Depletion of macrophages from Cytomegalovirus (CMV) latently infected donor allografts decreases CMV mediated immunopathology and prevents CMV-accelerated chronic rejection

Abstract

Abstract Cytomegalovirus (CMV), a ubiquitous β-herpesvirus, is linked to acceleration of solid organ transplant vascular sclerosis (TVS) and chronic rejection (CR). Latent CMV infection increases cardiac-resident macrophages and T cells that may increase inflammation and promote allograft rejection. To investigate the role of cardiac macrophages in CMV mediated TVS/CR, macrophages were depleted from CMV+ donor allografts prior to transplantation using clodronate liposomes (clod) in our rat heart transplant model. Latently rat CMV infected donor F344 rats were treated with clod or PBS or control liposomes 3 days prior to heterotopic cardiac transplant into CMV-naïve Lewis rats and macrophage depletion was validated. Donor hearts were transplanted and monitored daily for rejection. Clod treatment significantly increased graft survival from 61 days post-transplant to 84 days. The severity of graft vessel disease was decreased compared to controls. Clod treatment significant decreased macrophage and T cell infiltration into allograft tissue versus controls. Clod treatment also altered allograft tissue protein and gene expression cytokine/chemokine profiles toward a phenotype that promotes graft survival by reducing the allograft inflammation. Clod treatment did not prevent CMV reactivation since all recipients seroconverted and CMV DNA was detectable in recipient salivary glands. Depletion of donor macrophages prior to transplant represents a novel method to modulate allograft rejection immunity and prevent the negative impact of CMV on allograft recipient survival.