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 AmagaiHaruhiko Koseki, Fumihiko Ishikawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

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
Pages (from-to)584-596
Number of pages13
JournalEBioMedicine
Volume41
DOIs
Publication statusPublished - 2019 Mar

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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, L. D., Ohara, O., ... Ishikawa, F. (2019). Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model. EBioMedicine, 41, 584-596. https://doi.org/10.1016/j.ebiom.2019.02.001