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

• Published in: Blood Vol. 119; no. 2; pp. 619 - 628
• Main Authors: Hippen, Keli L., Bucher, Christoph, Schirm, Dawn K., Bearl, Amanda M., Brender, Ty, Mink, Kathy A., Waggie, Kimberly S., Peffault de Latour, Regis, Janin, Anne, Curtsinger, Julie M., Dillon, Stacey R., Miller, Jeffrey S., Socie, Gerard, Blazar, Bruce R.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12.01.2012; Americain Society of Hematology; American Society of Hematology
• Subjects: Adult; Animals; Antibodies, Monoclonal - therapeutic use; Biological and medical sciences; Enzyme-Linked Immunosorbent Assay; Fetal Blood; Flow Cytometry; Graft vs Host Disease - immunology; Graft vs Host Disease - mortality; Graft vs Host Disease - prevention & control; Hematologic and hematopoietic diseases; Humans; Immunobiology; Interleukins - antagonists & inhibitors; Interleukins - immunology; Lymphocyte Count; Lymphocytes - immunology; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Signal Transduction; Survival Rate; T-Lymphocytes, Regulatory - immunology; Transplantation; Weight Loss; Human; Immunopathology; Graft versus host disease; Signal transduction; Hematology; Stem cell; Interleukin 21; Hematopoietic cell; Xenogeneic system; Lymphocyte
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-07-368027

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.