Role of T regulatory suppression in autoimmunity and cancer

T 调节抑制在自身免疫和癌症中的作用

• 批准号: 7592869
• 负责人: JOOST J OPPENHEIM
• 金额: $ 39万
• 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/7592869
• 关键词: Accounting; Adjuvant; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; Back; Cells; Cortisone; Dexamethasone; Down-Regulation; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Feedback; Freund' s Adjuvant; Immune; Immune response; Immunosuppressive Agents; In Vitro; Incidence; Inflammatory; Interleukin-1; Interleukin-17; Interleukin-2; Interleukin-6; Knockout Mice; Malignant Neoplasms; Mouse Strains; Mus; Numbers; Pathway interactions; Pertussis Toxin; Production; Reaction; Reporting; Role; Severities; T-Lymphocyte Subsets; TLR4 gene; TNF gene; TNFRSF1B gene; Transforming Growth Factor beta; Tumor Immunity; Up-Regulation; Vaccines; anti-cancer therapeutic; cytokine; feeding; in vivo; receptor; response; septic; tumor

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 are reported to protect tumors from immune rejection. We previously 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 by cortisone-derivatives 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 was associated with a decrease in the number of functional Treg cells and concomitant activation of TLR4 by PTx. During the current fiscal year we established that PTx also has the capacity to induce DC to produce high levels of IL-6. This leads in conjunction with coproduced TGFbeta to the activation of the TH17 pathway with copious production of IL-17, which has been implicated in promoting a variety of autoimmune diseases. Thus, we plan to investigate the effect of the rather unique multiplicity of adjuvant effects of PTx on overcoming tolerance to tumor by using it in therapeutic anticancer vaccines. Finally, to our surprise our studies of the effects of various cytokines and alarmins on Tregs revealed that TNF also is a potent upregulator of Treg numbers and activity. Although TNF is a well known proinflammatory cytokine which has initial activating effects on T efferent cells, later in in vitro and in vivo mouse immune responses especially as a costimulant with IL-2, TNF induces the proliferative expansion of functional Treg cells that express the TNFR2 receptor. Neither IL-1 nor IL-6 had such biphasic effects. Thus, TNF appears to induce a unique delayed down regulatory effect on immune responses. This is absent in TNFR2 knockout mice and may account for their more severe (lethal) septic (LPS) induced inflammatory reactions. We are further investigating the role of TNFR2 on Tregs and the possibility that tumors by producing TNF may be promoting the increase in infiltrating Tregs detected in tumors with consequent down regulation of tumor immune responses.

最近已经清楚，T 细胞的一个子集，例如调节性 T (Treg) 细胞对免疫反应具有反馈抑制作用。据报道，这些 Treg 细胞可以抑制自身免疫反应，因此，不幸的是，据报道，这些 Treg 细胞也可以保护肿瘤免受免疫排斥。我们之前表明，用于治疗自身免疫性疾病的免疫抑制剂地塞米松 (DEX) 和淋巴细胞增殖细胞因子白介素-2 均可以上调小鼠 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效果。当在诱导实验性自身免疫性脑脊髓炎 (EAE) 的抗原 (MOG) 之前一起给药时，IL-2 加 DEX 可以降低易感小鼠中 EAE 的发生率和严重程度。因此，可的松衍生物对 Tregs 的上调可以抵消自身免疫反应的诱导。百日咳毒素 (PTX) 作为佐剂与完全弗氏佐剂 (CFA) 中的适当自身抗原共同施用，以诱导易感小鼠品系的 EAE。这与功能性 Treg 细胞数量的减少以及 PTx 伴随的 TLR4 激活有关。在本财年，我们确定 PTx 还具有诱导 DC 产生高水平 IL-6 的能力。这与共同产生的 TGFbeta 一起导致 TH17 途径的激活，并产生大量的 IL-17，这与促进多种自身免疫性疾病有关。因此，我们计划通过将 PTx 用于治疗性抗癌疫苗来研究 PTx 相当独特的多重佐剂作用对克服肿瘤耐受性的影响。最后，令我们惊讶的是，我们对各种细胞因子和警报素对 Treg 的影响的研究表明，TNF 也是 Treg 数量和活性的有效上调剂。尽管 TNF 是一种众所周知的促炎细胞因子，最初对传出 T 细胞具有激活作用，但随后在体外和体内小鼠免疫反应中，特别是作为 IL-2 的共刺激剂，TNF 诱导表达 TNFR2 受体的功能性 Treg 细胞的增殖扩张。 IL-1 和 IL-6 均不具有这种双相效应。因此，TNF 似乎对免疫反应产生独特的延迟下调调节作用。这在 TNFR2 敲除小鼠中不存在，并且可能是其更严重（致命）败血症（LPS）诱导的炎症反应的原因。我们正在进一步研究 TNFR2 对 Tregs 的作用，以及肿瘤通过产生 TNF 可能促进肿瘤中检测到的浸润性 Tregs 增加，从而下调肿瘤免疫反应的可能性。