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EBioMedicine. 2019 Mar;41:584-596. doi: 10.1016/j.ebiom.2019.02.001. Epub 2019 Feb 13.

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

Author information

1
Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
2
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
3
Disease Biology Group, RIKEN Medical Sciences Innovation Hub Program (MIH), Yokohama 230-0045, Japan.
4
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan.
5
Department of Haematology, Toranomon Hospital, Tokyo 105-8470, Japan.
6
Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan.
7
The Jackson Laboratory, Bar Harbor 04609, ME, United States.
8
Laboratory for Integrative Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Human Genome Research, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan.
9
Laboratory for Skin Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan; Department of Dermatology, Keio University School of Medicine, Tokyo 160-8582, Japan.
10
Laboratory for Human Disease Models, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan. Electronic address: fumihiko.ishikawa@riken.jp.

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.

KEYWORDS:

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

PMID:
30772305
PMCID:
PMC6441951
DOI:
10.1016/j.ebiom.2019.02.001
[Indexed for MEDLINE]
Free PMC Article

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