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Biol Blood Marrow Transplant. 2019 Dec;25(12):2338-2349. doi: 10.1016/j.bbmt.2019.08.001. Epub 2019 Aug 12.

Modeling Chronic Graft-versus-Host Disease in MHC-Matched Mouse Strains: Genetics, Graft Composition, and Tissue Targets.

Author information

1
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, California; Department of Hematology, University Hospital and University Zurich, Zurich, Switzerland. Electronic address: AntoniaMaria.Mueller@usz.ch.
2
Division of Pediatric Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California.
3
Department of Pathology, Stanford University School of Medicine, Stanford, California.
4
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida.
5
Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida.
6
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, California.
7
Department of Hematology, University Hospital and University Zurich, Zurich, Switzerland.
8
Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, California; Division of Pediatric Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, California.

Abstract

Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic cell transplantation. Acute GVHD (aGVHD) results from direct damage by donor T cells, whereas the biology of chronic GVHD (cGVHD) with its autoimmune-like manifestations remains poorly understood, mainly because of the paucity of representative preclinical models. We examined over an extended time period 7 MHC-matched, minor antigen-mismatched mouse models for development of cGVHD. Development and manifestations of cGVHD were determined by a combination of MHC allele type and recipient strain, with BALB recipients being the most susceptible. The C57BL/6 into BALB.B combination most closely modeled the human syndrome. In this strain combination moderate aGVHD was observed and BALB.B survivors developed overt cGVHD at 6 to 12 months affecting eyes, skin, and liver. Naïve CD4+ cells caused this syndrome as no significant pathology was induced by grafts composed of purified hematopoietic stem cells (HSCs) or HSC plus effector memory CD4+ or CD8+ cells. Furthermore, co-transferred naïve and effector memory CD4+ T cells demonstrated differential homing patterns and locations of persistence. No clear association with donor Th17 cells and the phenotype of aGVHD or cGVHD was observed in this model. Donor CD4+ cells caused injury to medullary thymic epithelial cells, a key population responsible for negative T cell selection, suggesting that impaired thymic selection was an underlying cause of the cGVHD syndrome. In conclusion, we report for the first time that the C57BL/6 into BALB.B combination is a representative model of cGVHD that evolves from immunologic events during the early post-transplant period.

KEYWORDS:

Chronic graft-versus-host disease; Mouse models; Pathophysiology; Thymic damage

PMID:
31415899
DOI:
10.1016/j.bbmt.2019.08.001

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