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. Littman; Bruce R Blazar

doi:10.1016/j.ajt.2023.01.030

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 journal › Article › peer-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 language	English (US)
Pages (from-to)	1102-1115
Number of pages	14
Journal	American Journal of Transplantation
Volume	23
Issue number	8
DOIs	https://doi.org/10.1016/j.ajt.2023.01.030
State	Published - Aug 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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10.1016/j.ajt.2023.01.030

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Larson, J. H., Jin, S., Loschi, M., Bolivar Wagers, S., Thangavelu, G., Zaiken, M. C., Mcdonald-Hyman, C. S., Saha, A., Aguilar, E., Koehn, B., Osborn, M. J., Panoskaltsis-Mortari, A., Macdonald, K. P. A., Hill, G. R., Murphy, W. J., Serody, J. S., Maillard, I., Kean, L. S., Kim, S. V., ... Blazar, B. R. (2023). Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity. American Journal of Transplantation, 23(8), 1102-1115. https://doi.org/10.1016/j.ajt.2023.01.030

Larson, JH, Jin, S, Loschi, M, Bolivar Wagers, S, Thangavelu, G, Zaiken, MC , Mcdonald-Hyman, CS , Saha, A, Aguilar, E, Koehn, B , Osborn, MJ , Panoskaltsis-Mortari, A, Macdonald, KPA, Hill, GR, Murphy, WJ, Serody, JS, Maillard, I, Kean, LS, Kim, SV, Littman, DR & Blazar, BR 2023, 'Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity', American Journal of Transplantation, vol. 23, no. 8, pp. 1102-1115. https://doi.org/10.1016/j.ajt.2023.01.030

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

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.",

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

note = "Funding Information: This work was supported by grants from the Children{\textquoteright}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: {\textcopyright} 2023 American Society of Transplantation & American Society of Transplant Surgeons",

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AU - Bolivar Wagers, Sara

AU - Thangavelu, Govindarajan

AU - Zaiken, Michael C

AU - Mcdonald-Hyman, Cameron S

AU - Saha, Asim

AU - Aguilar, Ethan

AU - Koehn, Brent

AU - Osborn, Mark J

AU - Panoskaltsis-Mortari, Angela

AU - Macdonald, Kelli P.A.

AU - Hill, Geoffrey R.

AU - Murphy, William J.

AU - Serody, Jonathan S.

AU - Maillard, Ivan

AU - Kean, Leslie S.

AU - Kim, Sangwon V.

AU - Littman, Dan R.

AU - Blazar, Bruce R

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PY - 2023/8

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N2 - 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.

AB - 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.

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KW - GPR15

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KW - lymphocyte homing

KW - regulatory T cell

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

Abstract

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Keywords

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

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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