TY - JOUR
T1 - Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model
AU - Ono, Rintaro
AU - Watanabe, Takashi
AU - Kawakami, Eiryo
AU - Iwasaki, Makoto
AU - Tomizawa-Murasawa, Mariko
AU - Matsuda, Masashi
AU - Najima, Yuho
AU - Takagi, Shinsuke
AU - Fujiki, Saera
AU - Sato, Rumi
AU - Mochizuki, Yoshiki
AU - Yoshida, Hisahiro
AU - Sato, Kaoru
AU - Yabe, Hiromasa
AU - Kato, Shunichi
AU - Saito, Yoriko
AU - Taniguchi, Shuichi
AU - Shultz, Leonard D.
AU - Ohara, Osamu
AU - Amagai, Masayuki
AU - Koseki, Haruhiko
AU - Ishikawa, Fumihiko
N1 - Funding Information:
This study was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (KAKENHI Grant Number JP24111009), by Japan Agency for Medical Research and Development (Japan AMED) (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and the Research Center Network for Realization of Regenerative Medicine for HK), and by NIHCA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
Funding Information:
This study was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (KAKENHI Grant Number JP24111009 ), by Japan Agency for Medical Research and Development (Japan AMED) (the Basic Science and Platform Technology Program for Innovative Biological Medicine for FI and the Research Center Network for Realization of Regenerative Medicine for HK), and by NIH CA034196 for LDS. The funders had no role in the study design, data collection, data analysis, interpretation nor writing of the report.
Publisher Copyright:
© 2019 The Authors
PY - 2019/3
Y1 - 2019/3
N2 - Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 + CD38 − CD45RA − haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34 − cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.
AB - Background: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. Methods: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 + CD38 − CD45RA − haematopoietic stem/progenitor cells (HSPCs) into hIL-6 transgenic NOD/SCID/Il2rgKO (NSG) newborns, and compared GVHD progression with NSG newborns receiving CB CD34 − cells mimicking acute GVHD. We characterised human immune cell subsets, target organ infiltration, T-cell repertoire (TCR) and transcriptome in the humanised mice. Findings: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. Interpretation: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD.
KW - Acute GVHD
KW - Chronic GVHD
KW - Humanised mouse
KW - IL-6
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U2 - 10.1016/j.ebiom.2019.02.001
DO - 10.1016/j.ebiom.2019.02.001
M3 - Article
C2 - 30772305
AN - SCOPUS:85061375445
VL - 41
SP - 584
EP - 596
JO - EBioMedicine
JF - EBioMedicine
SN - 2352-3964
ER -