Interactions Between The Human Immune System And Antigens In The Nervous System

人体免疫系统与神经系统抗原之间的相互作用

• 批准号: 7594643
• 负责人: Henry F McFarland
• 金额: $ 45.43万
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 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/7594643
• 关键词: Address; Alpha Interleukin 2 Receptor; Amino Acid Sequence; Antibodies; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Bacteria; Bioinformatics; Biological Assay; CD34 gene; Central Nervous System Infections; Chronic; Clinical; Clinical Trials; Collaborations; Complex; Complex Mixtures; Daclizumab; Databases; Disease; Effectiveness; Enhancing Lesion; Hematopoietic; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune response; Immune system; Immunosuppression; Interferon-beta; Jail; Knowledge; Lead; Ligands; Lyme Disease; Magnetic Resonance Imaging; Methodology; Molecular Mimicry; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Natural Killer Cells; Nervous system structure; Neuraxis; Outcome Measure; Pathogenesis; Pathway interactions; Patients; Peptide Library; Peptide Sequence Determination; Peptides; Personal Satisfaction; Phenotype; Process; Proteins; Purpose; Relapse; Relapsing-Remitting Multiple Sclerosis; Scanning; Specificity; Stem cells; T-Cell Receptor-Rearrangement Excision DNA Circles; T-Lymphocyte; Testing; Therapeutic immunosuppression; Transplantation; United States National Institutes of Health; Virus; autoreactive T cell; base; chemokine receptor; cohort; combinatorial; concept; cytokine; nervous system disorder; novel; protein aminoacid sequence; receptor expression; research study; tool

This project examines the immunological mechanisms which involved in the pathogenesis of autoimmune- and infectious diseases of the central nervous system such as multiple sclerosis (MS) and chronic Lyme disease. We characterize the fine specificity, function and phenotype of T lymphocytes in the above diseases. These experiments allow a better understanding of the foreign antigens that may trigger autoimmune responses in MS and also of their function with respect to cytokine secretion and chemokine receptor expression. Based on this knowledge the project attempts to develop both specific immunomodulatory treatments such as altered peptide ligands (APL) or therapies that influence immune recognition in MS in a broader way. Examples of the latter are the humanized antibody against the interleukin-2 receptor alpha chain (daclizumab). Treatment of relapsing-remitting MS patients failing interferon-beta with daclizumab has been well tolerated. The initial clinical trial that involved the treatment of patients already on interferon beta resulted in a marked decrease in contrast enhancing lesion (78%) as well as an improvement in clinical findings although the study was very small; 10 patients with relapsing remitting disease. In addition to the evidence of efficacy, the CIS has carefully studied the mechanisms of action of this treatment. The results have lead to the surprising finding that daclizumab acts primarily via expansion of immunoregulatory NK cells. The findings provide evidence for a unique immunorulatory pathway. These studies will help us to understand better the complex mechanism of action of these compounds and eventually also the disease pathogenesis itself. All the clinical projects are being pursued in close collaboration with the Neurological Disease Section Section/Office of the Chief. A second example of using immunological tools to examine the mechanisms of action of a potential therapy in MS include studies of hematopoietic stem cell transplantation (HSCT). HSCT represent an aggressive form of therapy involving severe immunosuppression followed by rescue with hematopoietic, CD34+, stem cells. The therapy has been studied in several small studies of MS patients as well as studies of patients with other autoimmune disorders. However debate exists not only over the effectiveness but also the mechanism. With respect to the latter the question is if this simply represents a form of aggressive immunosuppression or if it leads to a reprogramming of the immune repertoire. In a cohort of patients followed for two years post transplantation an expansion of naove T cells was demonstrated by TREC analysis. Analysis of the repertoire indicated that the diversity was increased suggesting a reprogramming of the repertoire. These studies are now being extended into a larger cohort with well defined clinical outcome measures. Another important project, which is currently being pursued at NIB, NINDS, NIH, addresses the question which foreign antigens, e.g. viruses or bacteria, may trigger the initiation or exacerbations of disease via a mechanism referred to as molecular mimicry. This concept refers to cross-recognition between autoantigens, e.g. derived from the myelin sheath, and antigens derived from foreign agents. For this purpose, we currently employ a novel methodology called combinatorial peptide libraries in the positional scanning format (ps-SCL) together with bioinformatic approaches to identify the entire spectrum of stimulatory ligands for autoreactive T cell clones derived from MS patients. In brief, we test T cell clones with ps-SCL, which represent highly complex mixtures of trillions of peptides, and deduce stimulatory peptide sequences from these assays before we screen the databases of all known protein sequences for potential stimulatory peptides.

