Genetic, Viral and Immunlogic Studies in New Zealand Mice

新西兰小鼠的遗传、病毒和免疫学研究

• 批准号: 7653136
• 负责人: SYAMAL K DATTA
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653136
• 关键词: Adrenal Cortex Hormones; Affect; American; Antigen-Presenting Cells; Antigens; Apoptosis; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Biological Assay; Blood Vessels; C-KIT Gene; CD4 Positive T Lymphocytes; Cell Lineage; Cell surface; Cells; Cessation of life; Characteristics; Clinic; Cytotoxic agent; Dendritic Cells; Disease; Disease remission; Dose; Epitopes; Future; Generations; Growth Factor; Helper-Inducer T-Lymphocyte; Histones; Human; Immune system; Immunosuppressive Agents; In Vitro; Infiltration; Inflammatory; Insulin-Dependent Diabetes Mellitus; Integrins; Interleukin-6; Kidney; Ligands; Lupus; Medical; Molecular; Morbidity - disease rate; Multiple Sclerosis; Mus; New Zealand; Nuclear; Nuclear Antigens; Nucleosomes; Organ; Pain; Pathogenesis; Pathway interactions; Patients; Peptides; Phenotype; Population; Production; Proto-Oncogene Protein c-kit; Public Health; Receptor Signaling; Regulation; Rheumatoid Arthritis; Risk; Role; Screening procedure; Signal Pathway; Signal Transduction; Splenocyte; Stem cells; System; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Thrombospondin 1; Thymus Gland; To autoantigen; Toll-like receptors; Treatment Protocols; Vaccines; Work; chemokine; cost; cytokine; effective therapy; immunoregulation; improved; inhibitor/antagonist; macrophage; mast cell; mortality; novel; particle; precursor cell; prevent; programs; protein complex; public health relevance; response; virus genetics

DESCRIPTION (provided by applicant): Our overall objective is to understand why the immune system in SLE (lupus) responds abnormally to nuclear autoantigens from cells undergoing physiologically programmed apoptosis, and how this response could be specifically downregulated for effective therapy? We have found that autoimmune T and B cells of lupus recognize certain critical histone peptide epitope/s from nucleosomes, which in a low-dose tolerance regimen blocks pathogenesis and progression of lupus by inducing potent regulatory T-cell (Treg) subsets. The induced Treg cells suppress autoimmune T helper (Th) cells, B cells and autoantigen presenting cells (APC), as well as inflammatory cell infiltration in kidneys and blood vessels in lupus. This therapy in SNF1 mice with spontaneous SLE, generates tolerogenic plasmacytoid dendritic cells (pDC) that cause expansion of autoantigen-specific Treg cells and contraction of autoimmune and inflammatory Th1 and Th17 cells. We propose to define molecular changes at the cell-surface and inside the cell that cause an increased TGF21 and decreased IL-6 expression program in the tolerogenic pDC. We will also devise a culture system for inducing low-dose peptide tolerance in vitro using lupus mouse cells to be used for defining toll-like receptor (TLR) and other signals in tolerance mechanisms, and for future application to screen tolerogenic peptides in lupus patients. Secondly, although nuclear antigens derived from apoptotic cells participate in cognate interactions between autoimmune Th cells and B cells in lupus leading to production of pathogenic anti-DNA autoantibodies, the initial steps are not known. In order to give help to autoimmune B cells, autoimmune CD4+ Th cells are required to be initially activated (primed) by APCs which present autoantigen particles, such as nucleosomes and ribonuclear protein complex from apoptotic cells. We have found that CD117+ cells in splenocytes of lupus-prone SNF1 mice present apoptotic nuclear autoantigen particles much more efficiently than conventional APCs (B cells, DC and Macrophages) to activate autoimmune Th1 and Th17 cells simultaneously. CD117 (c-Kit), a receptor for stem cell factor, is a marker expressed by macrophage/DC progenitor (MDP) cells, common DC precursor (CDP) cells, and mast cells. Therefore, we need to identify which lineage of cells the novel CD117+ APCs belong. We will also study the role of the novel APC in breaking B and T cell tolerance in lupus and other autoimmune diseases, identify other unique markers they may have, and study the molecular requirements for their unusual ability to present nuclear autoantigens to activate both Th1 and Th17 cells in lupus. Thus, our hypotheses and ensuing aims are focused on antigen presenting cells (APCs), to determine how novel APCs initiate breakdown of tolerance to nuclear antigens from apoptotic cells to induce pathogenic Th1 and Th17 responses simultaneously in lupus and how this priming step can be blocked; and conversely how other APCs, such as pDC can restore immunoregulation after antigen specific tolerance therapy of lupus. PUBLIC HEALTH RELEVANCE: We have invented and developed a non-toxic, antigen-specific tolerance therapy targeted against autoimmune cells that would spare SLE or lupus patients from receiving mutagenic cytotoxic agents, corticosteroids and global immunosuppressants. The therapy is also aimed at maintaining lupus patients in remission, and preventing the initiation or progression of organ damaging disease in patients at risk. In this application we will define how the therapy works to restore normal regulation of the immune system in lupus, and how it can be improved further. A detailed understanding of the mechanisms would rapidly bring this therapy to patients in the clinic. The proposed studies will also provide a better definition disease pathogenesis initiated by a novel antigen-presenting cell inducing autoimmune response in not only lupus, but also other autoimmune inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, and insulin-dependent diabetes mellitus. Collectively, these diseases affect tens of millions of Americans, resulting in considerable morbidity (sickness), mortality (death), pain and suffering, and medical costs. The studies would help in devising specific means to block the initial steps of tolerance breakdown in major autoimmune diseases.

