Prasad Suchitra, Xu Dan, Miller Stephen D
Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Rev Diabet Stud. 2012 Winter;9(4):319-27. doi: 10.1900/RDS.2012.9.319. Epub 2012 Dec 28.
The development of therapies that specifically target autoreactive immune cells for the prevention and treatment of type 1 diabetes (T1D) without inducing generalized immunosuppression that often compromises the host's ability to clear non-self antigen is highly desired. This review discusses the mechanisms and potential therapeutic applications of antigen-specific T cell tolerance techniques using syngeneic apoptotic cellular carriers and synthetic nanoparticles that are covalently cross-linked to diabetogenic peptides or proteins through ethylene carbodiimide (ECDI) to prevent and treat T1D. Experimental models have demonstrated that intravenous injection of autoantigen decorated splenocytes and biodegradable nanoparticles through ECDI fixation effectively induce and maintain antigen-specific T cell abortive activation and anergy by T cell intrinsic and extrinsic mechanisms. The putative mechanisms include, but are not limited to, the uptake and processing of antigen-coupled nanoparticles or apoptotic cellular carriers for tolerogenic presentation by host splenic antigen-presenting cells, the induction of regulatory T cells, and the secretion of immune-suppressive cytokines, such as IL-10 and TGF-β. The safety profile and efficacy of this approach in preclinical animal models of T1D, including non-obese diabetic (NOD), BDC2.5 transgenic, and humanized mice, have been extensively investigated, and will be the focus of this review. Translation of this approach to clinical trials of T1D and other T cell-mediated autoimmune diseases will also be reviewed in this chapter.
人们迫切希望开发出能够特异性靶向自身反应性免疫细胞的疗法，用于预防和治疗1型糖尿病（T1D），同时又不会引发通常会损害宿主清除非自身抗原能力的全身性免疫抑制。本综述讨论了使用同基因凋亡细胞载体和合成纳米颗粒的抗原特异性T细胞耐受技术的机制和潜在治疗应用，这些纳米颗粒通过碳二亚胺（ECDI）与致糖尿病肽或蛋白质共价交联，以预防和治疗T1D。实验模型表明，通过ECDI固定静脉注射自身抗原修饰的脾细胞和可生物降解的纳米颗粒，可通过T细胞内在和外在机制有效诱导并维持抗原特异性T细胞的流产激活和无反应性。推测的机制包括但不限于宿主脾抗原呈递细胞摄取和处理抗原偶联的纳米颗粒或凋亡细胞载体以进行耐受性呈递、诱导调节性T细胞以及分泌免疫抑制细胞因子，如IL-10和TGF-β。这种方法在T1D的临床前动物模型，包括非肥胖糖尿病（NOD）、BDC2.5转基因和人源化小鼠中的安全性和有效性已得到广泛研究，将是本综述的重点。本章还将综述这种方法向T1D和其他T细胞介导的自身免疫性疾病临床试验的转化情况。
