title: Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.
abstract: Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non-life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4(+) forkhead box P3(-) (Foxp3(-)) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4(+) Foxp3(+) regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non-life-threatening diseases.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Jörn C
authors.initials: JC
authors.lastname: Albring
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Sandau
authors.forename: Aaron S
authors.initials: AS
authors.lastname: Rapaport
authors.forename: Brian T
authors.initials: BT
authors.lastname: Edelson
authors.forename: Ansuman
authors.initials: A
authors.lastname: Satpathy
authors.forename: Mona
authors.initials: M
authors.lastname: Mashayekhi
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Lathrop
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
authors.forename: Matthias
authors.initials: M
authors.lastname: Stelljes
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease / Q000517:prevention & control*; D018380:Hematopoietic Stem Cell Transplantation; D007165:Immunosuppression Therapy; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C488868:BTLA protein, mouse; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse