DOWN-REGULATION OF DIABETOGENIC T-CELLS

描述：(改编自申请人的摘要)：胰岛素依赖型 糖尿病(IDDM)是一种慢性自身免疫性疾病 由T细胞介导的对胰岛β细胞的破坏引起。角色 自身反应性Th1细胞亚群在IDDM发病机制中的作用 演示了。针对非选择性免疫抑制药物和其他方法 在阻断糖尿病致T细胞免疫反应方面临床上仍然存在 效果不佳。 使用遗传方法，研究人员已经产生了一种二聚体 多肽/MHC-II类嵌合体(DEF)，具有显著的抗肿瘤活性 在体内使多肽特异性T细胞偏向Th2保护性反应。 DEF是由α-链和β-链的胞外区组成的 I-E(D)通过连接在C-末端的Ig2α的Fc部分进行二聚 贝塔链。流感病毒免疫优势的CD4-T细胞表位 A/PR/8/34血凝素(HA110-120)的N-末端是共价连接的 Beta链。与其他免疫治疗策略，即， 抗CD4、抗CD8或抗MHC II类抗体，需要高剂量和 增加感染的易感性，DEF方法的目的是 选择性下调致糖尿病T细胞。关于IDDM的模型 由表达流感病毒A/PR/8/34的双转基因小鼠组成 胰岛β细胞中的血凝素蛋白(HA)，以及 HA特异性T细胞。初步结果表明， DEF在IDDM双转基因小鼠模型中的抗糖尿病作用。 第一阶段的主要目标是评估DEF对IDDM的疗效 并测定DEF对糖尿病小鼠的治疗能力 预防/延缓糖尿病前期小鼠的IDDM发病。结果令人满意 将导致产生一种类似人类DEF的分子(HU-DEF)，该分子包括 人类白细胞抗原-DR*0401等位基因，也是人类最常见的致糖尿病多肽， GAD衍生的p270-283肽(LPRLIAFTSEHSHF)。DEF方法可能会打开新的 开发更有效的IDDM免疫治疗剂的途径。 建议的商业应用：不可用

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