IntroductionAllogeneic stem cell transplantation (allo-SCT) is effective in the treatment of hematologic malignant diseases, bone marrow failure, or inherited immunodeficiency syndromes. [1][2][3][4] However, the incidence of graft-versus-host disease (GVHD) significantly limits the applicability of allo-SCT. [5][6][7] Two different forms of GVHD have been described. 8 Acute GVHD is a proinflammatory process mediated in part by mature donor T cells present in the stem cell or marrow inoculum that are polarized toward a TH1 phenotype and recognize minor or major histocompatibility disparities between the donor and host. [8][9][10][11] Chronic GVHD may be due to impaired thymic education of recent T-cell bone marrow emigrants and mediates a fibrotic process. 12,13 Activation of donor T cells by host antigen-presenting cells initiates a cascade of events that eventually leads to tissue destruction in GVHD target organs such as the gastrointestinal (GI) tract, liver, and skin. 8,13 Previous work has focused on the cytokine profiles of alloreactive T-effector cells in GVHD. Here, the TH1 cytokine, interferon-␥ (IFN-␥), has been shown to be important in the pathogenesis of GVHD. [14][15][16] However, neutralization of IFN-␥ surprisingly led to exacerbated disease, implying both protective and pathogenic roles for this TH1 cytokine. 17,18 A recent report demonstrated that donor-derived IFN-␥, although amplifying GI tract tissue damage, was necessary for the prevention of idiopathic pneumonia syndrome (IPS). 19 For the past 3 decades, CD4 ϩ TH differentiation has been believed to be limited to 2 distinct pathways. 20,21 TH1 cells were required for clearance of intracellular pathogens and distinguished by the production of IFN-␥, tumor necrosis factor-␣ (TNF-␣), and IL-2. TH2 cells promoted humoral immune responses, important in the response to clear extracellular pathogens, and secreted IL-4, IL-5, and IL-13. Recent work has shown that the TH17 pathway of differentiation is separate from TH1 or TH2 CD4 ϩ T-cell development. [22][23][24][25] TH17 differentiation requires TGF-␤1 24,22,25 and is enhanced by IL-1␤ and TNF-␣. 25 In addition, the transcription factors retinoid-related orphan receptor (ROR)␥t 26,27 and ROR␣ 27 have been shown to be critical for TH17 development. TH1 and TH2 type cytokines inhibit TH17 differentiation, notably IL-2, 28 IFN-␥, 23 and are potent suppressors of TH17 development. In mice, TH17 cells are enriched in the lung and GI tract and are considered important in the maintenance of mucosal host defense. 29 TH17 cells have also been shown to mediate pathologic conditions in several autoimmune conditions once thought to be due to TH1 responses. Elevated levels of IL-17 have been observed in rheumatoid arthritis, 30 multiple sclerosis, 31 and inflammatory bowl disease. 32 Considering the pathogenic role IL-17 has in autoimmune/ chronic inflammatory diseases, we were interested in determining whether TH17 cells are important in the pathogenesis of acute GVHD. Here, we demonstrate that in vitro pol...

Recent data reveal an important role for B cells in the pathogenesis of chronic GVHD (cGVHD).

GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood.

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