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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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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. |
format | Online Article Text |
id | pubmed-8024657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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