Peptide Vaccine for Experimental Autoimmune Myocarditis

实验性自身免疫性心肌炎肽疫苗

• 批准号: 6643900
• 负责人: Daniel Hill Zimmerman
• 金额: $ 13.45万
• 依托单位: CEL-SCI CORPORATION
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2004-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643900
• 关键词: T lymphocyte; antigens; apoptosis; autoimmune disorder; biomarker; cell population study; cell type; cytokine; disease /disorder model; immunotherapy; laboratory mouse; myocarditis; myosins; synthetic vaccines; vaccine development

DESCRIPTION (provided by the applicant): In A/J Mice Experimental Autoimmune Myocarditis (EAM) can be induced by infection with coxsackie virus B 3 or by immunization with murine or porcine cardiac myosin or a cardiogenic peptide from the murine cardiac myosin (My-l). In all these three cases the mice develop autoantibodies to cardiac myosin, and the disease is characterized by a Th2 phenotype. Previously one of us has shown that the EAM disease process can be blocked by: (1) cobra venom factor (CVF), which depletes complement; or by (2) monoclonal antibodies to the complement receptors involved with the innate immune system; or by (3) antibodies to IL-4 or by (4) Interferon-gamma, which inhibit the Th2 pathway of the inductive immune system. Furthermore, anti-IFN-gamma, treatment exacerbated the EAM. More recently one of our (NRR) studies has demonstrated that IL-10 has a disease inhibiting effect during the later effector phase (after day 10) and not in the early inductor phase (before day 10) using a revised the model which eliminates the Pertussis toxin and results in a slower milder form of disease. Other recent reports also have show a role for IL-10 in disease control in EAM, including use of pentoxifylline which was reported as being used in the human condition. In preliminary studies we have found that pretreatment with a peptide conjugate of the cardiogenic peptide My-l, J-My-l, which is designed to promote a Th1 response against the My-1 antigen, has significantly reduced disease severity. In this study, we intend to examine in more detail and define the role and the effect this conjugate has using the slower progressing EAM model by eliminating the Pertussis toxin. While from a commercialization point the ultimate goal is a product that can be used after disease is diagnosed in this phase I SBIR we will determine whether administration of J-My-1 is beneficial if performed before (1) induction of disease, or (2) during either the induction or (3) effector phases. The specific aims are three Specific Aim 1 To evaluate and compare efficacy of the My-1 L.E.A.P.S. construct, J-My-l, as either an immunotherapeutic vaccine and/or prophylactic treatment for My-1 induced EAM in A/J mice. Specific Aim 2 To evaluate the TH1 and TH2 cytokine(s) profiles and apoptosis markers in spleen lymphocytes obtained from individual NJ mice immunized with J-My-1 to define some aspects of disease induction by the My-1 and the mode of action of J-My-land elucidate the cell population associated with the Thl, Th2 cytokines. The effects of J-My-1 administration on the presence and frequency of this cell type will be evaluated. Our goal is to demonstrate that the severity of EAM can be reduced by J-My-1 administration in animals with EAM.

描述（由申请人提供）：在A/J小鼠中，实验性自身免疫性心肌炎（EAM）可通过柯萨奇病毒b3感染或小鼠或猪心肌蛋白或小鼠心肌蛋白（my - 1）的心源性肽免疫诱导。在所有这三种情况下，小鼠都会产生针对心肌肌球蛋白的自身抗体，并且该疾病的特征是Th2表型。之前我们中的一个人已经证明EAM疾病过程可以被：(1)眼镜蛇毒液因子（CVF）阻断，它会消耗补体；或通过(2)与先天免疫系统相关的补体受体的单克隆抗体；或(3)IL-4抗体或(4)干扰素- γ，它们抑制诱导免疫系统的Th2途径。此外，抗ifn - γ治疗加重了EAM。最近，我们（NRR）的一项研究表明，IL-10在后期效应阶段（第10天之后）具有疾病抑制作用，而不是在早期诱导阶段（第10天之前）使用修订的模型，消除百日咳毒素并导致较慢的温和形式的疾病。最近的其他报告也显示了IL-10在EAM疾病控制中的作用，包括己酮茶碱的使用，据报道已在人类条件下使用。在初步研究中，我们发现用一种心源性肽My-1 （j - My-1）的肽偶联物进行预处理，其目的是促进Th1对My-1抗原的反应，可以显著降低疾病的严重程度。在本研究中，我们打算通过消除百日咳毒素，使用进展较慢的EAM模型来更详细地检查和定义这种共轭物的作用和效果。虽然从商业化的角度来看，最终目标是在I期SBIR中诊断出疾病后可以使用的产品，但我们将确定在(1)诱导疾病之前或(2)诱导或(3)效应阶段给药J-My-1是否有益。评估和比较My-1 L.E.A.P.S.构建体J- My-1作为A/J小鼠My-1诱导的EAM的免疫治疗疫苗和/或预防性治疗的疗效。目的2：评价经J-My-1免疫的NJ小鼠脾脏淋巴细胞中TH1和TH2细胞因子谱和凋亡标志物，以确定My-1诱导疾病的某些方面，以及J-My-land的作用模式，阐明与Thl、TH2细胞因子相关的细胞群。将评估J-My-1给药对这种细胞类型的存在和频率的影响。我们的目标是证明给药J-My-1可以减轻EAM动物的严重程度。