该项目研究了中枢神经系统的自身免疫性和传染病的发病机理，例如多发性硬化症（MS）和慢性莱姆病。我们表征了上述疾病中T淋巴细胞的精细特异性，功能和表型。这些实验可以更好地了解外国抗原，这些抗原可能会触发MS中的自身免疫反应以及它们在细胞因子分泌和趋化因子受体表达方面的功能。基于这些知识，该项目试图开发特定的免疫调节治疗方法，例如改变的肽配体（APL）或以更广泛的方式影响MS中免疫识别的疗法。后者的例子是针对白介素-2受体α链（Daclizumab）的人源化抗体。耐受性抗蛋白酶的干扰素β失败的复发的MS患者的治疗耐受性良好。最初的临床试验涉及对干扰素β的患者进行治疗，导致对比度增强病变的显着降低（78％），以及临床发现的改善，尽管该研究很小。 10例复发疾病的患者。除了疗效的证据外，CIS还仔细研究了该处理的作用机理。结果导致了令人惊讶的发现，即达氏珠单抗主要通过免疫调节NK细胞的扩展起作用。这些发现为独特的免疫通路提供了证据。这些研究将帮助我们更好地理解这些化合物的复杂作用机理，并最终也可以理解疾病发病机理。所有临床项目都与神经疾病部分/酋长办公室密切合作。使用免疫学工具检查潜在疗法在MS中的作用机理的第二个例子包括造血干细胞移植（HSCT）的研究。 HSCT代表了一种侵略性的治疗形式，涉及严重的免疫抑制，然后用造血，CD34+干细胞营救。该疗法已在几项MS患者的小型研究以及其他自身免疫性疾病的患者的研究中进行了研究。但是，辩论不仅在有效性上，而且还存在于机制上。关于后者的问题是，这是否仅代表了一种侵略性免疫抑制的形式，还是导致免疫库的重编程。 在移植后两年的患者队列中，通过TREC分析证明了NaOVE T细胞的扩张。对曲目的分析表明，多样性的增加表明曲目重新编程。现在，这些研究已扩展到具有明确定义的临床结局指标的较大队列。目前正在NIB，NINDS，NIH进行的另一个重要项目解决了外国抗原，例如病毒或细菌可能会通过称为分子模仿的机制触发疾病的起始或加剧。这个概念是指自动抗原之间的交叉认可，例如源自髓鞘和源自外国特工的抗原。为此，我们目前采用一种新型的方法论，以位置扫描格式（PS-SCL）以及生物信息学方法来识别自动反应性T细胞克隆的整个刺激性配体，以识别从MS患者获得的自动反应性T细胞克隆。简而言之，我们用PS-SCL测试T细胞克隆，该克隆代表了数万亿肽的高度复杂混合物，并从这些测定中推断出刺激性肽序列，然后我们在筛选所有已知蛋白质序列的数据库中，以实现潜在的刺激性肽。

项目成果

An altered peptide ligand antagonizes antigen-specific T cells of patients with human T lymphotropic virus type I-associated neurological disease.

一种改变的肽配体拮抗人类 T 淋巴细胞病毒 I 型相关神经系统疾病患者的抗原特异性 T 细胞。

• DOI: 10.4049/jimmunol.164.10.5192
• 发表时间: 2000
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kubota,R;Soldan,SS;Martin,R;Jacobson,S
• 通讯作者: Jacobson,S

Immunotherapy of multiple sclerosis: where are we? Where should we go?

多发性硬化症的免疫治疗：我们在哪里？

• DOI: 10.1038/ni0901-785
• 发表时间: 2001
• 期刊: Nature immunology
• 影响因子: 30.5
• 作者: Martin,R;Sturzebecher,CS;McFarland,HF
• 通讯作者: McFarland,HF

T-cell epitope prediction with combinatorial peptide libraries.

使用组合肽库进行 T 细胞表位预测。

• DOI: 10.1089/106652702760138619
• 发表时间: 2002
• 期刊: Journal of computational biology : a journal of computational molecular cell biology
• 作者: Sung,Myong-Hee;Zhao,Yingdong;Martin,Roland;Simon,Richard
• 通讯作者: Simon,Richard

Multiple Sclerosis: Immunotherapy.

多发性硬化症：免疫疗法。

• DOI: 10.1007/s11940-999-0004-x
• 发表时间: 1999
• 期刊: Current treatment options in neurology
• 影响因子: 2
• 作者: Bielekova,B;Martin,R
• 通讯作者: Martin,R

Kinematic specificity of cortical reorganization associated with motor training.

与运动训练相关的皮质重组的运动学特异性。

• DOI: 10.1016/j.neuroimage.2003.11.006
• 发表时间: 2004
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Morgen,Katrin;Kadom,Nadja;Sawaki,Lumy;Tessitore,Alessandro;Ohayon,Joan;Frank,Joseph;McFarland,Henry;Martin,Roland;Cohen,LeonardoG
• 通讯作者: Cohen,LeonardoG