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Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival
LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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The Rockefeller University Press
2002
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193745/ https://www.ncbi.nlm.nih.gov/pubmed/11901205 http://dx.doi.org/10.1084/jem.20012088 |
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author | Ye, Qunrui Fraser, Christopher C. Gao, Wei Wang, Liqing Busfield, Samantha J. Wang, Chichung Qiu, Yubin Coyle, Anthony J. Gutierrez-Ramos, Jose-Carlos Hancock, Wayne W. |
author_facet | Ye, Qunrui Fraser, Christopher C. Gao, Wei Wang, Liqing Busfield, Samantha J. Wang, Chichung Qiu, Yubin Coyle, Anthony J. Gutierrez-Ramos, Jose-Carlos Hancock, Wayne W. |
author_sort | Ye, Qunrui |
collection | PubMed |
description | LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT(−/−) mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT(−/−) mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT(+/+) mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT(+/+) mice (7 days). However, mean allograft survival in CsA-treated LIGHT(−/−) allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT(−/−) mice or CsA-treated LIGHT(+/+) controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-γ, plus IFN-γ–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT(+/+) allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection. |
format | Text |
id | pubmed-2193745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2002 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21937452008-04-14 Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival Ye, Qunrui Fraser, Christopher C. Gao, Wei Wang, Liqing Busfield, Samantha J. Wang, Chichung Qiu, Yubin Coyle, Anthony J. Gutierrez-Ramos, Jose-Carlos Hancock, Wayne W. J Exp Med Brief Definitive Report LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT(−/−) mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT(−/−) mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT(+/+) mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT(+/+) mice (7 days). However, mean allograft survival in CsA-treated LIGHT(−/−) allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT(−/−) mice or CsA-treated LIGHT(+/+) controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-γ, plus IFN-γ–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT(+/+) allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection. The Rockefeller University Press 2002-03-18 /pmc/articles/PMC2193745/ /pubmed/11901205 http://dx.doi.org/10.1084/jem.20012088 Text en Copyright © 2002, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Report Ye, Qunrui Fraser, Christopher C. Gao, Wei Wang, Liqing Busfield, Samantha J. Wang, Chichung Qiu, Yubin Coyle, Anthony J. Gutierrez-Ramos, Jose-Carlos Hancock, Wayne W. Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title | Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title_full | Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title_fullStr | Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title_full_unstemmed | Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title_short | Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival |
title_sort | modulation of light-hvem costimulation prolongs cardiac allograft survival |
topic | Brief Definitive Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193745/ https://www.ncbi.nlm.nih.gov/pubmed/11901205 http://dx.doi.org/10.1084/jem.20012088 |
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