Immunoregulation of Myelin Specific T Lymphocytes

髓磷脂特异性 T 淋巴细胞的免疫调节

• 批准号: 8971939
• 负责人: ARTHUR A. VANDENBARK
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8971939
• 关键词: Address; Affect; Animal Model; Autoimmune Process; Binding; C57BL/6 Mouse; Cell surface; Cells; Chronic; Clinical; Complex; Data; Development; Disease; Drug abuse; Eragrostis; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; HLA-DR Antigens; HLA-DR2 Antigen; Human; ITGAM gene; Immunosuppression; Immunotherapy; Infection; Inflammation; Inflammatory; Interferons; Laboratories; Life; Link; MHC Class II Genes; Migration Inhibitory Factor; Multiple Sclerosis; Mus; Myelin; Myelin Basic Proteins; Pathogenesis; Pattern; Peptides; Pharmaceutical Preparations; Phase; Post-Traumatic Stress Disorders; Process; Risk; Risk Factors; Safety; Signal Transduction; Specificity; Stroke; T-Cell Activation; T-Cell Immunologic Specificity; T-Lymphocyte; TNFRSF10A gene; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Transgenic Mice; Treatment Efficacy; Veterans; abstracting; cell motility; copolymer 1; cytokine; immunological synapse; immunoregulation; improved; invariant chain; macrophage migration inhibitory factor receptor; migration; monocyte; multiple sclerosis patient; multiple sclerosis treatment; novel; oligodendrocyte-myelin glycoprotein; phenylpyruvate tautomerase; pre-clinical; preclinical study; protein aminoacid sequence; public health relevance; receptor; research study; screening; synthetic peptide; treatment effect

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT New and improved drugs are needed for human multiple sclerosis (MS) given that available treatments have only modest effects on the disease course. Current drugs demonstrate better efficacy than the previous first- line treatments (interferon-¿ and glatiramer acetate), but have greatly increased toxicity and risk of serious life- threatening infections due to global immunosuppression. A preferred treatment approach would be a safe and well-tolerated biologic with a potent ability to inhibit key disease-associated mechanisms involved in the pathogenesis of MS. Our laboratory discovered and is developing partial MHC class II constructs (pMHC) as a possible immunotherapy for MS. pMHC containing the extracellular domains of the MS risk factor, HLA-DR2, linked covalently to the encephalitogenic myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide (pDR2/MOG-35-55) can reverse CNS inflammation and clinical signs of MOG-peptide-induced experimental autoimmune encephalomyelitis (EAE) in DR2 transgenic mice. The same construct (termed RTL1000) was recently used successfully in a Phase 1 safety trial in MS patients. We have strong pre-clinical evidence to support the idea that RTL1000 can specifically target both peptide-specific and bystander T-cells reactive to other encephalitogenic myelin peptides. This inhibitory activity of the pMHC complexes requires binding of the ¿1¿1 moiety to a specific receptor expressed predominantly on monocytes. We recently we discovered that pMHC can bind specifically to the invariant chain of MHC class II (CD74), down-regulating its expression on the monocyte cell surface and blocking the inflammatory effects of macrophage migration inhibitory factor (MIF) that is a key pathogenic cytokine for EAE and MS. We further demonstrated that the DR-¿1 domain is the major CD74 binding moiety of pDR2 constructs. Moreover, increased concentrations of DR-¿1 (in the absence of a bound antigenic peptide) could down-modulate CD74 levels on monocytes. These findings suggested that DR-¿1 alone might modulate MIF activity and treat EAE in an antigenic peptide-independent manner through its effects on CD74 expression. Indeed, our preliminary experiments demonstrated a significant treatment effect of DR-¿1on EAE. These data have important regulatory implications that enable the development of a new class of therapeutic DR-¿1-derived constructs for autoimmune and inflammatory conditions involving MIF signaling through CD74. We envision that modulation of CD74 by DR-¿1 through its CD74 binding region will provide significant therapeutic effects in a wide spectrum of inflammatory conditions even when the specificity of pathogenic T-cells has not been established, and that efficacy of treatment may be enhanced by attachment of specific antigenic peptides to the DR-¿1 moiety in conditions where pathogenic T- cell specificities are known or strongly suspected (eg. to myelin peptides in MS). Moreover, because the DR- ¿1 domain is present in all humans and thus would not be recognized as foreign, treatment using DR-¿1 constructs would not require HLA screening of potential recipients and could be used for treatment of MS subjects who do not express the HLA-DR2 risk factor. Our preliminary data suggest a significant increase in CD74 levels on monocytes in mice with EAE and subjects with MS, thus providing a compelling rationale for development off pMHC constructs that can inhibit MIF activity by down-regulating CD74 expression. In this application we will test the hypothesis that a specific segment of DR-¿1 binds to monocytes and decreases cell-surface expression of CD74 and MIF signaling that in turn blocks cell migration into the CNS and Teff-cell activation, resulting in reversal of clinical and histological signs of EAE. To address this hypothesis, we propose to 1) Identify the CD74-binding region within DR-¿1 and develop an optimal CD74-binding DR-¿1 construct; 2) Evaluate inhibitory effects of DR-¿1 constructs on monocyte and T-cell activation; and 3) Determine efficacy of DR-¿1 constructs for treatment of EAE induced by peptide-specific vs. non-specific (bystander) T-cell specificities.

