title: Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes.
abstract: In rodent graft-versus-host disease (GVHD) models, anti-IL-21 neutralizing mAb treatment ameliorates lethality and is associated with decreases in Th1 cytokine production and gastrointestinal tract injury. GVHD prevention was dependent on the in vivo generation of donor-inducible regulatory T cells (Tregs). To determine whether the IL-21 pathway might be targeted for GVHD prevention, skin and colon samples obtained from patients with no GVHD or grade 2 to 4 GVHD were analyzed for IL-21 protein expression. By immunohistochemistry staining, IL-21 protein-producing cells were present in all gastrointestinal tract samples and 54% of skin samples obtained from GVHD patients but not GVHD-free controls. In a human xenogeneic GVHD model, human IL-21-secreting cells were present in the colon of GVHD recipients and were associated with elevated serum IL-21 levels. A neutralizing anti-human IL-21 mAb given prophylactically significantly reduced GVHD-associated weight loss and mortality, resulting in a concomitant increase in Tregs and a decrease in T cells secreting IFN-γ or granzyme B. Based on these findings, anti-IL-21 mAb could be considered for GVHD prevention in the clinic.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology and Blood and Marrow Transplantation, University of Minnesota, Minneapolis, 55455, USA. hippe002@umn.edu
authors.forename: Keli L
authors.initials: KL
authors.lastname: Hippen
authors.forename: Christoph
authors.initials: C
authors.lastname: Bucher
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Schirm
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Bearl
authors.forename: Ty
authors.initials: T
authors.lastname: Brender
authors.forename: Kathy A
authors.initials: KA
authors.lastname: Mink
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Waggie
authors.forename: Regis
authors.initials: R
authors.lastname: Peffault de Latour
authors.forename: Anne
authors.initials: A
authors.lastname: Janin
authors.forename: Julie M
authors.initials: JM
authors.lastname: Curtsinger
authors.forename: Stacey R
authors.initials: SR
authors.lastname: Dillon
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Miller
authors.forename: Gerard
authors.initials: G
authors.lastname: Socie
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
mesh_terms: D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004797:Enzyme-Linked Immunosorbent Assay; D005312:Fetal Blood; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D006801:Humans; D007378:Interleukins / Q000037:antagonists & inhibitors* / Q000276:immunology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D015431:Weight Loss; D000098546:Interleukin-21
chemical_list: D000911:Antibodies, Monoclonal; D007378:Interleukins; D000098546:Interleukin-21
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