title: Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease.
abstract: The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (αDR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of αDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. αDR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from αDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from αDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4(+) T cells were maintained, resulting in improved survival. Conventional T cells derived from αDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNγ, IL-1β, and TNFα) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from αDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of αDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies.
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA; Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea;
authors.forename: Byung-Su
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA; Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishikii
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA;
authors.forename: Jeanette
authors.initials: J
authors.lastname: Baker
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA;
authors.forename: Antonio
authors.initials: A
authors.lastname: Pierini
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA;
authors.forename: Dominik
authors.initials: D
authors.lastname: Schneidawind
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA;
authors.forename: Yuqiong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany; Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Beilhack
authors.affiliation: Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Korea; Department of Biomedical Sciences, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Chung-Gyu
authors.initials: CG
authors.lastname: Park
authors.affiliation: Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University, Stanford, CA;
authors.forename: Robert S
authors.initials: RS
authors.lastname: Negrin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D020350:Graft vs Tumor Effect / Q000276:immunology*; D007136:Immunoglobulins / Q000008:administration & dosage; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007136:Immunoglobulins; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse