Koyama et al. showed that steady-state expression of MHC-II by ileal intestinal epithelial cells (IEC) differed in genetically identical mice, depending on the vendor of origin. Analysis of fecal and ileal samples identified vancomycin-sensitive bacterial taxa, transferrable by cohousing, that positively associated with IFNγ-induced IEC MHC-II expression. Taxa negatively regulating IEC MHC-II expression were also identified, but were not transferred by cohousing. Pre-graft oral vancomycin treatment of recipient mice reduced IEC MHC-II expression and CD4+ T cell-mediated GVHD. The pre-transplant fecal microbiota profile correlated with outcomes for a clinical cohort receiving allogeneic stem cell transplants.
Contributed by Paula Hochman
ABSTRACT: Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic stem cell transplantation (SCT), and severe intestinal manifestation is the major cause of early mortality. Intestinal microbiota control MHC class II (MHC-II) expression by ileal intestinal epithelial cells (IECs) that promote GVHD. Here, we demonstrated that genetically identical mice of differing vendor origins had markedly different intestinal microbiota and ileal MHC-II expression, resulting in discordant GVHD severity. We utilized cohousing and antibiotic treatment to characterize the bacterial taxa positively and negatively associated with MHC-II expression. A large proportion of bacterial MHC-II inducers were vancomycin sensitive, and peri-transplant oral vancomycin administration attenuated CD4(+) T cell-mediated GVHD. We identified a similar relationship between pre-transplant microbes, HLA class II expression, and both GVHD and mortality in a large clinical SCT cohort. These data highlight therapeutically tractable mechanisms by which pre-transplant microbial taxa contribute to GVHD independently of genetic disparity.
Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. Electronic address: mkoyama@fredhutch.org. (2) Clinical Research
Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. Electronic address: mkoyama@fredhutch.org. (2) Clinical Research Division, FHCC, Seattle, WA 98109, USA. (3) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA. (4) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA. (5) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (9) Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (13) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA. (14) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA. (16) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA. (17) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA. (18) Infection and Immunity Program and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, WA 6009, Australia. (19) Transplantation Immunology Laboratory, Cancer Research Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia; Faculty of Medicine, University of Queensland, St Lucia, QLD 4067, Australia. (20) Molecular and Cellular Pathology, University of Queensland, Brisbane, QLD 4006, Australia. (21) Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA; Department of Immunology, Sloan Kettering Institute, New York, NY 10065, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA. (23) Clinical Research Division, FHCC, Seattle, WA 98109, USA; Public Health Sciences Division, FHCC, WA 98109, USA. (24) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medical College, New York, NY 10065, USA. (25) Vaccine and Infectious Disease Division, FHCC, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA. (26) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center (FHCC), Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: grhill@fredhutch.org.
