title: Antibody-mediated depletion of lymphocyte-activation gene-3 (LAG-3(+) )-activated T lymphocytes prevents delayed-type hypersensitivity in non-human primates.
abstract: Lymphocyte-activation gene-3 (LAG-3, CD223) is a marker for recently activated effector T cells. Activated T lymphocytes are of major importance in many autoimmune diseases and organ transplant rejection. Therefore, specifically depleting LAG-3(+) T cells might lead to targeted immunosuppression that would spare resting T cells while eliminating pathogenic activated T cells. We have shown previously that anti-LAG-3 antibodies sharing depleting as well as modulating activities inhibit heart allograft rejection in rats. Here, we have developed and characterized a cytotoxic LAG-3 chimeric antibody (chimeric A9H12), and evaluated its potential as a selective therapeutic depleting agent in a non-human primate model of delayed-type hypersensitivity (DTH). Chimeric A9H12 showed a high affinity to its antigen and depleted both cytomegalovirus (CMV)-activated CD4(+) and CD8(+) human T lymphocytes in vitro. In vivo, a single intravenous injection at either 1 or 0·1 mg/kg was sufficient to deplete LAG-3(+) -activated T cells in lymph nodes and to prevent the T helper type 1 (Th1)-driven skin inflammation in a tuberculin-induced DTH model in baboons. T lymphocyte and macrophage infiltration into the skin was also reduced. The in vivo effect was long-lasting, as several weeks to months were required after injection to restore a positive reaction after antigen challenge. Our data confirm that LAG-3 is a promising therapeutic target for depleting antibodies that might lead to higher therapeutic indexes compared to traditional immunosuppressive agents in autoimmune diseases and transplantation.
authors.affiliation: Institut de Transplantation Urologie Nephrologie (ITUN), CHU de Nantes, Faculté de Médecine, France.
authors.forename: N
authors.initials: N
authors.lastname: Poirier
authors.forename: T
authors.initials: T
authors.lastname: Haudebourg
authors.forename: C
authors.initials: C
authors.lastname: Brignone
authors.forename: N
authors.initials: N
authors.lastname: Dilek
authors.forename: J
authors.initials: J
authors.lastname: Hervouet
authors.forename: D
authors.initials: D
authors.lastname: Minault
authors.forename: F
authors.initials: F
authors.lastname: Coulon
authors.forename: R V
authors.initials: RV
authors.lastname: de Silly
authors.forename: F
authors.initials: F
authors.lastname: Triebel
authors.forename: G
authors.initials: G
authors.lastname: Blancho
authors.forename: B
authors.initials: B
authors.lastname: Vanhove
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D015703:Antigens, CD / Q000276:immunology*; D001500:BCG Vaccine / Q000276:immunology; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007428:Intradermal Tests; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010215:Papio; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000276:immunology* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014373:Tuberculin / Q000633:toxicity; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D001500:BCG Vaccine; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D014373:Tuberculin; D000093322:Lymphocyte Activation Gene 3 Protein