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Author Notes:

Correspondence: Leslie S. Kean; Email Address : leslie.kean@emory.edu

Authors' Correspondence: Conceived and designed the experiments: JMB, SSH, SAS, CPL, ADK and LSK.

Performed the experiments: JMB, SSH, SAS, DD, LLS, SAM, JAC and KMH.

Analyzed the data: JMB, SSH, SAS and LSK.

Contributed reagents/materials/analysis tools: JMB, SAS, LLS, SHS, CPL, ADK and LSK.

Wrote the paper: JMB, ADK and LSK.

Acknowledgments: Viral antigen-specific tetramer reagents were synthesized by the NIH Tetramer Core Facility at Emory University.

The KT4 hybridoma was the kind gift of Dr. George S. Deepe of the University of Cincinnati.

The authors thank Mandy L. Ford, Aneesh K. Mehta, William H. Kitchens, and all members of the Emory Transplant Center for insightful discussions.

Disclosures: The authors have declared that no competing interests exist.

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Research Funding:

This work was supported by National Institutes of Health (NIH) NIAID 5P01AI044644 to LSK, ADK, and CPL (http://www.niaid.nih.gov/).

LSK was also supported by a Burroughs Wellcome Career Award in the Biological Sciences (http://www.bwfund.org/) and NIH K08AI065822 (http://www.niaid.nih.gov/).

JMB was supported by the Howard Hughes Medical Institute Medical Research Fellows Program (http://www.hhmi.org/) and the St. Baldrick’s Summer Fellows Program (http://www.stbaldricks.org/).

ADK was supported by the Georgia Research Alliance (http://gra.org).

Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection

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PLoS ONE

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Volume 8, Number 8

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Article | Final Publisher PDF

Abstract:

The mechanisms underlying latent-virus-mediated heterologous immunity, and subsequent transplant rejection, especially in the setting of T cell costimulation blockade, remain undetermined. To address this, we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation, which included increased secretion of CXCL9 and CXCL10, and with the expansion of a CD8dim T cell population. CD8dim T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules, LFA-1 and VLA-4. In the setting of MHV68 latency, recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals, p<.0001). In contrast, the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected, p = n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both, p<.0001 versus costimulation blockade for either). While in the non-infected cohort, either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance, in infected animals, the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig, MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection, synergy occurs predominantly between adhesion pathways and CD154-based costimulation, and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.

Copyright information:

© 2013 Beus et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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