Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes

Keli L. Hippen, Christoph Bucher, Dawn K. Schirm, Amanda M. Bearl, Ty Brender, Kathy A. Mink, Kimberly S. Waggie, Regis Peffault De Latour, Anne Janin, Julie M. Curtsinger, Stacey R. Dillon, Jeffrey S. Miller, Gerard Socie, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

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. Aneutralizing 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.

Original languageEnglish (US)
Pages (from-to)619-628
Number of pages10
JournalBlood
Volume119
Issue number2
DOIs
StatePublished - Jan 12 2012

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