title: Selective blockade of herpesvirus entry mediator-B and T lymphocyte attenuator pathway ameliorates acute graft-versus-host reaction.
abstract: The cosignaling network mediated by the herpesvirus entry mediator (HVEM; TNFRSF14) functions as a dual directional system that involves proinflammatory ligand, lymphotoxin that exhibits inducible expression and competes with HSV glycoprotein D for HVEM, a receptor expressed by T lymphocytes (LIGHT; TNFSF14), and the inhibitory Ig family member B and T lymphocyte attenuator (BTLA). To dissect the differential contributions of HVEM/BTLA and HVEM/LIGHT interactions, topographically-specific, competitive, and nonblocking anti-HVEM Abs that inhibit BTLA binding, but not LIGHT, were developed. We demonstrate that a BTLA-specific competitor attenuated the course of acute graft-versus-host reaction in a murine F(1) transfer semiallogeneic model. Selective HVEM/BTLA blockade did not inhibit donor T cell infiltration into graft-versus-host reaction target organs, but decreased the functional activity of the alloreactive T cells. These results highlight the critical role of HVEM/BTLA pathway in the control of the allogeneic immune response and identify a new therapeutic target for transplantation and autoimmune diseases.
authors.affiliation: Immunobiology Section, Institute of Biomedicine, University of Leon, 24007 Leon, Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: del Rio
authors.forename: Nick D
authors.initials: ND
authors.lastname: Jones
authors.forename: Leo
authors.initials: L
authors.lastname: Buhler
authors.forename: Paula
authors.initials: P
authors.lastname: Norris
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D016466:CHO Cells; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D005260:Female; D006087:Graft vs Host Reaction / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011917:Rats, Inbred Lew; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
chemical_list: C488868:BTLA protein, mouse; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011993:Recombinant Fusion Proteins