In acute graft-versus-host disease (GVHD), naive donor CD4

Th17 is a newly identified T-cell lineage IntroductionAcute graft-versus-host disease (GVHD), the leading cause of morbidity and mortality of allogeneic hematopoietic cell transplantation (HCT), is a complex process involving dysregulation of inflammatory cytokine cascades and distorted donor cellular response against host alloantigens. 1 Activation of alloreactive donor T cells is initiated by host antigen-presenting cells (APCs), especially dendritic cells (DCs). [2][3][4][5] Much effort has been devoted to understand how the polarization of donor T cells to the Th1 or Th2 phenotype contributes to acute GVHD. In some experimental models, it has been shown that Th1 cells augment and Th2 cells ameliorate acute GVHD. 1,[6][7][8] However, it was also reported that the absence of Th1 cytokine interferon (IFN)-␥ augments acute GVHD, but loss of the Th2 cytokine interleukin (IL)-4 reduces acute GVHD. 9,10 Furthermore, donor T cells deficient in either Th1 or Th2 differentiation were shown to be able to mediate acute GVHD. 11 Therefore, the role of donor T-cell subsets in GVHD pathogenesis is still controversial. It is likely that T-cell subsets other than Th1 or Th2 play a role in mediating acute GVHD.Th17 is a newly identified T-cell lineage that secretes the proinflammatory cytokine IL-17. 12 Naive CD4 ϩ T cells differentiate into Th17 cells in the presence of IL-6 and transforming growth factor (TGF)-␤. [13][14][15] Th17 cells express IL-23 receptor, and IL-23, an IL-12 family member, is critical for their survival and proliferation. [16][17][18] Orphan nuclear receptor ROR␥t is the key transcription factor that orchestrates differentiation of the Th17 lineage. 19 Interestingly, it has been shown that naive CD8 ϩ T cells can also differentiate into IL-17-producing T cells in the same culture condition as CD4 ϩ T cells. 20 One of the important functions of IL-17 is to coordinate local tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines. 21 Thus, IL-17 has been implicated in a critical role in the host defense against a series of extracellular pathogens, such as Klebsiella pneumoniae and Candida albicans. 22,23 However, uncontrolled Th17 cells have been reported to be involved in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE). [24][25][26][27] In contrast, IL-17 has also been shown to have some regulatory effect in mediating tissue inflammation. It was reported that IL-17 inhibited CD4 ϩ T-cell activation, 28 suppressed the tissue expression of chemokines (eg, CCL5 and CCL27), 29,30 and down-regulated VCAM-1 expression on epithelial cells. 31 Moreover, neutralization of IL-17 was reported to aggravate dextran sulfate sodium-induced colitis in mice, 32 and absence of IL-17 augmented allergic asthma. 33 The role of Th17 cells in GVHD pathogenesis is still unknown. In the current study, we demonstrated that IL-17 Ϫ/Ϫ donor T cells showed an augmented Th1 differentiation and IFN-␥ production and induc...

MSCs treatment can protect against experimental liver fibrosis in CCl4-induced or DMN-induced rats and the mechanisms of the anti-fibrosis by MSCs will be studied further.

Purpose: Stimulation of toll-like receptor-9 (TLR9) by CpG oligodeoxynucleotides (CpG) has been shown to counteract the immunosuppressive microenvironment and to inhibit tumor growth in glioma models. Because TLR9 is located intracellularly, we hypothesized that methods that enhance its internalization may also potentiate its immunostimulatory response. The goal of this study was to evaluate carbon nanotubes (CNT) as a CpG delivery vehicle in brain tumor models.Experimental Design: Functionalized single-walled CNTs were conjugated with CpG (CNT-CpG) and evaluated in vitro and in mice bearing intracranial GL261 gliomas. Flow cytometry was used to assess CNTCpG uptake and antiglioma immune response. Tumor growth was measured by bioluminescent imaging, histology, and animal survival.Results: CNT-CpG was nontoxic and enhanced CpG uptake both in vitro and intracranial gliomas. CNTmediated CpG delivery also potentiated proinflammatory cytokine production by primary monocytes. Interestingly, a single intracranial injection of low-dose CNT-CpG (but not free CpG or blank CNT) eradicated intracranial GL261 gliomas in half of tumor-bearing mice. Moreover, surviving animals exhibited durable tumor-free remission (>3 months), and were protected from intracranial tumor rechallenge, demonstrating induction of long-term antitumor immunity.Conclusions: These findings suggest that CNTs can potentiate CpG immunopotency by enhancing its delivery into tumor-associated inflammatory cells.