Role of T regulatory suppression in autoimmunity and can

T 调节抑制在自身免疫中的作用

• 批准号: 7338776
• 负责人: JOOST J OPPENHEIM
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338776
• 关键词: Role; regulatory; suppression; autoimmunity

It has recently become clear that a subset of T cells e.g. T regulatory (Treg) cells have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also reported to protect tumors from immune rejection. During this fiscal year, we showed that the immunosuppressive agent dexamethasone (DEX), which is used to treat autoimmune disease, and the lymphoproliferative cytokine Interleukin-2, each upregulated the number and function of Treg cells in mice. Furthermore, when administered together they had even greater effects in promoting immunosuppressive Treg cell activities. When administered together prior to an antigen (MOG) that induces experimental autoimmune encephalomyelitis (EAE), IL-2 plus DEX reduced the incidence and severity of EAE in susceptible mice. Thus, upregulation of Tregs can counteract induction of autoimmune reactions.Pertussis toxin (PTX) is coadministered as an adjuvant along with an appropriate autoantigen in Complete Freunds adjuvant (CFA) in order to induce EAE in susceptible mouse strains. This co-adjuvant effect of PTX has been ascribed to induction of increased permeability of the blood brain barrier. However, we observed that mice in the course of developing EAE experienced a decrease in the number of functional Treg cells. Independent evaluation of the different agents given to mice revealed that the PTX by itself rather than the CFA or antigen was responsible for the decrease in suppressive Treg cells. Obviously PTX has multiple biological effects of suppressing Treg cells in vivo and interfering with GiPCR signal transduction. In a separate study we observed that PTX also activated dendritic cell maturation in vitro and this required TLR4 expression and signal transduction. Thus, the adjuvant effects of PTX in addition to inhibiting Treg cells also involve activation of immunoenhancing TLR4 responses. Based on these observations the effects of PTX on inducing tumor immunity will be investigated. We plan to further pursue the identification of agents that influence Treg cell functions, since they can be used to modulate autoimmunity and tumor cell growth.

最近已经清楚的是，T细胞的子集例如T调节（Treg）细胞对免疫应答具有反馈抑制作用。据报道，这些Treg细胞抑制自身免疫反应，因此不幸的是，也报道了保护肿瘤免受免疫排斥。在本财政年度，我们发现用于治疗自身免疫性疾病的免疫抑制剂地塞米松（DEX）和淋巴增殖细胞因子白细胞介素-2各自上调了小鼠Treg细胞的数量和功能。此外，当一起施用时，它们在促进免疫抑制性Treg细胞活性方面具有更大的作用。当在诱导实验性自身免疫性脑脊髓炎（EAE）的抗原（MOG）之前一起施用时，IL-2加DEX降低易感小鼠中EAE的发生率和严重程度。百日咳毒素（PTX）作为佐剂与完全弗氏佐剂（CFA）中的适当自身抗原一起沿着给药，以在易感小鼠品系中诱导EAE。PTX的这种辅助作用归因于诱导血脑屏障通透性增加。然而，我们观察到，在发展EAE的过程中，小鼠经历了功能性Treg细胞数量的减少。对给予小鼠的不同药物的独立评估表明，导致抑制性Treg细胞减少的是紫杉醇本身，而不是CFA或抗原。显然PTX具有体内抑制Treg细胞和干扰GiPCR信号转导的多重生物学效应。在一项单独的研究中，我们观察到PTX也在体外激活树突状细胞成熟，这需要TLR 4表达和信号转导。因此，除了抑制Treg细胞外，PTX的佐剂作用还涉及免疫增强TLR 4反应的激活。基于这些观察，将研究PTX对诱导肿瘤免疫的作用。我们计划进一步研究影响Treg细胞功能的药物，因为它们可用于调节自身免疫和肿瘤细胞生长。