Modeling concurrent cytomegalovirus infection and transplantation tolerance

Project: Research project

Project Details

Description

Cytomegalovirus (CMV) seropositivity is highly prevalent among both organ donors and
recipients. Under life-long immunosuppression, post-transplant CMV disease is a
significant contributor to poor graft and recipient outcome. Transplant tolerance allows
complete avoidance of immunosuppression and is now clinically achievable. In such
tolerant hosts, how the course of CMV infection may be modified has not been
characterized. Conversely, how concurrent CMV infection may alter the outcome of
tolerance is also largely unknown. In this application, we propose to examine the
reciprocal interaction between CMV infection and transplant tolerance, using a highly
clinically relevant murine model of transplant tolerance. In this model, donor-specific
tolerance is achieved by pre-transplant delivery of donor “negative vaccination”
consisting of donor cells treated with a crosslinker 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide (ECDI). Our murine studies have already led to ongoing experiments in
non-human primates, demonstrating promising efficacy of this strategy for both
allogeneic and xenogeneic tolerance induction. More importantly, our colleagues
recently published a first-in-man clinical trial using ECDI-fixed peptide-coupled
autologous cells for multiple sclerosis, establishing the feasibility, safety and efficacy of
this novel tolerance strategy. Using murine CMV in this model, we demonstrate that both
acute and latent CMV infection impair tolerance induction and destabilize established
tolerance, likely via interfering with Receptor Tyrosine Kinase (RTK)-mediated
efferocytosis and directly or indirectly interfering with expansion of host myeloid derived
suppressor cells (MDSCs). Conversely, presence of donor-specific tolerance in the host
suppresses immediate early (IE) gene transcription necessary for latent CMV
reactivation. Based on these findings, we hypothesize that CMV infection impairs
tolerance via disrupting RTK-mediated tolerogenic interaction between host cells and
ECDI-fixed donor cells, and conversely tolerance inhibits CMV reactivation via inhibiting
transplant-induced inflammation, an obligatory early triggers for CMV genome epigenetic
reprogramming. In this application, we propose to examine: (1) the effects and
mechanisms of CMV-induced tolerance impairment; (2) the effects and mechanisms of
tolerance-induced inhibition of CMV reactivation. Our long-term goal is to define targeted
therapies for establishing and maintaining stable tolerance in hosts with CMV infection.
StatusFinished
Effective start/end date3/15/169/1/18

Funding

  • National Institute of Allergy and Infectious Diseases (5R01AI114824-03)

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