INDUCTION OF SPECIFIC IMMUNE TOLERANCE

诱导特异性免疫耐受

• 批准号: 6607263
• 负责人: TERRY A POTTER
• 金额: $ 29.02万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-15 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607263
• 关键词: B lymphocyte; CD8 molecule; Listeria; MHC class I antigen; chimeric proteins; cytotoxic T lymphocyte; dendritic cells; epithelium; fibroblasts; genetically modified animals; hybrid antibody; immune tolerance /unresponsiveness; immunoglobulin G; immunosuppressive; kidney transplantation; laboratory mouse; leukocyte activation /transformation; macrophage; pancreatic islet transplantation; technology /technique development; transplant rejection

DESCRIPTION: (Adapted from the Investigator's abstract): The immune system is the major biological defense system responsible for fighting disease. However, immune responses can also be detrimental. In the case of transplantation, although the immune system reacts appropriately, it nevertheless causes harm by destroying the transplanted organs. In autoimmune diseases, the immune system turns against self and attacks otherwise normal tissue. In both situations, it is important to suspend the destructive function of the immune system while maintaining normal immune responses. Presently, in the clinical situation, a general immune suppression is induced, and the patients' defenses against infectious challenges are impaired. Strategies are now being sought that successfully induce specific non-responsiveness (tolerance) without affecting normal immune functions. Important cells of the immune system are T cells. They control many immune responses and also act as effector cells. Their suppression is crucial for the induction of tolerance. Only cells that react with a given organ, e.g. a transplant or a target of an autoimmune disease, should be removed. As different types of cells express tissue-specific antigens, complete tolerance towards a given tissue is best induced by the tissue itself. This should be true for transplant rejections and also autoimmune diseases. It has long been held that the disease mechanisms underlying autoimmune diseases mimic those seen in transplant rejection. Therefore, it should be possible to adapt strategies that induce specific transplantation tolerance to the treatment of autoimmune diseases. The so-called veto-effect (conventional veto) has been shown to efficiently and specifically tolerize T cells. It functions by expression of the co-receptor CD8 on stimulator cells. Based on this original observation, the approach has been expanded toward the development of hybrid antibodies (hAb) that combine a targeting antibody moiety with the functional region of the CD4 or CD9 accessory molecules. The cells coated with these hAbs inhibited the activation of either CD4+ or CD8+ activation in a highly specific fashion. In the current application, it is proposed to examine the function and activity of the CD8 targeting hAb in animal models of organ transplantation.

描述：（改编自研究者的摘要）：免疫系统是 负责对抗疾病的主要生物防御系统。然而， 免疫反应也可能是有害的。在移植的情况下， 尽管免疫系统会做出适当的反应，但它仍然会造成伤害 破坏移植的器官。在自身免疫性疾病中，免疫系统 与自身作对并攻击其他正常组织。在这两种情况下，它 对于中止免疫系统的破坏性功能很重要，同时 维持正常的免疫反应。目前，在临床上， 诱导全身免疫抑制，患者的防御能力下降 传染性挑战受到损害。现在正在寻求策略 成功诱导特定的无反应性（耐受性）而不影响 正常的免疫功能。 免疫系统的重要细胞是 T 细胞。他们控制许多免疫 反应并也充当效应细胞。对他们的压制对于 诱导耐受。仅与给定器官发生反应的细胞，例如一个 移植物或自身免疫性疾病的目标，应被移除。作为 不同类型的细胞表达组织特异性抗原，完全耐受 朝向给定组织的最好由组织本身诱导。这应该是 对于移植排斥和自身免疫性疾病也是如此。早已是 认为自身免疫性疾病的疾病机制与这些疾病相似 见于移植排斥反应。因此，应该可以适应 诱导对治疗的特异性移植耐受的策略 自身免疫性疾病。 所谓的否决效应（传统否决权）已被证明可以有效且有效地 特异性耐受 T 细胞。它通过共受体的表达发挥作用 刺激细胞上的 CD8。基于这一原始观察，该方法已 已扩展到混合抗体 (hAb) 的开发，该抗体结合了 具有 CD4 或 CD9 功能区的靶向抗体部分 辅助分子。涂有这些 hAb 的细胞抑制了激活 以高度特异性的方式激活 CD4+ 或 CD8+。在当前 应用中，建议检查CD8的功能和活性 器官移植动物模型中的靶向 hAb。