MCMV dissemination from latently-infected allografts following transplantation into pre-tolerized recipients

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number607
Pages (from-to)1-17
Number of pages17
JournalPathogens
Volume9
Issue number8
DOIs
StatePublished - Aug 2020

Keywords

  • Cytomegalovirus
  • Donor specific transfusion
  • Latency
  • Transplant tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Molecular Biology
  • Immunology and Microbiology(all)
  • Microbiology (medical)
  • Infectious Diseases

Fingerprint Dive into the research topics of 'MCMV dissemination from latently-infected allografts following transplantation into pre-tolerized recipients'. Together they form a unique fingerprint.

Cite this