MCMV Dissemination from Latently-Infected Allografts Following Transplantation into Pre-Tolerized Recipients.

Sahil Shah,Mary Hummel,Zheng J Zhang,Edward B Thorp,Xunrong Luo,Longhui Qiu,Matthew Deberge,Jiao-Jing Wang,Shixian Yan,Yashpal S Kanwar,Michael M Abecassis,Andre Iovane

doi:10.3390/pathogens9080607

Sahil Shah, Mary Hummel + Show 10 more

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https://doi.org/10.3390/pathogens9080607

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Abstract

Transplantation tolerance is achieved when recipients are unresponsive to donor alloantigen yet mobilize against third-party antigens, including virus. After transplantation, cytomegalovirus (CMV) reactivation in latently-infected transplants reduces allograft viability. To determine if pre-tolerized recipients are resistant to viral dissemination in this setting, we transfused chemically-fixed donor splenocytes (1-ethyl-3- (3′-dimethyl-aminopropyl)-carbo-diimide (ECDI)-treated splenocytes (ECDIsp)) to induce donor antigen tolerance without immunosuppression. In parallel, we implanted donor islet cells to validate operational tolerance. These pre-tolerized recipients were implanted with murine CMV (MCMV) latently-infected donor kidneys (a validated model of CMV latency) to monitor graft inflammation and viral dissemination. Our results indicate that tolerance to donor islets was sustained in recipients after implantation of donor kidneys. In addition, kidney allografts implanted after ECDIsp and islet implantation exhibited low levels of fibrosis and tubulitis. In contrast, kidney cellular and innate immune infiltrates trended higher in the CMV group and exhibited increased markers of CD8+ T cell activation. Tolerance induction was unable to prevent increases in MCMV-specific CD8+ T cells or dissemination of viral IE-1 DNA. Our data suggest that latently-infected allografts are inherently more susceptible to inflammation that is associated with viral dissemination in pre-tolerized recipients. Thus, CMV latently-infected allografts require enhanced strategies to protect allograft integrity and viral spread.

Highlights

The current standard of care following transplantation is the use of broad spectrum immunosuppressants [1]
Transfusion (DST), in which donor splenocytes are fixed with cross-linker ethylcarbodiimide (ECDIsp) [25] and pre-infused into selected recipients 7 days prior to implantation and again at 1 day post implantation
Our findings indicate that murine CMV (MCMV) latently-infected allografts are more susceptible to viral dissemination and exhibit heightened inflammatory trends following transplantation into pre-tolerized recipients

Summary

Introduction

The current standard of care following transplantation is the use of broad spectrum immunosuppressants [1]. The administration of immunosuppression to promote engraftment is associated with viral reactivation, hypertension, diabetes mellitus, anemia, and nephrotoxicity [2,3,4]. As an alternative to chronic immunosuppression, transplantation tolerance may be achieved in allograft recipients that are unresponsive to donor antigen but maintain reactivity to third-party antigens, including virus. Tolerogenic strategies include regulatory T cell infusion, donor-derived modified immune cells, and mixed chimerism via bone marrow transplantation [5,6,7]. Another tolerance approach is with chemically-modified donor specific transfusion (DST) [8,9,10,11]

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