virus-associated allograft injury. The long-term goal of these studies is to identiy predictors of patients likely to develop virus-associated allograft dysfunction, and to suggest future strategies to improve graft function by modifying these virus-associated mechanisms of allograft injury.

Public Health Relevance

Kidney transplantation improves longevity and quality of life for patients with renal failure, but loss of graft function over time limits the long-term survivalof many transplant recipients. Identification of pathogenic mechanisms of graft loss may lead to new strategies to prolong graft function and patient survival. Viral infections, particularly human cytomegalovirus (HCMV) infection, are associated epidemiologically with inferior transplant outcomes. CMV infection is well recognized to activate innate effectors such as natural killer (NK) cells. To better understand how CMV infection contributes to renal allograft loss, we have developed a murine transplant model for CMV effects in renal transplantation. Murine CMV (MCMV) infected grafts demonstrate accelerated and intensified tissue damage compared to uninfected grafts, and contain increased numbers of NK cells compared to uninfected grafts. We will use this model to determine whether NK responses in MCMV infected allografts induce direct antiviral-directed graft damage, or whether virus-induced NK activity might exacerbate allogeneic responses. We will then use information gained from the animal model to guide analysis of archival human renal transplant biopsies to identify potential mechanisms of virus associated graft loss and factors that may predict patients likely to experience adverse viral effects. Understanding these events in both the animal model and in patient samples may contribute to a better understanding of virus associated allograft loss and identify future strategies to improve graft function and survival of CMV infected transplant patients.