Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity

Jemma H Larson, Sujeong Jin, Michael Loschi, Sara Bolivar Wagers, Govindarajan Thangavelu, Michael C Zaiken, Cameron S Mcdonald-Hyman, Asim Saha, Ethan Aguilar, Brent Koehn, Mark J Osborn, Angela Panoskaltsis-Mortari, Kelli P.A. Macdonald, Geoffrey R. Hill, William J. Murphy, Jonathan S. Serody, Ivan Maillard, Leslie S. Kean, Sangwon V. Kim, Dan R. LittmanBruce R Blazar

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Damage to the gastrointestinal tract following allogeneic hematopoietic stem cell transplantation is a significant contributor to the severity and perpetuation of graft-versus-host disease. In preclinical models and clinical trials, we showed that infusing high numbers of regulatory T cells reduces graft-versus-host disease incidence. Despite no change in in vitro suppressive function, transfer of ex vivo expanded regulatory T cells transduced to overexpress G protein–coupled receptor 15 or C-C motif chemokine receptor 9, specific homing receptors for colon or small intestine, respectively, lessened graft-versus-host disease severity in mice. Increased regulatory T cell frequency and retention within the gastrointestinal tissues of mice that received gut homing T cells correlated with lower inflammation and gut damage early post-transplant, decreased graft-versus-host disease severity, and prolonged survival compared with those receiving control transduced regulatory T cells. These data provide evidence that enforced targeting of ex vivo expanded regulatory T cells to the gastrointestinal tract diminishes gut injury and is associated with decreased graft-versus-host disease severity.

Original languageEnglish (US)
Pages (from-to)1102-1115
Number of pages14
JournalAmerican Journal of Transplantation
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2023

Bibliographical note

Funding Information:
This work was supported by grants from the Children’s Cancer Research Fund and National Institutes of Health , R01 HL11879 , R01 HL56067 , and R01 AI091627 , National Institute of Allergy and Infectious Diseases grant R37 AI34495 , and the Hematology Research Training Program T32 HL007062 .

Publisher Copyright:
© 2023 American Society of Transplantation & American Society of Transplant Surgeons

Keywords

  • CCR9
  • GPR15
  • GVHD
  • lymphocyte homing
  • regulatory T cell

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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