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Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells

Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of...

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Autores principales: Monlish, Darlene A., Beezhold, Kevin J., Chiaranunt, Pailin, Paz, Katelyn, Moore, Nathan J., Dobbs, Andrea K., Brown, Rebecca A., Ozolek, John A., Blazar, Bruce R., Byersdorfer, Craig A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410053/
https://www.ncbi.nlm.nih.gov/pubmed/34291733
http://dx.doi.org/10.1172/jci.insight.143811
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author Monlish, Darlene A.
Beezhold, Kevin J.
Chiaranunt, Pailin
Paz, Katelyn
Moore, Nathan J.
Dobbs, Andrea K.
Brown, Rebecca A.
Ozolek, John A.
Blazar, Bruce R.
Byersdorfer, Craig A.
author_facet Monlish, Darlene A.
Beezhold, Kevin J.
Chiaranunt, Pailin
Paz, Katelyn
Moore, Nathan J.
Dobbs, Andrea K.
Brown, Rebecca A.
Ozolek, John A.
Blazar, Bruce R.
Byersdorfer, Craig A.
author_sort Monlish, Darlene A.
collection PubMed
description Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4(+) and CD8(+) effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution.
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spelling pubmed-84100532021-09-07 Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells Monlish, Darlene A. Beezhold, Kevin J. Chiaranunt, Pailin Paz, Katelyn Moore, Nathan J. Dobbs, Andrea K. Brown, Rebecca A. Ozolek, John A. Blazar, Bruce R. Byersdorfer, Craig A. JCI Insight Research Article Allogeneic hematopoietic stem cell transplantation is a viable treatment for multiple hematologic diseases, but its application is often limited by graft-versus-host disease (GVHD), where donor T cells attack host tissues in the skin, liver, and gastrointestinal tract. Here, we examined the role of the cellular energy sensor AMP kinase (AMPK) in alloreactive T cells during GVHD development. Early posttransplant, AMPK activity increased more than 15-fold in allogeneic T cells, and transplantation of T cells deficient in both AMPKα1 and AMPKα2 decreased GVHD severity in multiple disease models. Importantly, a lack of AMPK lessened GVHD without compromising antileukemia responses or impairing lymphopenia-driven immune reconstitution. Mechanistically, absence of AMPK decreased both CD4(+) and CD8(+) effector T cell numbers as early as day 3 posttransplant, while simultaneously increasing regulatory T cell (Treg) percentages. Improvements in GVHD resulted from cell-intrinsic perturbations in conventional effector T cells as depletion of donor Tregs had minimal impact on AMPK-related improvements. Together, these results highlight a specific role for AMPK in allogeneic effector T cells early posttransplant and suggest that AMPK inhibition may be an innovative approach to mitigate GVHD while preserving graft-versus-leukemia responses and maintaining robust immune reconstitution. American Society for Clinical Investigation 2021-07-22 /pmc/articles/PMC8410053/ /pubmed/34291733 http://dx.doi.org/10.1172/jci.insight.143811 Text en © 2021 Monlish et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Monlish, Darlene A.
Beezhold, Kevin J.
Chiaranunt, Pailin
Paz, Katelyn
Moore, Nathan J.
Dobbs, Andrea K.
Brown, Rebecca A.
Ozolek, John A.
Blazar, Bruce R.
Byersdorfer, Craig A.
Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title_full Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title_fullStr Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title_full_unstemmed Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title_short Deletion of AMPK minimizes graft-versus-host disease through an early impact on effector donor T cells
title_sort deletion of ampk minimizes graft-versus-host disease through an early impact on effector donor t cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410053/
https://www.ncbi.nlm.nih.gov/pubmed/34291733
http://dx.doi.org/10.1172/jci.insight.143811
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