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

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 alloimmu...

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Autores principales: Beus, Jonathan M., Hashmi, Salila S., Selvaraj, Saranya A., Duan, Danxia, Stempora, Linda L., Monday, Stephanie A., Cheeseman, Jennifer A., Hamby, Kelly M., Speck, Samuel H., Larsen, Christian P., Kirk, Allan D., Kean, Leslie S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733932/
https://www.ncbi.nlm.nih.gov/pubmed/23940724
http://dx.doi.org/10.1371/journal.pone.0071221
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author Beus, Jonathan M.
Hashmi, Salila S.
Selvaraj, Saranya A.
Duan, Danxia
Stempora, Linda L.
Monday, Stephanie A.
Cheeseman, Jennifer A.
Hamby, Kelly M.
Speck, Samuel H.
Larsen, Christian P.
Kirk, Allan D.
Kean, Leslie S.
author_facet Beus, Jonathan M.
Hashmi, Salila S.
Selvaraj, Saranya A.
Duan, Danxia
Stempora, Linda L.
Monday, Stephanie A.
Cheeseman, Jennifer A.
Hamby, Kelly M.
Speck, Samuel H.
Larsen, Christian P.
Kirk, Allan D.
Kean, Leslie S.
author_sort Beus, Jonathan M.
collection PubMed
description 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 CD8(dim) T cell population. CD8(dim) 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.
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spelling pubmed-37339322013-08-12 Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection Beus, Jonathan M. Hashmi, Salila S. Selvaraj, Saranya A. Duan, Danxia Stempora, Linda L. Monday, Stephanie A. Cheeseman, Jennifer A. Hamby, Kelly M. Speck, Samuel H. Larsen, Christian P. Kirk, Allan D. Kean, Leslie S. PLoS One Research Article 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 CD8(dim) T cell population. CD8(dim) 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. Public Library of Science 2013-08-05 /pmc/articles/PMC3733932/ /pubmed/23940724 http://dx.doi.org/10.1371/journal.pone.0071221 Text en © 2013 Beus et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Beus, Jonathan M.
Hashmi, Salila S.
Selvaraj, Saranya A.
Duan, Danxia
Stempora, Linda L.
Monday, Stephanie A.
Cheeseman, Jennifer A.
Hamby, Kelly M.
Speck, Samuel H.
Larsen, Christian P.
Kirk, Allan D.
Kean, Leslie S.
Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title_full Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title_fullStr Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title_full_unstemmed Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title_short Heterologous Immunity Triggered by a Single, Latent Virus in Mus musculus: Combined Costimulation- and Adhesion- Blockade Decrease Rejection
title_sort heterologous immunity triggered by a single, latent virus in mus musculus: combined costimulation- and adhesion- blockade decrease rejection
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3733932/
https://www.ncbi.nlm.nih.gov/pubmed/23940724
http://dx.doi.org/10.1371/journal.pone.0071221
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