Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.
Acute Disease
Animals
Animals, Newborn
Chronic Disease
Disease Models, Animal
Graft vs Host Disease
/ etiology
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
/ cytology
Humans
Interleukin Receptor Common gamma Subunit
/ deficiency
Interleukin-6
/ genetics
Keratinocytes
/ cytology
Macrophages
/ immunology
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Survival Rate
T-Lymphocytes
/ immunology
Transcriptome
Acute GVHD
Chronic GVHD
Humanised mouse
IL-6
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Mar 2019
Mar 2019
Historique:
received:
07
11
2018
revised:
25
01
2019
accepted:
01
02
2019
pubmed:
18
2
2019
medline:
13
7
2019
entrez:
18
2
2019
Statut:
ppublish
Résumé
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. We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 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. 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.
Sections du résumé
BACKGROUND
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
METHODS
We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34
FINDINGS
RESULTS
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
CONCLUSIONS
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.
Identifiants
pubmed: 30772305
pii: S2352-3964(19)30073-8
doi: 10.1016/j.ebiom.2019.02.001
pmc: PMC6441951
pii:
doi:
Substances chimiques
IL6 protein, human
0
Il2rg protein, mouse
0
Interleukin Receptor Common gamma Subunit
0
Interleukin-6
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
584-596Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.
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