Regulation of Type I IFNs in Tolerance and Autoimmunity

I 型干扰素在耐受性和自身免疫中的调节

• 批准号: 8317533
• 负责人: STEFANIA GALLUCCI
• 金额: $ 32.28万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317533
• 关键词: Address; Adenoviruses; Adverse effects; Affect; Antibodies; Antigen-Presenting Cells; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biological Factors; Biological Products; Bone Marrow; Bone Marrow Transplantation; Candidate Disease Gene; Clinical; Cross-Priming; Dendritic Cells; Dendritic cell activation; Development; Disease; Feedback; Gene Transfer; Genes; Genetic Transcription; Goals; IL4 gene; Immune response; In Vitro; Injection of therapeutic agent; Interferon Suppression; Interferon Type I; Interferon-alpha; Interferons; Interleukin-4; Ligands; Light; Literature; Lupus; Measures; Mediating; Modeling; Molecular; Mus; Outcome; Pathogenesis; Phosphorylation; Play; Proteins; Protocols documentation; Regulation; Reporting; Role; SLEB1 gene; STAT1 gene; Signal Pathway; Subfamily lentivirinae; T-Lymphocyte; Testing; Therapeutic Effect; Transplantation; Treatment Efficacy; Virus Diseases; Work; adaptive immunity; autocrine; base; cytokine; immunoregulation; in vivo; lupus prone mice; novel; novel strategies; novel therapeutics; paracrine; prevent; progenitor; research study; response; therapeutic development

PROJECT SUMMARY/ABSTRACT: Interferon alpha (IFN-a) is a pivotal player in the regulation of the innate and the adaptive immune responses, primarily through the activation of dendritic cells (DCs). Abnormal activation of DCs may shift the presentation of self-Ags from tolerance to autoimmunity and, indeed, excessive responses to IFN-a have been proposed to be pathogenic in autoimmune diseases such as lupus. Our long-term goal is to discover biologic factors able to inhibit the response to IFN-a in DCs and determine their effects on the development of autoimmune diseases. Our recent studies indicate that IL-4 suppresses the response of DCs to IFN-a in vitro and in vivo. We propose to investigate the molecular mechanisms by which IL-4 inhibits the innate response to IFN-a and the consequences on the adaptive immune responses. Furthermore, we have found that bone marrow-derived DCs from lupus-prone mice have an intrinsic hyperactivation of the Type I IFN response that is inhibited by IL-4 and we intend to determine the potential of IL-4 as therapy in lupus. In Aim I, we will determine the molecular mechanisms underlying IL-4 suppressive effects on IFN responses. We hypothesize that IL-4 acts on molecules that affect both the first response to paracrine IFN-a/b and the positive feedback loop induced by autocrine IFNab. On the basis of our Preliminary Studies and available literature on IL-4, we hypothesize that a newly IL-4-induced protein inhibits either 1) the phosphorylation of STAT1-2 or 2) the transcription of IFN stimulated genes (ISG) such as IFN-a/b. We will address which signaling pathway, downstream of IL-4R, is mediating IL-4 suppression of IFN response, which mechanism is blocking the STAT1-2 phosphorylation and which mechanism is blocking IFN-b transcription during IL-4 suppression of IFN response. In Aim II, we will test the effects of IL-4 on the stimulation of two adaptive immune responses stimulated by IFN-a, cross-priming and isotype antibody switching in vivo. In Aim III, we will determine the effects of IL-4 targeted to DCs on the development of lupus autoimmunity. We will use two protocols: a) injection of DCs transduced with a lentivirus carrying IL-4, and b) transplantation of bone marrow progenitors transduced with the same lentivirus, and will compare them with systemic administration of IL-4, in terms of therapeutic efficacy and development of side effects. This project will shed light on the regulation of the innate and adaptive responses by cytokines and their potential as novel therapeutic strategy to cure systemic lupus erythematosous. In addition, we will test two novel protocols of gene transfer targeting DCs that may be useful to deliver candidate genes for immune-modulation and induction of tolerance in autoimmunity and transplantation.

项目总结/摘要： 干扰素α（IFN-α）是调节先天性和适应性免疫系统的关键参与者。 免疫反应，主要通过激活树突状细胞（DC）。异常活化 DCs可能将自身抗原的呈递从耐受性转变为自身免疫性，甚至过度表达。 对IFN-α的应答被认为是自身免疫性疾病如狼疮的致病因素。 我们的长期目标是发现能够抑制DCs对IFN-α反应的生物因子， 确定它们对自身免疫性疾病发展的影响。我们最近的研究表明 IL-4在体内外均能抑制DC对IFN-α的应答。我们建议调查 IL-4抑制对IFN-α的先天性应答的分子机制， 对适应性免疫反应的影响。另外，我们发现这块骨头 来自狼疮易感小鼠的骨髓来源的DC具有I型IFN的内在超活化 我们打算确定IL-4作为治疗的潜力， 狼疮在目标I中，我们将确定IL-4抑制作用的分子机制 干扰素反应。我们假设IL-4作用于影响第一反应和第二反应的分子。 旁分泌IFN-α/B和自分泌IFN α B诱导的正反馈环。根据我们的 根据对IL-4的初步研究和现有文献，我们假设一种新的IL-4诱导的 蛋白抑制1）STAT 1 -2的磷酸化或2）IFN刺激的转录 基因（ISG），如IFN-α/B。我们将讨论IL-4 R下游的信号通路， 介导IL-4抑制IFN应答，其机制是阻断STAT 1 -2， 其机制是在IL-4抑制IFN-β表达的过程中阻断IFN-β的转录。 IFN应答。在目的II中，我们将测试IL-4对两种适应性免疫刺激的影响。 通过IFN-α刺激的应答、交叉致敏和体内同种型抗体转换。在Aim III中，我们 将确定靶向DC的IL-4对狼疮自身免疫发展的影响。我们 将使用两种方案：a）注射用携带IL-4的慢病毒转导的DC，和B） 移植用相同慢病毒转导的骨髓祖细胞，并将比较 在治疗效果和副作用的发生方面， 方面的影响.这个项目将阐明先天和适应性反应的调节， 细胞因子及其作为治疗系统性红斑狼疮的新治疗策略的潜力。 此外，我们将测试两种新的靶向DC的基因转移方案， 递送用于免疫调节和诱导自身免疫耐受的候选基因， 移植