Altered homeostatic regulation of innate and adaptive immunity in lower gastrointestinal tract GVHD pathogenesis
James L.M. Ferrara,1 Christopher M. Smith,1 Julia Sheets,2 Pavan Reddy,3 and Jonathan S. Serody4
1Departments of Medicine, Pediatrics, and Academic Informatics and Technology, Icahn School of Medicine at Mount Sinai and Tisch Cancer Institute, New York, New York, USA.
2University of North Carolina Hospital, Chapel Hill, North Carolina, USA.
3Department of Medicine and University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
4Department of Medicine and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Address correspondence to: Jonathan S. Serody, University of North Carolina School of Medicine, 125 Marsico Hall, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.6975; Email: Jonathan_Serody@med.unc.edu.
Find articles by Ferrara, J. in: JCI | PubMed | Google Scholar
1Departments of Medicine, Pediatrics, and Academic Informatics and Technology, Icahn School of Medicine at Mount Sinai and Tisch Cancer Institute, New York, New York, USA.
2University of North Carolina Hospital, Chapel Hill, North Carolina, USA.
3Department of Medicine and University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
4Department of Medicine and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Address correspondence to: Jonathan S. Serody, University of North Carolina School of Medicine, 125 Marsico Hall, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.6975; Email: Jonathan_Serody@med.unc.edu.
Find articles by Smith, C. in: JCI | PubMed | Google Scholar
1Departments of Medicine, Pediatrics, and Academic Informatics and Technology, Icahn School of Medicine at Mount Sinai and Tisch Cancer Institute, New York, New York, USA.
2University of North Carolina Hospital, Chapel Hill, North Carolina, USA.
3Department of Medicine and University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
4Department of Medicine and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Address correspondence to: Jonathan S. Serody, University of North Carolina School of Medicine, 125 Marsico Hall, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.6975; Email: Jonathan_Serody@med.unc.edu.
Find articles by Sheets, J. in: JCI | PubMed | Google Scholar
1Departments of Medicine, Pediatrics, and Academic Informatics and Technology, Icahn School of Medicine at Mount Sinai and Tisch Cancer Institute, New York, New York, USA.
2University of North Carolina Hospital, Chapel Hill, North Carolina, USA.
3Department of Medicine and University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
4Department of Medicine and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Address correspondence to: Jonathan S. Serody, University of North Carolina School of Medicine, 125 Marsico Hall, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.6975; Email: Jonathan_Serody@med.unc.edu.
Find articles by Reddy, P. in: JCI | PubMed | Google Scholar
1Departments of Medicine, Pediatrics, and Academic Informatics and Technology, Icahn School of Medicine at Mount Sinai and Tisch Cancer Institute, New York, New York, USA.
2University of North Carolina Hospital, Chapel Hill, North Carolina, USA.
3Department of Medicine and University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
4Department of Medicine and UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Address correspondence to: Jonathan S. Serody, University of North Carolina School of Medicine, 125 Marsico Hall, Chapel Hill, North Carolina 27599-7295, USA. Phone: 919.966.6975; Email: Jonathan_Serody@med.unc.edu.
Find articles by Serody, J. in: JCI | PubMed | Google Scholar
First published June 5, 2017 - More info
J Clin Invest. 2017;127(7):2441–2451. doi:10.1172/JCI90592.
Copyright © 2017, American Society for Clinical Investigation
Lower gastrointestinal (GI) tract graft-versus-host disease (GVHD) is the predominant cause of morbidity and mortality from GVHD after allogeneic stem cell transplantation. Recent data indicate that lower GI tract GVHD is a complicated process mediated by donor/host antigenic disparities. This process is exacerbated by significant changes to the microbiome, and innate and adaptive immune responses that are critical to the induction of disease, persistence of inflammation, and a lack of response to therapy. Here, we discuss new insights into the biology of lower GI tract GVHD and focus on intrinsic pathways and regulatory mechanisms crucial to normal intestinal function. We then describe multiple instances in which these homeostatic mechanisms are altered by donor T cells or conditioning therapy, resulting in exacerbation of GVHD. We also discuss data suggesting that some of these mechanisms produce biomarkers that could be informative as to the severity of GVHD and its response to therapy. Finally, novel therapies that might restore homeostasis in the GI tract during GVHD are highlighted.
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