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Sci Rep. 2018 Aug 20;8(1):12475. doi: 10.1038/s41598-018-30814-x.

Murine Models of Steroid Refractory Graft-versus-Host Disease.

Author information

1
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. toubai@med.id.yamagata-u.ac.jp.
2
Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University Faculty of Medicine, Yamagata, Japan. toubai@med.id.yamagata-u.ac.jp.
3
Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
4
Department of Pediatrics, Division of Hematology and Oncology, University Hospital of Heidelberg, Heidelberg, Germany.
5
Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie, Japan.
6
Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
7
Division of Hematology and Oncology, Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.

Abstract

Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, the outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. The development of therapies for SR-GVHD is limited by an incomplete understanding of its pathophysiology partly because of the absence of clinically relevant animal models of SR-GVHD. Here we addressed the need for a SR-GVHD animal model by developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and MHC mismatched haploidentical murine models of SR-GVHD. We demonstrate that animals can develop SR-GVHD regardless of whether steroids are initiated early or late post allogeneic bone marrow transplantation (allo-BMT). In general, we observed increased GVHD specific histopathological damage of target organs in SR-GVHD animals relative to steroid responsive animals. Interestingly, we found no significant differences in donor T cell characteristics between steroid refractory and responsive animals suggesting that donor T cell independent mechanisms may play more prominent roles in the pathogenesis of SR-GVHD than was considered previously.

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