Fimbriae Countermeasures for Type 1 Diabetes

 描述(申请人提供)：在美国，1型糖尿病(T1D)影响着130万患者，他们因肾脏、心血管、眼睛和/或神经并发症而表现出发病率和过早死亡率的增加。这种T细胞介导的疾病以胰岛产生胰岛素的b细胞的自身免疫破坏为特征，导致血糖调节失调。虽然刺激免疫调节通路可以成功地干预治疗自身免疫性疾病，但目前对T1D的对策大多依赖于胰岛素替代疗法。在治疗人类自身免疫性疾病方面，实施耐受性方案仍然存在问题。一种替代方案是以旁观者的方式刺激免疫无反应，而不施加全球免疫抑制。这种方法特别有吸引力，因为事先不需要自体抗原的知识，并且可以使用无害的抗原，例如产肠毒素大肠杆菌的定植因子抗原I(CFA/I)菌毛来实现。我们过去的自身免疫研究表明，CFA/I菌毛可以建立一个有利于建立疾病特异性调节性T细胞(Tregs)的环境。当CFA/I菌毛经鼻或口服给药时，通过刺激产生IL-10的调节性树突状细胞(DC)诱导Tregs产生IL-10和转化生长因子-b，从而减轻实验性自身免疫性疾病。为了便于其最终在人类中的使用，一种表达CfA/I菌毛的乳球菌菌株(Lactorics-CFA/I)被发现在提供对自身免疫性疾病的保护方面优于可溶性菌毛。基于乳球菌的疗法已经被测试用于治疗人类自身免疫性疾病，通常被认为是安全的。鉴于这一方法的成功，拟议的研究将建立CFA/I菌毛作为治疗T1D的基础。这将通过检验这一假设来实现，即CFA/I菌毛在与组织DC相互作用时促进调节微环境，进而激活T1D特异性Tregs产生转化生长因子-b、IL-10和/或IL-35，从而抑制或灭活致病的CD4+和CD8+T细胞。为了验证这一假设，本文提出了两个具体目标。针对特定目的1的研究将表明，由乳球菌-CFA/I介导的旁观者免疫可以通过疾病特异性Tregs来预防和阻止T1D。具体目标2的研究将确定DC和Tregs对T1D保护的负责机制。这项工作的影响将辨别这些驱动疾病特异性Treg的新方法是否可以防止进一步的胰岛破坏，并减少对胰岛素替代疗法的依赖。

 DESCRIPTION (provided by applicant): In the US, type 1 diabetes (T1D) impacts 1.3 million patients who exhibit increased morbidity and premature mortality due to renal, cardiovascular, ocular, and/or neurological complications. This T cell-mediated disease is noted by the autoimmune destruction of the insulin-producing b cells of the pancreatic islets leading to glycemic dysregulation. Although stimulation of immune regulatory pathways can successfully intervene to treat autoimmune diseases, current countermeasures for T1D mostly rely on insulin replacement therapies. Implementing a tolerogenic regimen still remains problematic for treating human autoimmune diseases. One alternative is to stimulate immune unresponsiveness in a bystander fashion without imposing global immunosuppression. Such an approach is particularly attractive since prior knowledge of the auto-Ag is not required and can be accomplished using an innocuous antigen, such as colonization factor antigen I (CFA/I) fimbriae from enterotoxigenic E. coli. Our past autoimmune studies have shown CFA/I fimbriae can establish an environment conducive to establishing disease-specific regulatory T cells (Tregs). When administered nasally or orally, CFA/I fimbriae mitigate experimental autoimmune diseases by inducing Tregs to produce IL-10 and TGF-b via the stimulation of IL-10-producing regulatory dendritic cells (DCs). To facilitate its eventual use in humans, a Lactococcus lactis strain expressing CFA/I fimbriae (Lactococcus-CFA/I) was generated and found to be superior to soluble fimbriae in conferring protection against autoimmune diseases. Lactococcus-based therapeutics has already been tested for treating autoimmune diseases in humans, and is generally regarded as safe. Given the success of this approach, the proposed studies will establish CFA/I fimbriae as the basis for a therapeutic for T1D. This will be accomplished by testing the hypothesis that CFA/I fimbriae promote a regulatory microenvironment upon interaction with tissue DCs, which in turn, activate T1D-specific Tregs to produce TGF-b, IL-10, and/or IL-35 which suppress or anergize pathogenic CD4+ and CD8+ T cells. To test this hypothesis, two Specific Aims are proposed. Studies in Specific Aim 1 will show that bystander immunity mediated by Lactococcus-CFA/I can prevent and stop T1D via disease-specific Tregs. Studies in Specific Aim 2 will determine mechanisms responsible for DCs and Tregs for conferring T1D protection. The impact of this work will discern whether these novel approaches in driving disease-specific Tregs can prevent further pancreatic islet destruction, and reduce the reliance on insulin replacement therapy.