DOWN-REGULATION OF DIABETOGENIC T-CELLS

下调糖尿病 T 细胞

• 批准号: 6055867
• 负责人: TEODOR-DORU BRUMEANU BRUMEANU
• 金额: $ 10万
• 依托单位: ALLIANCE PHARMACEUTICAL CORPORATION
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6055867
• 关键词: MHC class II antigen; T lymphocyte; genetically modified animals; hemagglutinin; immunomodulators; immunoregulation; immunotherapy; influenzavirus A; insulin dependent diabetes mellitus; laboratory mouse; peptides

DESCRIPTION: (Adapted from the applicant's abstract): Insulin-dependent diabetes mellitus (IDDM, diabetes type I) is a chronic autoimmune disease resulting from T-cell mediated destruction of pancreatic beta-cells. The role of autoreactive Th1 cell subset in IDDM pathogenesis has been widely demonstrated. Non selective immunosuppressive drugs and other approaches aimed at blocking the diabetogenic T-cell immune response remain clinically ineffective. Using a genetic approach, the investigators have generated a dimeric peptide/MHC class-II chimera (DEF), which exhibits remarkable potency to deviate the peptide-specific T-cells toward a Th2 protective response in vivo. DEF is composed of the extracellular domains of the alpha- and beta-chains of I-E(d) dimerized through the Fc portion of IgG 2 alpha linked at the C-termini of the beta-chains. The immunodominant CD4-T-cell epitope of the influenza type A/PR/8/34 hemagglutinin (HA110-120) is covalently linked at the N-termini of the beta-chains. In contrast to other immunotherapeutic strategies i.e., anti-CD4, anti-CD8, or anti-MHC class II Abs, which require high doses and increase the susceptibility to infections, the DEF approach is aimed at down-regulating selectively the diabetogenic T-cells. The model for IDDM consists of double transgenic mice expressing influenza virus A/PR/8/34 hemagglutinin protein (HA) in the pancreatic beta cells, and the HA-specificT-cells. Preliminary results have indicated a potential anti-diabetogenic effect of DEF in this double transgenic mouse model of IDDM. The major goal for Phase I is to evaluate the curative efficacy of DEF in IDDM mice with overt diabetes, and to determine the capacity of DEF for preventing/delaying the onset of IDDM in prediabetic mice. Satisfactory results will lead to the generation of a human DEF-like molecule (hu-DEF) consisting of the HLA-DR*0401 allele, and the most common diabetogenic peptide in humans, GAD-derived p270-283 peptide (LPRLIAFTSEHSHF). The DEF approach may open new avenues for the development of more efficient immunotherapeutic agents in IDDM. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE

描述：（改编自申请人摘要）：胰岛素依赖型 糖尿病（IDDM，I型糖尿病）是一种慢性自身免疫性疾病 由T细胞介导的胰腺β细胞破坏引起。的作用 自身反应性Th 1细胞亚群在IDDM发病机制中的作用已被广泛研究， 演示。非选择性免疫抑制药物和其他针对 在阻断致糖尿病T细胞免疫反应方面， 无效。 利用遗传学方法，研究人员已经产生了一个二聚体， 肽/MHC II类嵌合体（DEF），其表现出显着的效力， 使肽特异性T细胞偏向体内Th 2保护性应答。 DEF是由α-和β-链的胞外结构域组成的， I-E（d）通过在C-末端连接的IgG 2 α的Fc部分二聚化 β-链流感型的免疫显性CD 4-T细胞表位 A/PR/8/34血凝素（HA 110 -120）共价连接在 β链与其他免疫策略相比， 抗-CD 4、抗-CD 8或抗-MHC II类Ab，其需要高剂量， 增加感染的易感性，DEF方法旨在 选择性下调致糖尿病T细胞。胰岛素依赖型糖尿病模型 由表达流感病毒A/PR/8/34的双转基因小鼠组成 血凝素蛋白（HA）在胰腺β细胞，和 HA特异性T细胞。初步结果显示， DEF在该IDDM双转基因小鼠模型中的抗糖尿病作用。 I期的主要目的是评价DEF治疗IDDM的疗效 明显糖尿病小鼠，并确定DEF的能力， 预防/延迟前驱糖尿病小鼠中IDDM的发作。满意的结果 将导致产生人DEF样分子（hu-DEF），其由以下组成： HLA-DR*0401等位基因，以及人类中最常见的致糖尿病肽， GAD衍生的p270-283肽（LPRLIAFTSEHSHF）。DEF方法可能会打开新的 开发更有效的免疫抑制剂治疗胰岛素依赖型糖尿病的途径。 拟议商业应用：不可用

项目成果

Modulation of CD4 T cell function by soluble MHC II-peptide chimeras.

• DOI: 10.3109/08830180109045578
• 发表时间: 2001-10-01
• 期刊: International reviews of immunology
• 影响因子: 5
• 作者: Casares, S;Bona, C A;Brumeanu, T D
• 通讯作者: Brumeanu, T D