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...

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Type 1 diabetes in both humans and nonobese diabetic (NOD) mice results from autoreactive T cell destruction of insulin-producing ␤ cells. Cure of type 1 diabetes may require both reversal of autoimmunity and regeneration of ␤ cells. Induction of chimerism via allogeneic hematopoietic cell transplantation has been shown to reestablish tolerance in both prediabetic and diabetic NOD mice. However, it is unclear whether this therapy augments ␤ cell regeneration. Furthermore, this procedure usually requires total body irradiation conditioning of recipients. The toxicity of total body irradiation conditioning and potential for graft-versus-host disease (GVHD) limit the application of allogeneic hematopoietic cell transplantation for treating type 1 diabetes. Here we report that injection of donor bone marrow and CD4 ؉ T cell-depleted spleen cells induced chimerism without causing GVHD in overtly diabetic NOD mice conditioned with anti-CD3/CD8 and that induction of chimerism in new-onset diabetic NOD mice led to elimination of insulitis, regeneration of host ␤ cells, and reversal of hyperglycemia. Therefore, this radiation-free GVHD preventive approach for induction of chimerism may represent a viable means for reversing type 1 diabetes.hematopoietic cell transplantation ͉ type 1 diabetes ͉ anti-CD3-conditioning ͉ reversal of diabetes ͉ reversal of autoimmunity

In allogeneic hematopoietic cell transplantation (HCT), donor T cellmediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8 ؉ T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow ( anti-CD3 mAb ͉ graft versus host disease ͉ hematopoietic cell transplantation ͉ systemic lupus erythematosus ͉ suberoylanilide hydroxamic acid