title: B7-H3 expression in donor T cells and host cells negatively regulates acute graft-versus-host disease lethality.
abstract: Members of the B7 family have been shown to be important for regulating immune responses by providing either positive or negative costimulatory signals. The function of B7-H3 has been controversial. We show that B7-H3 is upregulated in graft-versus-host disease (GVHD) target organs, including the colon, liver, and lung. Infusion of allogeneic donor T cells into B7-H3(-/-) vs wild-type (WT) recipients resulted in increased GVHD lethality associated with increased T-cell proliferation, colonic inflammatory cytokines, and destruction of epithelial barriers. Allogeneic B7-H3(-/-) vs WT donor T cells also had increased T-cell proliferation and GVHD lethality associated with increased proliferation and cytokine secretion in the spleen, intraepithelial lymphocyte inflammatory cytokines, and intestinal permeability. Both resting and activated regulatory T cells (Tregs) lack B7-H3 messenger RNA. Consistent with these data, GVHD was augmented in recipients of B7-H3(-/-) Treg-depleted grafts. In two delayed lymphocyte infusion (DLI) models, T cells lacking B7-H3 are capable of providing graft-versus-leukemia (GVL) effects. We conclude that B7-H3 is responsible for providing a negative costimulatory signal. Our studies provide support for developing and testing new therapies directed toward the B7-H3 pathway, including approaches to augment host B7-H3 early after bone marrow transplantation to prevent GVHD and to develop potent antagonistic antibodies later after transplant to facilitate DLI-mediated GVL without GVHD complications.
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Rachelle G
authors: RG
authors: Veenstra
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Ryan
authors: R
authors: Flynn
authors: Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors: Katharina
authors: K
authors: Kreymborg
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Cameron
authors: C
authors: McDonald-Hyman
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Asim
authors: A
authors: Saha
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Patricia A
authors: PA
authors: Taylor
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Mark J
authors: MJ
authors: Osborn
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Angela
authors: A
authors: Panoskaltsis-Mortari
authors: Department of Pathology, and.
authors: Annette
authors: A
authors: Schmitt-Graeff
authors: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors: Elisabeth
authors: E
authors: Lieberknecht
authors: Department of Dermatology, School of Medicine, University of California at Davis, Sacramento, CA;
authors: William J
authors: WJ
authors: Murphy
authors: Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC;
authors: Jonathan S
authors: JS
authors: Serody
authors: Department of Pediatrics, Immunotherapy Center, Medical College of Georgia, Augusta, GA;
authors: David H
authors: DH
authors: Munn
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors: Gordon J
authors: GJ
authors: Freeman
authors: Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX; and.
authors: James P
authors: JP
authors: Allison
authors: Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada.
authors: Tak W
authors: TW
authors: Mak
authors: Department of Immunology and Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;
authors: Marcel
authors: M
authors: van den Brink
authors: Department of Hematology and Oncology, Freiburg University Medical Center, Freiburg, Germany;
authors: Robert
authors: R
authors: Zeiser
authors: Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Cancer Center, Minneapolis, MN;
authors: Bruce R
authors: 0000-0001-9608-9841
authors: BR
authors: Blazar
mesh_terms: D064591:Allografts; D000818:Animals; D060887:B7 Antigens / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects*; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D060887:B7 Antigens; C486038:Cd276 protein, mouse