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: 8719540
• 负责人: STEFANIA GALLUCCI
• 金额: $ 6.55万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719540
• 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.

项目概要/摘要： 干扰素α（IFN-a）是先天性和适应性调节的关键参与者 免疫反应，主要是通过激活树突状细胞（DC）。异常激活 DC 可能会将自身抗原的表现从耐受性转变为自身免疫性，并且事实上，过度的 对 IFN-α 的反应已被认为是狼疮等自身免疫性疾病的致病因素。 我们的长期目标是发现能够抑制 DC 和 IFN-a 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 在体外和体内抑制 DC 对 IFN-α 的反应。我们建议调查 IL-4 抑制对 IFN-a 的先天反应的分子机制以及 对适应性免疫反应的影响。此外，我们还发现骨 来自狼疮易感小鼠的骨髓来源的 DC 具有 I 型 IFN 的内在过度激活 IL-4 抑制反应，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 关于干扰素反应。我们假设 IL-4 作用于影响第一反应的分子 旁分泌 IFN-a/b 和自分泌 IFNab 诱导的正反馈回路。在我们的基础上 根据有关 IL-4 的初步研究和现有文献，我们假设新的 IL-4 诱导 蛋白质抑制 1) STAT1-2 的磷酸化或 2) IFN 刺激的转录 基因 (ISG)，例如 IFN-a/b。我们将讨论 IL-4R 下游的信号传导途径是 介导 IL-4 抑制 IFN 反应，其机制是阻断 STAT1-2 磷酸化以及在 IL-4 抑制过程中阻断 IFN-b 转录的机制 干扰素反应。在目标II中，我们将测试IL-4对刺激两种适应性免疫的影响 IFN-a、交叉引发和体内同种型抗体转换刺激的反应。在目标 III 中，我们 将确定针对 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，以及 b) 用相同的慢病毒转染的骨髓祖细胞进行移植，并将进行比较 IL-4的全身给药，在治疗效果和副作用方面的发展 影响。该项目将揭示先天性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，我们将测试两种针对 DC 的基因转移新方案，这可能有助于 提供用于免疫调节和诱导自身免疫耐受的候选基因 移植。

项目成果

TLR ligands up-regulate Trex1 expression in murine conventional dendritic cells through type I Interferon and NF-κB-dependent signaling pathways.

TLR 配体通过 I 型干扰素和 NF-κB 依赖性信号通路上调小鼠传统树突状细胞中 Trex1 的表达。

• DOI: 10.1189/jlb.2a0713-393rr
• 发表时间: 2014
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Xu,Jun;Zoltick,PhilipW;Gamero,AnaM;Gallucci,Stefania
• 通讯作者: Gallucci,Stefania

Myeloid dendritic cells from B6.NZM Sle1/Sle2/Sle3 lupus-prone mice express an IFN signature that precedes disease onset.

• DOI: 10.4049/jimmunol.1101686
• 发表时间: 2012-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Sriram U;Varghese L;Bennett HL;Jog NR;Shivers DK;Ning Y;Behrens EM;Caricchio R;Gallucci S
• 通讯作者: Gallucci S

IL-4 suppresses the responses to TLR7 and TLR9 stimulation and increases the permissiveness to retroviral infection of murine conventional dendritic cells.

• DOI: 10.1371/journal.pone.0087668
• 发表时间: 2014
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sriram U;Xu J;Chain RW;Varghese L;Chakhtoura M;Bennett HL;Zoltick PW;Gallucci S
• 通讯作者: Gallucci S

The cytokine network type I IFN-IL-27-IL-10 is augmented in murine and human lupus.

• DOI: 10.1002/jlb.3ab0518-180rr
• 发表时间: 2019-10
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Lee MH;Gallo PM;Hooper KM;Corradetti C;Ganea D;Caricchio R;Gallucci S
• 通讯作者: Gallucci S