Cargando…

Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation

Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can...

Descripción completa

Detalles Bibliográficos
Autores principales: Araki, Koichi, Gangappa, Shivaprakash, Dillehay, Dirck L., Rouse, Barry T., Larsen, Christian P., Ahmed, Rafi
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964579/
https://www.ncbi.nlm.nih.gov/pubmed/20921283
http://dx.doi.org/10.1084/jem.20100124
_version_ 1782189389880754176
author Araki, Koichi
Gangappa, Shivaprakash
Dillehay, Dirck L.
Rouse, Barry T.
Larsen, Christian P.
Ahmed, Rafi
author_facet Araki, Koichi
Gangappa, Shivaprakash
Dillehay, Dirck L.
Rouse, Barry T.
Larsen, Christian P.
Ahmed, Rafi
author_sort Araki, Koichi
collection PubMed
description Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues. However, despite the apparent absence of an antiviral immune response, this disease was orchestrated by virus-specific T cells. FK506 did not prevent the generation and proliferation of LCMV-specific T cells but instead altered their differentiation so that these effector T cells lost the ability to control virus but were still capable of mediating disease. These pathogenic T cells initiated a cytokine storm characterized by high levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6), and depletion of T cells or blockade of these inflammatory cytokines prevented the lethal disease. Our study shows that inhibiting calcineurin can generate pathogenic T cells and indicates that T cell–mediated viral disease can occur even under conditions of immunosuppression. Furthermore, we identify a potential strategy (blockade of TNF and IL-6) for treatment of transplant recipients who have acute complications of viral infection.
format Text
id pubmed-2964579
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher The Rockefeller University Press
record_format MEDLINE/PubMed
spelling pubmed-29645792011-04-25 Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation Araki, Koichi Gangappa, Shivaprakash Dillehay, Dirck L. Rouse, Barry T. Larsen, Christian P. Ahmed, Rafi J Exp Med Article Recently, several cases of fatal lymphocytic choriomeningitis virus (LCMV) infection occurred in transplant recipients being treated with the immunosuppressive calcineurin inhibitor FK506. These findings were surprising because LCMV is a noncytolytic virus. To understand how a noncytolytic virus can cause disease under conditions of immunosuppression, we used the mouse LCMV model and found that, similar to the observations in human transplant recipients, LCMV infection of FK506-treated mice resulted in a lethal disease characterized by viremia, lack of seroconversion, and minimal lymphocytic infiltrates in the tissues. However, despite the apparent absence of an antiviral immune response, this disease was orchestrated by virus-specific T cells. FK506 did not prevent the generation and proliferation of LCMV-specific T cells but instead altered their differentiation so that these effector T cells lost the ability to control virus but were still capable of mediating disease. These pathogenic T cells initiated a cytokine storm characterized by high levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6), and depletion of T cells or blockade of these inflammatory cytokines prevented the lethal disease. Our study shows that inhibiting calcineurin can generate pathogenic T cells and indicates that T cell–mediated viral disease can occur even under conditions of immunosuppression. Furthermore, we identify a potential strategy (blockade of TNF and IL-6) for treatment of transplant recipients who have acute complications of viral infection. The Rockefeller University Press 2010-10-25 /pmc/articles/PMC2964579/ /pubmed/20921283 http://dx.doi.org/10.1084/jem.20100124 Text en © 2010 Araki et al. 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 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Araki, Koichi
Gangappa, Shivaprakash
Dillehay, Dirck L.
Rouse, Barry T.
Larsen, Christian P.
Ahmed, Rafi
Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title_full Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title_fullStr Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title_full_unstemmed Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title_short Pathogenic virus-specific T cells cause disease during treatment with the calcineurin inhibitor FK506: implications for transplantation
title_sort pathogenic virus-specific t cells cause disease during treatment with the calcineurin inhibitor fk506: implications for transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964579/
https://www.ncbi.nlm.nih.gov/pubmed/20921283
http://dx.doi.org/10.1084/jem.20100124
work_keys_str_mv AT arakikoichi pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation
AT gangappashivaprakash pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation
AT dillehaydirckl pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation
AT rousebarryt pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation
AT larsenchristianp pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation
AT ahmedrafi pathogenicvirusspecifictcellscausediseaseduringtreatmentwiththecalcineurininhibitorfk506implicationsfortransplantation