Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice

Yue Li; Hung-Lin Chen; Nadine Bannick; Michael Henry; Adrian N Holm; Ahmed Metwali; Joseph F Urban Jr; Paul B Rothman; George J Weiner; Bruce R Blazar; David E Elliott; M Nedim Ince

doi:10.4049/jimmunol.1303099

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Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice

Journal article

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Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice

Yue Li, Hung-Lin Chen, Nadine Bannick, Michael Henry, Adrian N Holm, Ahmed Metwali, Joseph F Urban Jr, Paul B Rothman, George J Weiner, Bruce R Blazar, …

The Journal of immunology (1950), Vol.194(3), pp.1011-1020

02/01/2015

DOI: 10.4049/jimmunol.1303099

PMCID: PMC4297687

PMID: 25527786

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https://www.ncbi.nlm.nih.gov/pmc/articles/4297687View

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Abstract

Donor T lymphocyte transfer with hematopoietic stem cells suppresses residual tumor growth (graft-versus-tumor [GVT]) in cancer patients undergoing bone marrow transplantation (BMT). However, donor T cell reactivity to host organs causes severe and potentially lethal inflammation called graft-versus-host disease (GVHD). High-dose steroids or other immunosuppressive drugs are used to treat GVHD that have limited ability to control the inflammation while incurring long-term toxicity. Novel strategies are needed to modulate GVHD, preserve GVT, and improve the outcome of BMT. Regulatory T cells (Tregs) control alloantigen-sensitized inflammation of GVHD, sustain GVT, and prevent mortality in BMT. Helminths colonizing the alimentary tract dramatically increase the Treg activity, thereby modulating intestinal or systemic inflammatory responses. These observations led us to hypothesize that helminths can regulate GVHD and maintain GVT in mice. Acute GVHD was induced in helminth (Heligmosomoides polygyrus)-infected or uninfected BALB/c recipients of C57BL/6 donor grafts. Helminth infection suppressed donor T cell inflammatory cytokine generation and reduced GVHD-related mortality, but maintained GVT. H. polygyrus colonization promoted the survival of TGF-β-generating recipient Tregs after a conditioning regimen with total body irradiation and led to a TGF-β-dependent in vivo expansion/maturation of donor Tregs after BMT. Helminths did not control GVHD when T cells unresponsive to TGF-β-mediated immune regulation were used as donor T lymphocytes. These results suggest that helminths suppress acute GVHD using Tregs and TGF-β-dependent pathways in mice. Helminthic regulation of GVHD and GVT through intestinal immune conditioning may improve the outcome of BMT.

Bone Marrow Transplantation

Neoplasms - metabolism

T-Lymphocyte Subsets - immunology

T-Lymphocytes, Regulatory - metabolism

Male

Adoptive Transfer

Graft vs Host Disease - metabolism

Graft vs Host Disease - immunology

Intestines - immunology

Transplantation, Homologous

T-Lymphocytes, Regulatory - immunology

Helminths - immunology

Graft vs Host Disease - mortality

Helminthiasis, Animal - immunology

Intestines - parasitology

Disease Models, Animal

Acute Disease

Immunomodulation

Neoplasms - mortality

Immunophenotyping

Animals

Neoplasms - immunology

T-Lymphocyte Subsets - metabolism

Mice

Transplantation Conditioning

Transforming Growth Factor beta - metabolism

Cytokines - biosynthesis

Details

Title: Subtitle: Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice
Creators: Yue Li - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Hung-Lin Chen - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Nadine Bannick - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Michael Henry - Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Adrian N Holm - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Ahmed Metwali - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Joseph F Urban Jr - Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705; and
Paul B Rothman - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
George J Weiner - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Bruce R Blazar - Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455
David E Elliott - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242
M Nedim Ince - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, Iowa City, IA 52242; m-nedim-ince@uiowa.edu
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.194(3), pp.1011-1020
DOI: 10.4049/jimmunol.1303099
PMID: 25527786
PMCID: PMC4297687
NLM abbreviation: J Immunol
ISSN: 0022-1767
eISSN: 1550-6606
Publisher: United States
Grant note: P01 CA065493 / NCI NIH HHS R01 AI034495 / NIAID NIH HHS R56 AI116715 / NIAID NIH HHS R01 HL118979 / NHLBI NIH HHS I01 BX002715 / BLRD VA R01 HL56067 / NHLBI NIH HHS P01 CA142106 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R37 AI034495 / NIAID NIH HHS P50 CA097274 / NCI NIH HHS R01 AI34495 / NIAID NIH HHS R01 HL11879 / NHLBI NIH HHS K08 DK082913 / NIDDK NIH HHS P01 AI056299 / NIAID NIH HHS R01 HL056067 / NHLBI NIH HHS
Language: English
Date published: 02/01/2015
Academic Unit: Molecular Physiology and Biophysics; Hematology, Oncology, and Blood & Marrow Transplantation; Gastroenterology and Hepatology; Pathology; Pharmaceutical Sciences and Experimental Therapeutics; Radiation Oncology; Urology; Internal Medicine
Record Identifier: 9984025339502771

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