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Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the ef...

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Autores principales: Mammadli, Mahinbanu, Huang, Weishan, Harris, Rebecca, Xiong, Hui, Weeks, Samuel, May, Adriana, Gentile, Teresa, Henty-Ridilla, Jessica, Waickman, Adam T., August, Avery, Bah, Alaji, Karimi, Mobin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024657/
https://www.ncbi.nlm.nih.gov/pubmed/33851101
http://dx.doi.org/10.1016/j.isci.2021.102286
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author Mammadli, Mahinbanu
Huang, Weishan
Harris, Rebecca
Xiong, Hui
Weeks, Samuel
May, Adriana
Gentile, Teresa
Henty-Ridilla, Jessica
Waickman, Adam T.
August, Avery
Bah, Alaji
Karimi, Mobin
author_facet Mammadli, Mahinbanu
Huang, Weishan
Harris, Rebecca
Xiong, Hui
Weeks, Samuel
May, Adriana
Gentile, Teresa
Henty-Ridilla, Jessica
Waickman, Adam T.
August, Avery
Bah, Alaji
Karimi, Mobin
author_sort Mammadli, Mahinbanu
collection PubMed
description Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8(+) and CD4(+) donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8(+) and CD4(+) donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment.
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spelling pubmed-80246572021-04-12 Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT Mammadli, Mahinbanu Huang, Weishan Harris, Rebecca Xiong, Hui Weeks, Samuel May, Adriana Gentile, Teresa Henty-Ridilla, Jessica Waickman, Adam T. August, Avery Bah, Alaji Karimi, Mobin iScience Article Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8(+) and CD4(+) donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8(+) and CD4(+) donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment. Elsevier 2021-03-11 /pmc/articles/PMC8024657/ /pubmed/33851101 http://dx.doi.org/10.1016/j.isci.2021.102286 Text en © 2021 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Mammadli, Mahinbanu
Huang, Weishan
Harris, Rebecca
Xiong, Hui
Weeks, Samuel
May, Adriana
Gentile, Teresa
Henty-Ridilla, Jessica
Waickman, Adam T.
August, Avery
Bah, Alaji
Karimi, Mobin
Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title_full Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title_fullStr Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title_full_unstemmed Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title_short Targeting SLP76:ITK interaction separates GVHD from GVL in allo-HSCT
title_sort targeting slp76:itk interaction separates gvhd from gvl in allo-hsct
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8024657/
https://www.ncbi.nlm.nih.gov/pubmed/33851101
http://dx.doi.org/10.1016/j.isci.2021.102286
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