title: Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice.
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.
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Hung-Lin
authors.initials: HL
authors.lastname: Chen
authors.affiliation: Department of Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Nadine
authors.initials: N
authors.lastname: Bannick
authors.affiliation: 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;
authors.forename: Michael
authors.initials: M
authors.lastname: Henry
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Adrian N
authors.initials: AN
authors.lastname: Holm
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Ahmed
authors.initials: A
authors.lastname: Metwali
authors.affiliation: Diet, Genomics, and Immunology Laboratory, Beltsville Human Nutrition Research Center, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, MD 20705; and.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Urban
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
authors.affiliation: 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;
authors.forename: George J
authors.initials: GJ
authors.lastname: Weiner
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: David E
authors.initials: DE
authors.lastname: Elliott
authors.affiliation: 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.
authors.forename: M Nedim
authors.initials: MN
authors.lastname: Ince
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D006374:Helminthiasis, Animal / Q000276:immunology; D006376:Helminths / Q000276:immunology*; D056747:Immunomodulation; D016130:Immunophenotyping; D007422:Intestines / Q000276:immunology* / Q000469:parasitology*; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000401:mortality; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D016212:Transforming Growth Factor beta