title: Prevention of graft-versus-host disease by anti IL-7Ralpha antibody.
abstract: Graft-versus-host disease (GVHD) continues to be a serious complication that limits the success of allogeneic bone marrow transplantation (BMT). Using IL-7-deficient murine models, we have previously shown that IL-7 is necessary for the pathogenesis of GVHD. In the present study, we determined whether GVHD could be prevented by antibody-mediated blockade of IL-7 receptor alpha (IL-7Ralpha) signaling. C57/BL6 (H2K(b)) recipient mice were lethally irradiated and underwent cotransplantation with T-cell-depleted (TCD) BM and lymph node (LN) cells from allogeneic BALB/c (H2K(d)) donor mice. Following transplantation, the allogeneic BMT recipients were injected weekly with either anti-IL-7Ralpha antibody (100 mug per mouse per week) or PBS for 4 weeks. Anti-IL-7Ralpha antibody treatment significantly decreased GVHD-related morbidity and mortality compared with placebo (30% to 80%). IL-7Ralpha blockade resulted in the reduction of donor CD4(+) or CD8(+) T cells in the periphery by day 30 after transplantation. Paradoxically, the inhibition of GVHD by anti-IL-7Ralpha antibody treatment resulted in improved long-term thymic and immune function. Blockade of IL-7R by anti-IL-7Ralpha antibody resulted in elimination of alloreactive T cells, prevention of GVHD, and improvement of donor T-cell reconstitution.
authors.affiliation: Division of Stem Cell Transplantation, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Brile
authors.initials: B
authors.lastname: Chung
authors.forename: Eric P
authors.initials: EP
authors.lastname: Dudl
authors.forename: Dullei
authors.initials: D
authors.lastname: Min
authors.forename: Lora
authors.initials: L
authors.lastname: Barsky
authors.forename: Nancy
authors.initials: N
authors.lastname: Smiley
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000187:drug effects; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016130:Immunophenotyping; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors*; D013601:T-Lymphocytes / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain