title: Therapeutic blockade of LIGHT interaction with herpesvirus entry mediator and lymphotoxin β receptor attenuates in vivo cytotoxic allogeneic responses.
abstract: BACKGROUND
  Tumor necrosis factor/tumor necrosis factor receptor superfamily members conform a group of molecular interaction pathways of essential relevance during the process of T-cell activation and differentiation toward effector cells and particularly for the maintenance phase of the immune response. Specific blockade of these interacting pathways, such as CD40-CD40L, contributes to modulate the deleterious outcome of allogeneic immune responses. We postulated that antagonizing the interaction of LIGHT expression on activated T cells with its receptors, herpesvirus entry mediator and lymphotoxin β receptor, may decrease T cell-mediated allogeneic responses.
  
  
  METHODS
  A flow cytometry competition assay was designed to identify anti-LIGHT monoclonal antibodies capable to prevent the interaction of mouse LIGHT with its receptors expressed on transfected cells. An antibody with the desired specificity was evaluated in a short-term in vivo allogeneic cytotoxic assay and tested for its ability to detect endogenous mouse LIGHT.
  
  
  RESULTS
  We provide evidence for the first time that in mice, as previously described in humans, LIGHT protein is rapidly and transiently expressed after T-cell activation, and this expression was stronger on CD8 T cells than on CD4 T cells. Two anti-LIGHT antibodies prevented interactions of mouse LIGHT with its two known receptors, herpesvirus entry mediator and lymphotoxin β receptor. In vivo administration of anti-LIGHT antibody (clone 10F12) ameliorated host antidonor short-term cytotoxic response in wild type B6 mice, although to a lesser extent than that observed in LIGHT-deficient mice.
  
  
  CONCLUSIONS
  The therapeutic targeting of LIGHT may contribute to achieve a better control of cytotoxic responses refractory to current immunosuppressive drugs in transplantation.
authors.affiliation: 1 Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Leon, Spain. 2 Institute of Medical Microbiology and Hospital Hygiene, University of Duesseldorf, Universitaetsstr., Duesseldorf, Germany. 3 Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan. 4 Center for Infectious Disease, Autoimmune Research, La Jolla Institute for Allergy and Immunology, La Jolla, CA. 5 CNRS UPR 3572, IBMC, Immunopathologie et Chimie Thérapeutique, Strasbourg, France. 6 Department of Biochemistry, University of Lausanne, Epalinges, Switzerland. 7 Address correspondence to: Jose-Ignacio Rodríguez-Barbosa, D.V.M., Ph.D., Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon, 24007 Leon, Spain; Maria-Luisa del Rio, D.V.M., Ph.D., Transplantation Immunobiology Section, Institute of Biomedicine, University of Leon and Castilla and Leon Regional Transplantation Coordination, Leon University Hospital, Leon, Spain.
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: del Rio
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandez-Renedo
authors.forename: Stefanie
authors.initials: S
authors.lastname: Scheu
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfeffer
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Olivier
authors.initials: O
authors.lastname: Chaloin
authors.forename: Pascal
authors.initials: P
authors.lastname: Schneider
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D005434:Flow Cytometry; D057809:HEK293 Cells; D006564:Herpesviridae / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053259:Lymphotoxin beta Receptor; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D023201:CD40 Ligand