Local immunometabolism modulating biomaterials for immunosuppressive applications

摘要 基于生物材料的调节免疫应答的策略已经引起了对免疫调节的极大兴趣。 过去十年值得注意的是，生物材料不仅可以用于递送药物（合成或生物制剂），而且可以通过 它们本身可以调节不同细胞的功能。最近，我们已经证明， α-酮戊二酸酯（aKG）可以聚合，并且这些聚合物本身能够抑制 树突状细胞（DCs -形成先天性和适应性免疫系统之间的桥梁）的激活。 有趣的是，我们的初步数据还表明，PFK 15，一种PFKFB 3酶的抑制剂（a 糖酵解的关键步骤）下调CD 86（共刺激分子），但维持MHC-II（刺激分子） 抗原呈递分子）。值得注意的是，糖酵解可以控制激活的DC的功能。 因此，糖酵解抑制介导的DC活化和同时抗原表达的预防， 导致抗原特异性免疫抑制反应。然而，糖酵解的全身性抑制 与之相关的固有毒性（临床试验），并且具有临床使用的监管障碍。因此 该R 01计划的主要目标是开发能够递送糖酵解抑制剂的药物递送载体， 抗原局部地结合到DC，其然后将全身性地抑制炎症。这个问题的核心假设是 提出抗原和糖酵解抑制剂共递送将诱导DC耐受并产生外周免疫应答， 抗原特异性抑制性T细胞，这将促进组织炎症的逆转。这一战略将 在类风湿性关节炎动物模型中进行测试。这一假设将通过以下实验进行检验： 目的1：测试paKG制剂是否可以通过维持 关节组织的代谢平衡。目的2：确定paKG制剂对细胞相关性的影响。 关节炎组织目的3：测试paKG制剂预防K/BxN小鼠中RA进展的能力 目的4：开发用于安全性/毒性特征的缩放paKG制剂。这项研究将是一个重要的 为基于免疫细胞代谢调节的自身免疫技术的发展奠定了基础 疾病治疗该项目的成果将产生一个持续的发布平台， 应用可以阻止RA的进展，甚至逆转损害。

Abstract Biomaterials-based strategies to modulate the immune responses has generated tremendous interest in the past decade. Notably, biomaterials can not only be used for delivering drugs (synthetic or biologics) but by themselves can modulate the function of different cells. Recently, we have demonstrated that the metabolite alpha-ketoglutarate (aKG) can be polymerized, and these polymers by themselves are able to suppress activation of dendritic cells (DCs – forms the bridge between innate and adaptive immune system). Interestingly, our preliminary data also demonstrates that delivery of PFK15, an inhibitor of PFKFB3 enzyme (a key step in glycolysis) downregulates CD86 (co-stimulatory molecule) but maintains MHC-II (stimulatory antigen presenting molecules) on DCs. Notably, glycolysis can control the function of activated DCs. Therefore, glycolysis-inhibition mediated prevention of DC activation and simultaneous antigen expression, can lead to antigen-specific immunosuppression responses. However, systemic inhibition of glycolysis has inherent toxicity (clinical trials) associated with it, and have regulatory hurdles for clinical use. Therefore, the main goal of this R01 program is to develop drug delivery vehicles that can deliver glycolysis inhibitors and antigens locally to DCs, which will then systemically suppress inflammation. The central hypothesis of this proposal is that co-delivery of antigen and glycolytic inhibitor will induce DC tolerance and generate peripheral antigen-specific suppressive T-cells, which will then promote reversal of tissue inflammation. This strategy will be tested in a rheumatoid arthritis animal model. This hypothesis will be tested by performing experiments in the following aims: AIM 1: Test if paKG formulations can generate long-term remission of RA by maintaining metabolic homeostasis in joint tissues. AIM 2: Determine the effect of paKG formulations on cells associated with arthritic tissue. AIM 3: Test the ability of paKG formulations to prevent progression of RA in K/BxN mice AIM 4: Develop scaled paKG formulations for safety/toxicity profiles. This research will be an important foundation in the development of technologies based on metabolic modulation of immune cells for autoimmune disorder treatment. The results from this project will generate a sustained release platform, which after application can prevent the progression of RA, or even reverse the damage.