描述（由申请人提供）：我们的总体目标是了解为什么SLE（狼疮）中的免疫系统对来自经历生理程序性凋亡的细胞的核自身抗原产生异常反应，以及如何特异性下调这种反应以进行有效治疗？我们已经发现狼疮的自身免疫T和B细胞识别来自核小体的某些关键组蛋白肽表位，其在低剂量耐受方案中通过诱导有效的调节性T细胞（Treg）亚群来阻断狼疮的发病机制和进展。诱导的Treg细胞抑制自身免疫性T辅助（Th）细胞、B细胞和自身抗原呈递细胞（APC），以及狼疮中肾脏和血管中的炎性细胞浸润。在患有自发性SLE的SNF 1小鼠中的这种疗法产生致耐受性浆细胞样树突状细胞（pDC），其引起自身抗原特异性Treg细胞的扩增以及自身免疫性和炎性Th 1和Th 17细胞的收缩。我们建议确定在细胞表面和细胞内的分子变化，导致在耐受原性pDC中增加的TGF 21和减少的IL-6表达程序。我们还将设计一种培养系统，用于诱导低剂量的肽耐受性在体外使用狼疮小鼠细胞被用于定义toll样受体（TLR）和其他信号的耐受机制，并为未来的应用程序，以筛选耐受性肽在狼疮患者。第二，虽然来自凋亡细胞的核抗原参与狼疮中自身免疫Th细胞和B细胞之间的同源相互作用，导致致病性抗DNA自身抗体的产生，但初始步骤尚不清楚。为了帮助自身免疫性B细胞，自身免疫性CD 4 + Th细胞需要被呈递自身抗原颗粒的APC初始活化（致敏），所述自身抗原颗粒例如来自凋亡细胞的核小体和核糖核蛋白复合物。我们已经发现，在狼疮倾向的SNF 1小鼠脾细胞中的CD 117+细胞比传统的APC（B细胞、DC和巨噬细胞）更有效地呈递凋亡的核自身抗原颗粒，以同时激活自身免疫性Th 1和Th 17细胞。CD 117（c-Kit）是干细胞因子的受体，是由巨噬细胞/DC祖细胞（MDP）、普通DC前体（CDP）细胞和肥大细胞表达的标志物。因此，我们需要鉴定新的CD 117 + APC属于哪种细胞谱系。我们还将研究新的APC在破坏狼疮和其他自身免疫性疾病中的B和T细胞耐受性中的作用，鉴定它们可能具有的其他独特标记，并研究它们呈递核自身抗原以激活狼疮中的Th 1和Th 17细胞的不寻常能力的分子要求。因此，我们的假设和随后的目标是集中在抗原呈递细胞（APC），以确定新的APC如何启动从凋亡细胞的核抗原的耐受性的破坏，以诱导致病性的Th 1和Th 17的反应，同时在狼疮和这个启动步骤可以被阻止;相反，其他APC，如pDC如何可以恢复免疫调节后，抗原特异性耐受治疗狼疮。公共卫生关系：我们已经发明并开发了一种针对自身免疫细胞的无毒抗原特异性耐受疗法，该疗法将使SLE或狼疮患者免于接受致突变细胞毒性剂、皮质类固醇和全局免疫抑制剂。该疗法还旨在维持狼疮患者的缓解，并防止处于危险中的患者的器官损伤疾病的开始或进展。在本申请中，我们将定义该疗法如何恢复狼疮免疫系统的正常调节，以及如何进一步改善。对机制的详细了解将迅速将这种疗法带到临床患者中。拟议的研究还将提供一个更好的定义疾病的发病机制发起的一种新的抗原呈递细胞诱导自身免疫反应，不仅在狼疮，但也有其他自身免疫性炎症性疾病，如类风湿性关节炎，多发性硬化症，胰岛素依赖型糖尿病。总的来说，这些疾病影响了数千万美国人，导致相当大的发病率（疾病），死亡率（死亡），疼痛和痛苦，以及医疗费用。这些研究将有助于设计特定的方法来阻止主要自身免疫性疾病耐受性破坏的最初步骤。