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Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity
Graft‐vs‐host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo‐BMT). We examined whether the administration of human, bone marrow‐derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596993/ https://www.ncbi.nlm.nih.gov/pubmed/34255899 http://dx.doi.org/10.1002/stem.3434 |
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author | Metheny, Leland Eid, Saada Wuttisarnwattana, Patiwet Auletta, Jeffery J. Liu, Chen Van Dervort, Alana Paez, Conner Lee, ZhengHong Wilson, David Lazarus, Hillard M. Deans, Robert Vant Hof, Wouter Ktena, Yiouli Cooke, Kenneth R. |
author_facet | Metheny, Leland Eid, Saada Wuttisarnwattana, Patiwet Auletta, Jeffery J. Liu, Chen Van Dervort, Alana Paez, Conner Lee, ZhengHong Wilson, David Lazarus, Hillard M. Deans, Robert Vant Hof, Wouter Ktena, Yiouli Cooke, Kenneth R. |
author_sort | Metheny, Leland |
collection | PubMed |
description | Graft‐vs‐host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo‐BMT). We examined whether the administration of human, bone marrow‐derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity of MAPC cells was evaluated in vivo using established murine GvHD models. Injection of MAPC cells on day +1 (D1) and +4 (D4) significantly reduced T‐cell expansion and the numbers of donor‐derived, Tumor Necrosis Factor Alpha (TNFα) and Interferon Gamma (IFNγ)‐producing, CD4+ and CD8+ cells by D10 compared with untreated controls. These findings were associated with reductions in serum levels of TNFα and IFNγ, intestinal and hepatic inflammation and systemic GvHD as measured by survival and clinical score. Biodistribution studies showed that MAPC cells tracked from the lung and to the liver, spleen, and mesenteric nodes within 24 hours after injection. MAPC cells inhibited mouse T‐cell proliferation in vitro and this effect was associated with reduced T‐cell activation and inflammatory cytokine secretion and robust increases in the concentrations of Prostaglandin E2 (PGE2) and Transforming Growth Factor Beta (TGFβ). Indomethacin and E‐prostanoid 2 (EP2) receptor antagonism both reversed while EP2 agonism restored MAPC cell‐mediated in vitro T‐cell suppression, confirming the role for PGE2. Furthermore, cyclo‐oxygenase inhibition following allo‐BMT abrogated the protective effects of MAPC cells. Importantly, MAPC cells had no effect on the generation cytotoxic T lymphocyte activity in vitro, and the administration of MAPC cells in the setting of leukemic challenge resulted in superior leukemia‐free survival. Collectively, these data provide valuable information regarding the biodistribution and regulatory capacity of MAPC cells, which may inform future clinical trial design. |
format | Online Article Text |
id | pubmed-8596993 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85969932021-11-22 Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity Metheny, Leland Eid, Saada Wuttisarnwattana, Patiwet Auletta, Jeffery J. Liu, Chen Van Dervort, Alana Paez, Conner Lee, ZhengHong Wilson, David Lazarus, Hillard M. Deans, Robert Vant Hof, Wouter Ktena, Yiouli Cooke, Kenneth R. Stem Cells Tissue‐specific Stem Cells Graft‐vs‐host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo‐BMT). We examined whether the administration of human, bone marrow‐derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity of MAPC cells was evaluated in vivo using established murine GvHD models. Injection of MAPC cells on day +1 (D1) and +4 (D4) significantly reduced T‐cell expansion and the numbers of donor‐derived, Tumor Necrosis Factor Alpha (TNFα) and Interferon Gamma (IFNγ)‐producing, CD4+ and CD8+ cells by D10 compared with untreated controls. These findings were associated with reductions in serum levels of TNFα and IFNγ, intestinal and hepatic inflammation and systemic GvHD as measured by survival and clinical score. Biodistribution studies showed that MAPC cells tracked from the lung and to the liver, spleen, and mesenteric nodes within 24 hours after injection. MAPC cells inhibited mouse T‐cell proliferation in vitro and this effect was associated with reduced T‐cell activation and inflammatory cytokine secretion and robust increases in the concentrations of Prostaglandin E2 (PGE2) and Transforming Growth Factor Beta (TGFβ). Indomethacin and E‐prostanoid 2 (EP2) receptor antagonism both reversed while EP2 agonism restored MAPC cell‐mediated in vitro T‐cell suppression, confirming the role for PGE2. Furthermore, cyclo‐oxygenase inhibition following allo‐BMT abrogated the protective effects of MAPC cells. Importantly, MAPC cells had no effect on the generation cytotoxic T lymphocyte activity in vitro, and the administration of MAPC cells in the setting of leukemic challenge resulted in superior leukemia‐free survival. Collectively, these data provide valuable information regarding the biodistribution and regulatory capacity of MAPC cells, which may inform future clinical trial design. John Wiley & Sons, Inc. 2021-07-28 2021-11 /pmc/articles/PMC8596993/ /pubmed/34255899 http://dx.doi.org/10.1002/stem.3434 Text en © 2021 The Authors. STEM CELLS published by Wiley Periodicals LLC on behalf of AlphaMed Press. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Tissue‐specific Stem Cells Metheny, Leland Eid, Saada Wuttisarnwattana, Patiwet Auletta, Jeffery J. Liu, Chen Van Dervort, Alana Paez, Conner Lee, ZhengHong Wilson, David Lazarus, Hillard M. Deans, Robert Vant Hof, Wouter Ktena, Yiouli Cooke, Kenneth R. Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title | Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title_full | Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title_fullStr | Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title_full_unstemmed | Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title_short | Human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
title_sort | human multipotent adult progenitor cells effectively reduce graft‐vs‐host disease while preserving graft‐vs‐leukemia activity |
topic | Tissue‐specific Stem Cells |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596993/ https://www.ncbi.nlm.nih.gov/pubmed/34255899 http://dx.doi.org/10.1002/stem.3434 |
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