New way in delivering immunomodulatory drugs in T1D

由于迄今为止没有有效的治疗方法，正在进行的1型糖尿病（T1D）流行仍然是一个主要的健康问题。 问题.虽然免疫疗法对T1D的治疗有很大的希望，但它们的不足、严重的局限性和局限性仍然存在。 毒性、副作用和发病率限制了终身免疫抑制方法的研究努力。 这一缺陷促使调查人员寻找替代方法。靶向纳米医学 使用聚合物纳米颗粒（NPs）特别有希望增强免疫治疗剂的递送 来治疗T1D这种策略可以通过递送免疫治疗剂来最小化免疫治疗剂的不良副作用。 它们被转移到患病的组织中，在那里它们可以持续释放。在这个多学科项目中，我们的目标是 开发一种创新的，有针对性的纳米递送方法，用于T1D的免疫治疗。尽管进展 在开发新的制剂，一种有针对性地提供纳米粒子到特定组织部位的方法， 系统给药后的效果仍有待开发。自身反应性T细胞的致敏和活化 发生在胰腺淋巴结（PLN）中，其中初始T细胞通过淋巴结（LN）限制性进入。 称为高内皮小静脉（HEVs）的血管系统，并遇到来自胰腺的自身抗原 由树突状细胞呈递。活化的T细胞随后运输到胰腺，引起胰岛炎和 自身免疫性糖尿病值得注意的是，我们已经发现，在胰腺炎发作期间， NOD小鼠的糖尿病在这里，我们第一次开发了一种将治疗剂纳米递送到PLN的方法， 静脉注射靶向HEV的NOD小鼠胰腺。我们已经产生了一种新的单克隆抗体和scFV 针对外周淋巴结地址素（PNAd），一种仅由血管内皮细胞表达的糖蛋白家族， HEV。我们还提供支持我们的交付平台的临床适用性的人体数据。而且我们 初步数据显示，使用我们的HEV靶向的抗CD3抗体的递送前所未有地增加了抗CD3抗体的表达。 抗CD3抗体抑制NOD小鼠自身免疫性糖尿病的功效。我们的主要假设是 将抗CD3递送至胰腺淋巴结（PLN）和胰腺将增加其功效， 通过显著减少全身剂量来降低毒性。在目标1中，我们将检查和优化 抗HEV mAb缀合的NP在NOD小鼠中的稳定性、结合效力和生物分布。在目标2中，我们将 评估使用抗HEV mAb递送抗CD3的临床疗效和机制， 缀合的NP逆转NOD小鼠的自身免疫性糖尿病。在目标3中，我们计划测试结合能力， 我们的优化的抗HEV mAb缀合的NP的人T1D患者的PLN和胰腺。这 多学科的合作方法将为引入一种创新的、有针对性的 T1D免疫治疗剂的递送方法。

With no effective therapy to date, the ongoing Type 1 diabetes (T1D) epidemic continues to be a major health problem. While immune therapeutics hold great promise for the treatment of T1D, their inadequacy, serious toxicity, side effects, and morbidity have limited research efforts in the lifelong immunosuppression approach. This shortcoming has prompted investigators to search for alternative approaches. Targeted nanomedicine using polymeric nanoparticles (NPs) holds particular promise to enhance the delivery of immune therapeutics to treat T1D. This strategy can minimize the undesirable side effects of immune therapeutics by delivering them to diseased tissues, where they can undergo sustained release. In this multidisciplinary project, we aim to develop an innovative, targeted nanodelivery method for immune therapeutics for T1D. Although progress has been made in developing new formulations, a method of targeted delivery of NPs to specific tissue sites following systemic administration remains to be developed. The priming and activation of autoreactive T cells occurs in the pancreatic lymph nodes (PLNs), where naive T cells enter through lymph node (LN)-restricted vasculature known as high endothelial venules (HEVs) and encounter autoantigens from the pancreas presented by dendritic cells. Activated T cells traffic subsequently to the pancreas, causing insulitis and autoimmune diabetes. Notably, we have found that HEVs are also formed in the pancreas during the onset of diabetes in NOD mice. Here, for the first time, we have developed a nanodelivery of therapeutics to PLN and Pancreata of NOD mice targeting HEV with intra venous injection. We have generated a novel mAb and scFV against the peripheral node addressin (PNAd), a glycoprotein family expressed only by endothelial cells of the HEV. We also provide human data that supports the clinical applicability of our delivery platform. Moreover, our preliminary data shows that delivery of anti-CD3 antibody using our HEV targeted unprecedently increases the efficacy of anti CD3 in suppressing autoimmune diabetes in NOD mice. Our main hypothesis is that targeted delivery of anti-CD3 to the pancreatic lymph nodes (PLNs) and pancreata will increase its efficacy and decrease toxicity by reducing systemic dosing significantly. In Aim 1, we will examine and optimize the stability, binding efficacy, and biodistribution of anti HEV mAb-conjugated NPs in NOD mice. In Aim 2, we will assess the clinical efficacy and the mechanisms by which the delivery of anti-CD3 using anti HEV mAb- conjugated NPs reverse autoimmune diabetes in NOD mice. In Aim 3, we plan to test the binding capacity to the PLNs and pancreata of human T1D patients of our optimized anti HEV mAb-conjugated NPs. This multidisciplinary, collaborative approach will lay the groundwork for the introduction of an innovative, targeted delivery method of immune therapeutics for T1D.