Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD

Danny W. Bruce; Oleg Kolupaev; Sonia J. Laurie; Hemamalini Bommiasamy; Heather E Stefanski; Bruce R. Blazar; James M. Coghill; Jonathan S. Serody

doi:10.1182/bloodadvances.2020001514

Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD

Danny W. Bruce
, Oleg Kolupaev
, Sonia J. Laurie
, Hemamalini Bommiasamy
, Heather E Stefanski
, Bruce R. Blazar
, James M. Coghill
, Jonathan S. Serody

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an "off-the-shelf" reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.

Original language	English (US)
Pages (from-to)	4578-4589
Number of pages	12
Journal	Blood Advances
Volume	5
Issue number	22
DOIs	https://doi.org/10.1182/bloodadvances.2020001514
State	Published - Nov 23 2021

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (RO1 HL139730, J.S.S.; R01 HL155098, J.S.S.; R01 HL56067, B.R.B.; and R01 HL11879, B.R.B.), National Institute of Allergy and Infectious Diseases (R37 AI34495, B.R.B.), and National Cancer Institute (P01 CA065493, H.S. and B.R.B.). It was also supported by a TRP Grant from the Leukemia and Lymphoma Society (J.S.S. and B.R.B.).

Funding Information:
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Biopharmaceuticals, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics and an inventor on a pending patent application for use of ILC2s in GVHD. J.S.S. is supported by grants from Merck Sharpe & Dohme, Carisma Therapeutics, and GlaxoSmithKline. He has filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. D.W.B., H.S., and J.M.C. have filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. The remaining authors declare no competing financial interests.

Publisher Copyright:
ß 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Gastrointestinal Tract
Graft vs Host Disease/prevention & control
Hematopoietic Stem Cell Transplantation/adverse effects
Humans
Immunity, Innate
Lymphocytes

PubMed: MeSH publication types

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

Publisher link

10.1182/bloodadvances.2020001514

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title = "Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD",

abstract = "Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15\% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an {"}off-the-shelf{"} reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.",

keywords = "Gastrointestinal Tract, Graft vs Host Disease/prevention \& control, Hematopoietic Stem Cell Transplantation/adverse effects, Humans, Immunity, Innate, Lymphocytes",

author = "Bruce, \{Danny W.\} and Oleg Kolupaev and Laurie, \{Sonia J.\} and Hemamalini Bommiasamy and Stefanski, \{Heather E\} and Blazar, \{Bruce R.\} and Coghill, \{James M.\} and Serody, \{Jonathan S.\}",

note = "Funding Information: This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (RO1 HL139730, J.S.S.; R01 HL155098, J.S.S.; R01 HL56067, B.R.B.; and R01 HL11879, B.R.B.), National Institute of Allergy and Infectious Diseases (R37 AI34495, B.R.B.), and National Cancer Institute (P01 CA065493, H.S. and B.R.B.). It was also supported by a TRP Grant from the Leukemia and Lymphoma Society (J.S.S. and B.R.B.). Funding Information: Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Biopharmaceuticals, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics and an inventor on a pending patent application for use of ILC2s in GVHD. J.S.S. is supported by grants from Merck Sharpe \& Dohme, Carisma Therapeutics, and GlaxoSmithKline. He has filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. D.W.B., H.S., and J.M.C. have filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. The remaining authors declare no competing financial interests. Publisher Copyright: {\ss} 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.",

year = "2021",

month = nov,

day = "23",

doi = "10.1182/bloodadvances.2020001514",

language = "English (US)",

volume = "5",

pages = "4578--4589",

journal = "Blood Advances",

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publisher = "American Society of Hematology",

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T1 - Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD

AU - Bruce, Danny W.

AU - Kolupaev, Oleg

AU - Laurie, Sonia J.

AU - Bommiasamy, Hemamalini

AU - Stefanski, Heather E

AU - Blazar, Bruce R.

AU - Coghill, James M.

AU - Serody, Jonathan S.

N1 - Funding Information: This work was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute (RO1 HL139730, J.S.S.; R01 HL155098, J.S.S.; R01 HL56067, B.R.B.; and R01 HL11879, B.R.B.), National Institute of Allergy and Infectious Diseases (R37 AI34495, B.R.B.), and National Cancer Institute (P01 CA065493, H.S. and B.R.B.). It was also supported by a TRP Grant from the Leukemia and Lymphoma Society (J.S.S. and B.R.B.). Funding Information: Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre Biopharmaceuticals, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics and an inventor on a pending patent application for use of ILC2s in GVHD. J.S.S. is supported by grants from Merck Sharpe & Dohme, Carisma Therapeutics, and GlaxoSmithKline. He has filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. D.W.B., H.S., and J.M.C. have filed for intellectual property for the use of ILCs to treat and/or prevent aGVHD. The remaining authors declare no competing financial interests. Publisher Copyright: ß 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

PY - 2021/11/23

Y1 - 2021/11/23

N2 - Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an "off-the-shelf" reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.

AB - Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an "off-the-shelf" reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.

KW - Gastrointestinal Tract

KW - Graft vs Host Disease/prevention & control

KW - Hematopoietic Stem Cell Transplantation/adverse effects

KW - Humans

KW - Immunity, Innate

KW - Lymphocytes

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DO - 10.1182/bloodadvances.2020001514

M3 - Article

C2 - 34619767

AN - SCOPUS:85120421841

SN - 2473-9529

VL - 5

SP - 4578

EP - 4589

JO - Blood Advances

JF - Blood Advances

IS - 22

ER -

Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD

Abstract

Bibliographical note

UN SDGs

Keywords

PubMed: MeSH publication types

Publisher link

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