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.

最近发现，T细胞的一个亚群，例如T调节(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，据报道也有保护肿瘤免受免疫排斥的作用。我们之前的研究表明，用于治疗自身免疫性疾病的免疫抑制剂地塞米松(DEX)和淋巴增殖性细胞因子白细胞介素2(IL-2)分别上调了小鼠Treg细胞的数量和功能。此外，当它们一起使用时，它们在促进免疫抑制Treg细胞活性方面有更大的效果。当在抗原(MOG)诱导实验性自身免疫性脑脊髓炎(EAE)之前联合应用IL-2和DEX时，可降低易感小鼠EAE的发生率和严重程度。因此，可的松衍生物上调Tregs可以抵消自身免疫反应的诱导。百日咳毒素(PTX)作为佐剂与适当的自身抗原在完全弗氏佐剂(CFA)中联合应用，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对TLR4的激活有关。在本财政年度，我们确定PTX也有能力诱导DC产生高水平的IL-6。这与共同产生的TGFbeta一起激活了TH17途径，并产生了大量的IL-17，这与多种自身免疫性疾病的发生有关。因此，我们计划通过将PTX用于治疗性抗癌疫苗来研究PTX在克服肿瘤耐受性方面的独特的多样性佐剂作用。最后，令我们惊讶的是，我们对各种细胞因子和警素对Treg的影响的研究表明，肿瘤坏死因子也是Treg数量和活性的有力上调。虽然肿瘤坏死因子是一种众所周知的促炎细胞因子，最初对T传出细胞有激活作用，但在后来的体外和体内小鼠免疫反应中，尤其是作为与IL-2的共刺激因子，肿瘤坏死因子诱导表达TNFR2受体的功能性Treg细胞的增殖。IL-1和IL-6均不具有这种双相效应。因此，肿瘤坏死因子似乎对免疫反应具有独特的延迟下调调节作用。这在TNFR2基因敲除小鼠中是不存在的，这可能是它们更严重的(致命的)脓毒症(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，以及肿瘤通过产生肿瘤坏死因子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。