Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

Abstract Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the e...

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Autores principales:	Makoto Nakamura, Yusuke Meguri, Shuntaro Ikegawa, Takumi Kondo, Yuichi Sumii, Takuya Fukumi, Miki Iwamoto, Yasuhisa Sando, Hiroyuki Sugiura, Noboru Asada, Daisuke Ennishi, Shuta Tomida, Emi Fukuda-Kawaguchi, Yasuyuki Ishii, Yoshinobu Maeda, Ken-ichi Matsuoka
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/388351f9d0984b6baabda3767f059358
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spelling	oai:doaj.org-article:388351f9d0984b6baabda3767f0593582021-12-02T16:07:02ZReduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression10.1038/s41598-021-92526-z2045-2322https://doaj.org/article/388351f9d0984b6baabda3767f0593582021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92526-zhttps://doaj.org/toc/2045-2322Abstract Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.Makoto NakamuraYusuke MeguriShuntaro IkegawaTakumi KondoYuichi SumiiTakuya FukumiMiki IwamotoYasuhisa SandoHiroyuki SugiuraNoboru AsadaDaisuke EnnishiShuta TomidaEmi Fukuda-KawaguchiYasuyuki IshiiYoshinobu MaedaKen-ichi MatsuokaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Makoto Nakamura Yusuke Meguri Shuntaro Ikegawa Takumi Kondo Yuichi Sumii Takuya Fukumi Miki Iwamoto Yasuhisa Sando Hiroyuki Sugiura Noboru Asada Daisuke Ennishi Shuta Tomida Emi Fukuda-Kawaguchi Yasuyuki Ishii Yoshinobu Maeda Ken-ichi Matsuoka Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
description	Abstract Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.
format	article
author	Makoto Nakamura Yusuke Meguri Shuntaro Ikegawa Takumi Kondo Yuichi Sumii Takuya Fukumi Miki Iwamoto Yasuhisa Sando Hiroyuki Sugiura Noboru Asada Daisuke Ennishi Shuta Tomida Emi Fukuda-Kawaguchi Yasuyuki Ishii Yoshinobu Maeda Ken-ichi Matsuoka
author_facet	Makoto Nakamura Yusuke Meguri Shuntaro Ikegawa Takumi Kondo Yuichi Sumii Takuya Fukumi Miki Iwamoto Yasuhisa Sando Hiroyuki Sugiura Noboru Asada Daisuke Ennishi Shuta Tomida Emi Fukuda-Kawaguchi Yasuyuki Ishii Yoshinobu Maeda Ken-ichi Matsuoka
author_sort	Makoto Nakamura
title	Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
title_short	Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
title_full	Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
title_fullStr	Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
title_full_unstemmed	Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression
title_sort	reduced dose of ptcy followed by adjuvant α-galactosylceramide enhances gvl effect without sacrificing gvhd suppression
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/388351f9d0984b6baabda3767f059358
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Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

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