描述（由申请人提供）： 鉴于可用治疗对疾病病程的影响仅适度，人类多发性硬化症（MS）需要项目摘要/抽象的新药物和改进的药物。目前的药物表现出比以前的一线治疗（干扰素 - 乙酸盐）更好的有效性，但由于全球免疫抑制而引起的严重生命感染的毒性和风险大大增加了。首选的治疗方法将是一种安全且耐受良好的生物学，具有抑制MS发病机理涉及的关键疾病相关机制的潜在能力。我们的实验室发现并正在开发部分MHC II类构建体（PMHC）作为MS的免疫疗法。 PMHC包含MS危险因素HLA-DR2的细胞外域，将共价链接到脑生成髓磷脂的少突胶质细胞糖蛋白（MOG）-35-55肽（PDR2/MOG-35-55）可以反向CNS Infiction和Clinical clinical Suilt sip simm MOG-MOG-PETTIDES MOG-MOG PETTIDES MOG-PETTIDES MOG-PETTIDES MOG-PEPTIDE DR2转基因小鼠中的脑脊髓炎（EAE）。最近在MS患者的1期安全试验中成功使用了相同的构建体（称为RTL1000）。我们有大量的临床前证据支持RTL1000可以针对肽特异性和旁观者T细胞反应对其他脑源性髓磷脂肽反应的想法。 PMHC复合物的这种抑制活性需要将€1的部分与主要在单核细胞上表达的特定接收器结合。我们最近发现，PMHC可以与MHC II类（CD74）的不变链特异性结合，从而下调其在单核细胞表面上的表达，并阻止巨噬细胞迁移抑制因子（MIF）的炎症作用，这是EAE和MS的键入病原体。我们进一步证明了DR-€1域是PDR2构建体的主要CD74结合部分。此外，Dr-¿1（在没有结合的抗原肽的情况下）的浓度增加可能会在单核细胞上调节CD74水平。这些发现表明，仅DR-€1可以通过其对CD74表达的影响以抗原肽独立的方式调节MIF活性并以抗原肽的方式处理EAE。实际上，我们的初步实验表明DR-€1 ON EAE具有显着的治疗作用。这些数据具有重要的调节含义，可以开发新的自身免疫性和炎症条件的新型治疗性DR-€1衍生构造，涉及通过CD74信号传导。我们设想，即使没有确定致病性T细胞的特异性，Dr-€1通过其CD74结合区域对CD74的调节也将在各种炎症条件下提供显着的治疗效果，并且可以通过在已知的T-Cell ing to dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-dr-teception te ceeltiment te ceeld cell-neceptions to ceell te celliment tecelliment tecelliment Tementical cell ing tecelliment tecelligation（可能会增强治疗的有效性）。 MS中的辣椒）。此外，由于在所有人类中都呈现了1个域，因此不会被认为是外国的，因此使用DR-€1构造的治疗不需要HLA筛查潜在的受体，并且可以用于治疗未表达HLA-DR2风险因素的MS受试者。我们的初步数据表明，具有EAE和具有MS受试者的小鼠的单核细胞的CD74水平显着提高，因此为开发pMHC构建体提供了令人信服的理由，可以通过下调CD74表达来抑制MIF活性。在此应用中，我们将检验以下假设：DR-€1的特定片段与单核细胞结合并降低CD74和MIF信号的细胞表面表达，而MIF信号反过来又阻止了细胞迁移到中枢神经系统和TEFF细胞激活中，从而导致EAE的临床和组织学符号反向。为了解决这一假设，我们建议1）确定DR-€1中的CD74结合区域，并开发出最佳的CD74结合DR-€1构建体； 2）评估DR-€1构建体对单核细胞和T细胞激活的抑制作用； 3）确定Dr-€1构建体的效率，用于治疗由肽特异性与非特异性（旁观者）T细胞规格诱导的EAE的效率。