Type I Diabetes Mellitus Prevention using Cell Vaccine

使用细胞疫苗预防 I 型糖尿病

• 批准号: 6352267
• 负责人: Nick Giannoukakis
• 金额: $ 17.5万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352267
• 关键词: CD40 molecule; NOD mouse; animal genetic material tag; antisense nucleic acid; autoantigens; autoimmunity; blood glucose; bone marrow; dendritic cells; diabetes mellitus therapy; disease /disorder prevention /control; female; femur; flow cytometry; gene therapy; injection /infusion; lymphocyte; lysine; nonhuman therapy evaluation; nuclear factor kappa beta; oligonucleotides; ovalbumin; pancreatic islet neoplasm; pancreatic islets; urine; vaccine development

DESCRIPTION (provided by applicant): Type I diabetes mellitus is an autoimmune disease whose etiopathogenesis lies in the selective destruction of the insulin-producing beta cells of the islets of Langerhans in the pancreas. The current insulin replacement therapy strategies are not fully effective at recapitulating tight glucose control and consequently, many patients eventually succumb to debilitating and life-threatening complications such as kidney failure and heart disease. While transplantation of intact islets of Langerhans offers the potential to restore physiologic glycemic control, the requirement for life-long immunosuppressive interventions carries with it significant risks of rendering the islet transplants dysfunctional. Moreover, these strategies can lead to an array of other problems including kidney failure and a risk of malignancy. In contrast, preventing autoimmunity altogether will prevent beta cell destruction, thereby obviating the need for life-long insulin therapy or transplantation concomitant with chronic immunosuppressive therapy. Most of the preventive strategies in experimental animals to date have focused on the induction of tolerance to either soluble islet antigens or putative autoantigens like insulin and glutamic acid decarboxylase. Intrathymic injection of islet lysates or putative autoantigens has resulted in either the prevention of diabetes or prolongation of time to onset in diabetic rodent models. Intrathymic injection, however, is not practical in humans, and the candidate autoantigen approach is risky in that the identity of the causative diabetogenic autoantigens remains unknown. This application focuses on developing proof-of-principle studies of an alternative means of achieving tolerance to autoantigens by manipulating a subtype of the diabetic host's immune cells in order to educate the host immune system to ignore beta cell antigens before the onset of disease. The subtype of immune cells that this application aims to manipulate into a cell vaccine are dendritic cells, considered to be the body's natural adjuvant. These cells normally initiate potent immune responses against foreign tissue. Dendritic cells however, have also been manipulated to tolerise the host immune system to foreign antigens, including allogeneic, and it is possible that similar manipulation may promote tolerance to autoantigens in diabetes. By blocking co-stimulatory pathways in which dendritic cells figure prominently, it has been possible to achieve long-term acceptance of both allogeneic and xenogeneic transplants. The central hypothesis that this application will test is whether administration of a prediabetic animal host's dendritic cells, rendered unable to provide adequate costimulatory signals by ex vivo gene transfer technology and presenting islet antigens, can prevent or prolong the time to onset of diabetes when reintroduced into the host. Oligonucleotide decoys for NF-kappaB, a transcriptional regulator of dendritic cell activation, as well as antisense oligonucleotides against the transcripts encoding the costimulation molecules CD80 and CD86 will be used to engineer the host's dendritic cells into a cell vaccine for autoimmune diabetes.

描述（申请人提供）：I型糖尿病是一种自身免疫性疾病，其发病机制在于选择性破坏 胰腺中朗格汉斯岛产生胰岛素的β细胞。 目前的胰岛素替代治疗策略并不完全有效 重述严格的血糖控制，因此，许多患者 最终死于使人衰弱和危及生命的并发症，例如 肾衰竭和心脏病。 移植完整的胰岛时 朗格汉斯具有恢复生理血糖控制的潜力， 终身免疫抑制干预的需要 导致胰岛移植功能障碍的重大风险。 而且， 这些策略可能会导致一系列其他问题，包括肾脏问题 失败和恶性肿瘤的风险。 相反，预防自身免疫 完全可以防止β细胞破坏，从而无需 终生胰岛素治疗或移植伴随慢性 免疫抑制治疗。 大多数预防策略都在实验中 迄今为止，动物的重点是诱导对任一可溶性物质的耐受性 胰岛抗原或假定的自身抗原，如胰岛素和谷氨酸 脱羧酶。 胸腺内注射胰岛裂解物或假定的 自身抗原已导致糖尿病的预防或延长 糖尿病啮齿动物模型中的发病时间。 然而，胸腺内注射 在人类中不实用，并且候选自身抗原方法在以下方面存在风险： 致病性糖尿病自身抗原的身份仍然未知。 该应用程序侧重于开发原理验证研究 通过操纵a来实现对自身抗原的耐受性的替代方法 糖尿病宿主免疫细胞的亚型，以教育宿主 免疫系统在疾病发作前忽略β细胞抗原。 这 此应用程序旨在将其转化为细胞的免疫细胞亚型 疫苗是树突状细胞，被认为是人体的天然佐剂。 这些细胞通常会启动针对外来组织的有效免疫反应。 然而，树突状细胞也已被操纵以耐受宿主 免疫系统对外来抗原，包括同种异体抗原，并且有可能 类似的操作可能会促进糖尿病患者对自身抗原的耐受性。 通过阻断树突状细胞参与的共刺激途径 突出的是，有可能实现两者的长期接受 同种异体和异种移植。 中心假设是这 应用程序将测试是否给予糖尿病前期动物宿主 树突状细胞，无法提供足够的共刺激信号 离体基因转移技术和呈递胰岛抗原，可以预防或 当重新引入宿主时，延长糖尿病发病的时间。 树突转录调节因子 NF-kappaB 的寡核苷酸诱饵 细胞激活，以及针对转录物的反义寡核苷酸 编码共刺激分子 CD80 和 CD86 将用于设计 将宿主的树突状细胞转化为治疗自身免疫性糖尿病的细胞疫苗。