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Blood ; 119(2): 619-28, 2012 Jan 12.
Article in English | MEDLINE | ID: mdl-22077059

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.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Graft vs Host Disease/immunology , Graft vs Host Disease/prevention & control , Interleukins/antagonists & inhibitors , Lymphocytes/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Animals , Enzyme-Linked Immunosorbent Assay , Fetal Blood , Flow Cytometry , Graft vs Host Disease/mortality , Humans , Interleukins/immunology , Lymphocyte Count , Mice , Mice, Inbred NOD , Mice, SCID , Signal Transduction , Survival Rate , Weight Loss
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