Type I Diabetes Mellitus Prevention using Cell Vaccine

描述(申请人提供)：I型糖尿病是一种自身免疫性疾病，其病因在于选择性破坏 胰腺中朗格汉斯胰岛的分泌胰岛素的β细胞。 目前的胰岛素替代治疗策略并不是完全有效的 重述严格的血糖控制，因此，许多患者 最终会死于令人衰弱和危及生命的并发症，如 肾衰竭和心脏病。而完整的胰岛移植 朗格汉斯提供了恢复生理性血糖控制的潜力， 对终身免疫抑制干预的要求随之而来 造成胰岛移植功能障碍的巨大风险。此外， 这些策略可能会导致一系列其他问题，包括肾脏 失败和恶变的风险。相比之下，预防自身免疫 总之，将防止贝塔细胞的破坏，从而消除了 终生胰岛素治疗或移植伴随慢性疾病 免疫抑制疗法。大多数实验中的预防策略 到目前为止，动物们一直专注于诱导对任何一种可溶物质的耐受 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推定 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的发病时间。然而，胸腺内注射， 在人类身上是不实用的，候选自身抗原方法在 致病的糖尿病原性自身抗原的身份尚不清楚。 此应用程序侧重于开发一个原则证明研究 获得对自身抗原耐受性的替代方法是通过操纵 糖尿病宿主的免疫细胞亚型，以教育宿主 免疫系统在疾病发作前忽略β细胞抗原。这个 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。 这些细胞通常会对外来组织发起强大的免疫反应。 然而，树突状细胞也被操纵来耐受宿主 免疫系统对外来抗原，包括同种异体抗原，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所在的共刺激通路 值得注意的是，已经有可能实现对两者的长期接受 同种异体和异种移植。核心假设是这一点 应用程序将测试糖尿病前期动物宿主的给药 树突状细胞，不能提供足够的共刺激信号 体外基因转移技术和胰岛抗原的提呈，可以预防或 当再次进入宿主体内时，延长糖尿病发作的时间。 树突状细胞转录调控因子--核因子-kappaB的寡核苷酸诱骗 细胞激活，以及针对转录本的反义寡核苷酸 编码共刺激分子CD80和CD86将被用于工程 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。

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.