耐受型DC/TGF-β联合诱导的iTreg细胞能有效抑制自身免疫性关节炎

目的 初步探讨通过成熟耐受型DC(mtDC)与转化生长因子-β(TGF-β)联合诱导的诱导型调节性T细胞(iTreg细胞)对自身免疫性关节炎的抑制作用.方法 在体外,对CD4+CD25-T细胞进行TGF-β诱导和mtDC细胞扩增,获得iTregmtDC细胞.通过流式细胞术、细胞计数、CBA等方法检测iTregmtDC细胞的表型、对CD4+T效应细胞增殖的抑制作用.在体内实验中,iTregmtDC细胞以1×106个细胞/ml的剂量过继性输注入胶原诱导性关节炎(CIA)小鼠体内,并通过关节病变评分、病理组织病变评分、血清中细胞因子、总anti-CⅡIgG的分泌情况来评价iTregmtDC细胞对CIA的抑制作用.结果 在体外,通过TGF-β 和mtDC细胞两轮诱导/扩增后,TregmtDC细胞得以大量扩增,并能持续表达高水平的Foxp3.在体外,与iTreg细胞相比,TregmtDC细胞有更强的抑制效应T细胞增殖的能力.在体内,与iTreg细胞相比,TregmtDC细胞的过继性输注能更有效地减少发病关节处的炎性浸润,进一步改善CIA的症状;对CIA小鼠体内细胞因子的分泌有更强的调节能力,能更显著地减少炎性因子肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)、白介素-17(IL-17)的分泌,并促进大量TGF-β产生;更明显地降低总anti-CⅡIgG的分泌量;进而更有效地抑制CIA病程的发展.结论 与iTreg相比,iTregmtDC细胞能通过调节体内细胞因子和抗CⅡIgG的分泌更有效地抑制CIA病程发展.     

A role for impaired regulatory T cell function in adverse responses to aluminum adjuvant-containing vaccines in genetically susceptible individuals

Regulatory T cells play a critical role in the immune response to vaccination, but there is only a limited understanding of the response of regulatory T cells to aluminum adjuvants and the vaccines that contain them. Available studies in animal models show that although induced T regulatory cells may be induced concomitantly with effector T cells following aluminum-adjuvanted vaccination, they are unable to protect against sensitization, suggesting that under the Th2 immune-stimulating effects of aluminum adjuvants, Treg cells may be functionally compromised. Allergic diseases are characterized by immune dysregulation, with increases in IL-4 and IL-6, both of which exert negative effects on Treg function. For individuals with a genetic predisposition, the beneficial influence of adjuvants on immune responsiveness may be accompanied by immune dysregulation, leading to allergic diseases. This review examines aspects of the regulatory T cell response to aluminum-adjuvanted immunization and possible genetic susceptibility factors related to that response.     

Induced and thymus‐derived Foxp3+ regulatory T cells share a common niche

Foxp3⁺ regulatory T (Treg) cells, which play a central role for the maintenance of immune homeostasis and self‐tolerance, are known to be both generated in the thymus (thymus‐derived, tTreg cells) and in the periphery, where they are converted from conventional CD4⁺ T cells (induced Treg (iTreg) cells). Recent data suggest a division of labor between these two Treg‐cell subsets since their combined action was shown to be essential for protection in inflammatory disease models. Here, using the transfer colitis model, we examined whether tTreg cells and iTreg cells fill different niches within the CD4⁺ T‐cell compartment. When naive T cells were co‐transferred with either pure tTreg cells or with a mixture of tTreg cells and iTreg cells, induction of Foxp3⁺ Treg cells from naive T cells was not hampered by preoccupation of the Treg‐cell niche. Using neuropilin‐1 (Nrp1) as a surface marker to separate tTreg cells and iTreg cells, we demonstrate that tTreg cells and iTreg cells alone can completely fill the Treg‐cell niche and display comparable TCR repertoires. However, when transferred together Nrp1⁺ tTreg cells outcompeted Nrp1^? iTreg cells and dominated the Treg‐cell compartment. Taken together, our data suggest that tTreg cells and iTreg cells share a common peripheral niche.     

An immunotherapeutic treatment against flea allergy dermatitis in cats by co-immunization of DNA and protein vaccines

Flea allergy dermatitis (FAD) is considered a harmful and persistent allergic disease in cats, dogs and humans. Effective and safe antigen-specific treatments are lacking. Previously we reported that the simultaneous co-immunization with a DNA vaccine and its cognate coded protein antigen could induce antigen-specific iTreg cells (inducible Treg cells); demonstrating its potential to protect animals from FAD in a murine model. Its clinical efficacy however, remains to be demonstrated. In this report, we clinically tested this protocol to treat established FAD in cats following flea infestations. We present data showing a profound therapeutic improvement of dermatitis in these FAD cats following two co-immunizations, not only in relieving clinical symptoms, but also the amelioration of the allergic responses, including antigen-induced wheal formation, elevated T cell proliferation, infiltration of lymphocytes and migration of mast cells to the sites. This study demonstrates that a co-immunization approach as described can be used to treat flea-induced allergic disease in animals, thus implicating its potential for a practical clinical application.