Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model

Rintaro Ono, Takashi Watanabe, Eiryo Kawakami, Makoto Iwasaki, Mariko Tomizawa-Murasawa, Masashi Matsuda, Yuho Najima, Shinsuke Takagi, Saera Fujiki, Rumi Sato, Yoshiki Mochizuki, Hisahiro Yoshida, Kaoru Sato, Hiromasa Yabe, Shunichi Kato, Yoriko Saito, Shuichi Taniguchi, Leonard D. Shultz, Osamu Ohara, Masayuki Amagai & 2 others Haruhiko Koseki, Fumihiko Ishikawa

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
JournalEBioMedicine
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

T-cells
Macrophage Activation
Macrophages
Graft vs Host Disease
Grafts
Transgenic Mice
Interleukin-6
Chemical activation
T-Lymphocytes
Hematopoietic Stem Cells
Stem cells
Liver
Fetal Blood
Lung
Disease Progression
Molecular Medicine
Bronchioles
Skin
Blood
Stem Cell Transplantation

Keywords

  • Acute GVHD
  • Chronic GVHD
  • Humanised mouse
  • IL-6

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Ono, R., Watanabe, T., Kawakami, E., Iwasaki, M., Tomizawa-Murasawa, M., Matsuda, M., ... Ishikawa, F. (2019). Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model. EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.02.001

Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model. / Ono, Rintaro; Watanabe, Takashi; Kawakami, Eiryo; Iwasaki, Makoto; Tomizawa-Murasawa, Mariko; Matsuda, Masashi; Najima, Yuho; Takagi, Shinsuke; Fujiki, Saera; Sato, Rumi; Mochizuki, Yoshiki; Yoshida, Hisahiro; Sato, Kaoru; Yabe, Hiromasa; Kato, Shunichi; Saito, Yoriko; Taniguchi, Shuichi; Shultz, Leonard D.; Ohara, Osamu; Amagai, Masayuki; Koseki, Haruhiko; Ishikawa, Fumihiko.

In: EBioMedicine, 01.01.2019.

Research output: Contribution to journalArticle

Ono, R, Watanabe, T, Kawakami, E, Iwasaki, M, Tomizawa-Murasawa, M, Matsuda, M, Najima, Y, Takagi, S, Fujiki, S, Sato, R, Mochizuki, Y, Yoshida, H, Sato, K, Yabe, H, Kato, S, Saito, Y, Taniguchi, S, Shultz, LD, Ohara, O, Amagai, M, Koseki, H & Ishikawa, F 2019, 'Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model', EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.02.001
Ono, Rintaro ; Watanabe, Takashi ; Kawakami, Eiryo ; Iwasaki, Makoto ; Tomizawa-Murasawa, Mariko ; Matsuda, Masashi ; Najima, Yuho ; Takagi, Shinsuke ; Fujiki, Saera ; Sato, Rumi ; Mochizuki, Yoshiki ; Yoshida, Hisahiro ; Sato, Kaoru ; Yabe, Hiromasa ; Kato, Shunichi ; Saito, Yoriko ; Taniguchi, Shuichi ; Shultz, Leonard D. ; Ohara, Osamu ; Amagai, Masayuki ; Koseki, Haruhiko ; Ishikawa, Fumihiko. / Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model. In: EBioMedicine. 2019.
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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

PY - 2019/1/1

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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.

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KW - Chronic GVHD

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