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，可以通过用Coxsackie病毒B 3或用鼠或猪心肌球蛋白或鼠心脏肌球蛋白（my-L）感染coxsackie病毒B 3或用鼠类或猪心肌球蛋白或心脏疾病肽免疫来诱导自身免疫性心肌炎（EAM）。在所有这三种情况下，小鼠为心脏肌球蛋白发展自身抗体，该疾病的特征是Th2表型。以前，我们中的一个表明，可以通过以下方式阻止EAM疾病过程：（1）COBRA毒液因子（CVF），它耗尽了补体；或通过（2）与先天免疫系统涉及的补体受体的单克隆抗体；或通过（3）抗IL-4或（4）干扰素抗体，抑制电感免疫系统的Th2途径。此外，抗IFN-gamma治疗加剧了EAM。最近，我们（NRR）的一项研究表明，IL-10在后来的效应阶段（第10天后）具有抑制疾病的作用，而不是使用修订的模型，而不是在早期的电感器阶段（第10天之前），从而消除了百日咳毒素，从而消除了疾病较慢的疾病。其他最近的报告还显示了IL-10在EAM中的疾病控制中的作用，包括使用五氧化苯胺，据报道在人类状况中使用。在初步研究中，我们发现用心源性肽My-L My-L My-L J-My-L进行预处理，旨在促进针对MY-1抗原的Th1反应，显着降低了疾病的严重程度。在这项研究中，我们打算更详细地检查并定义这种结合物通过消除百日咳毒素来使用较慢的EAM模型的作用和影响。虽然从商业化点开始，最终目标是可以在此阶段诊断出疾病后使用的产品，但在（1）诱导疾病或（2）诱导或（3）效应子阶段，J-MY-1的施用是有益的。具体目的是评估和比较My-1 L.E.A.P.S.的效力的三个特定目标1。构造，J-my-L，作为A/J小鼠中My-1诱导的My-1诱导的EAM的免疫治疗疫苗和/或预防性治疗。具体目标2评估从用J-MY-1免疫的单个NJ小鼠获得的脾淋巴细胞中Th1和Th2细胞因子的特征和凋亡标记，以通过My-1和My-1定义疾病诱导的某些方面，以及J-My-land的作用模式，使J-My-land降低了与Th2 Cytokines相关的细胞群体。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EAM的J-MY-1给药可以降低EAM的严重程度。