title: In vivo depletion of lymphotoxin-alpha expressing lymphocytes inhibits xenogeneic graft-versus-host-disease.
abstract: Graft-versus-host disease (GVHD) is a major barrier to successful allogeneic hematopoietic cell transplantation and is largely mediated by activated donor lymphocytes. Lymphotoxin (LT)-α is expressed by subsets of activated T and B cells, and studies in preclinical models demonstrated that targeted depletion of these cells with a mouse anti-LT-α monoclonal antibody (mAb) was efficacious in inhibiting inflammation and autoimmune disease. Here we demonstrate that LT-α is also upregulated on activated human donor lymphocytes in a xenogeneic model of GVHD and targeted depletion of these donor cells ameliorated GVHD. A depleting humanized anti-LT-α mAb, designated MLTA3698A, was generated that specifically binds to LT-α in both the soluble and membrane-bound forms, and elicits antibody-dependent cellular cytotoxicity (ADCC) activity in vitro. Using a human peripheral blood mononuclear cell transplanted SCID (Hu-SCID) mouse model of GVHD, the anti-human LT-α mAb specifically depleted activated LT-expressing human donor T and B cells, resulting in prolonged survival of the mice. A mutation in the Fc region, rendering the mAb incapable of mediating ADCC, abolished all in vitro and in vivo effects. These data support a role for using a depleting anti-LT-α antibody in treating immune diseases such as GVHD and autoimmune diseases.
authors.affiliation: Department of Immunology, Genentech Inc, South San Francisco, California, United States of America.
authors.forename: Eugene Y
authors.initials: EY
authors.lastname: Chiang
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.forename: Krista M
authors.initials: KM
authors.lastname: McCutcheon
authors.forename: Judy
authors.initials: J
authors.lastname: Young
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Lin
authors.forename: Mercedesz
authors.initials: M
authors.lastname: Balazs
authors.forename: Jane L
authors.initials: JL
authors.lastname: Grogan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control*; D006801:Humans; D008214:Lymphocytes / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000172:deficiency* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D020349:Surface Plasmon Resonance; D014184:Transplantation, Homologous / Q000009:adverse effects* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D008233:Lymphotoxin-alpha