Core B

核心B--摘要/摘要 Core B将提供抗体包裹的纳米颗粒(NP)和FRC用于体内给药，以重新编程 在微环境中朝着促进移植耐受的调控环境发展。这些策略 代表了仅由这里的团队提出的尖端方法，因此他们 这代表着从根本上背离了诱导宽容的传统方法。这些技术提供了 为开发旨在重新编程的一流疗法奠定了基础 LN的微环境。除了这些数据在移植方面的应用外，他们还可以 在LN在发病机制中扮演中心角色的其他免疫条件下的主要影响(例如， 自身免疫性疾病和肿瘤免疫)。这一核心将充分表征和合成大量 MecA-79-抗层粘连蛋白α5(LAMA5)和抗CD40L单抗的偶联载体(项目2-Bromberg)，AS 以及增感剂(SAS)(项目1-Abdi)。核心B还将合成含有染料的NPs(包括 红外线染料)，以核实贩运到LNS以及控制批次的质量。这将是第一次 针对LNS进行药物输送的平台，以重新编程其微环境以实现免疫耐受。在……里面 此外，Core B将扩展从健康小鼠的LNS中分离出来的FRC，并将充分表征 FRC特定的标记。这些细胞将被提供给项目1进行实验，以评估它们对 下调LN纤维化及其对移植耐受的有害影响。 核心B的具体目标如下： 目的1.鉴定并提供抗体偶联的纳米粒用于免疫靶向传递 向LN提供治疗以促进移植耐受。 目的2.鉴定并提供健康的FRCs，用于体内给药以促进移植 通过重新编程LN微环境来耐受。

CORE B - SUMMARY/ABSTRACT Core B will provide antibody-coated nanoparticles (NPs) and FRCs for in vivo administration to reprogram the LN microenvironment towards a regulatory milieu that promotes transplant tolerance. These strategies represent cutting-edge approaches which have been set forth only by the teams here, and hence they represent a radical departure from the traditional approaches to induce tolerance. These techniques provided by Core B lay the groundwork for developing first class of therapeutics aimed towards reprogramming the microenvironment of the LN. In addition to the applications of these data to transplantation, they can also have a major impact in other immune conditions in which the LN plays a central role in the pathogenesis (e.g., autoimmune diseases and tumor immunity). This Core will fully characterize and synthesize large quantities of MECA-79-conjugated carriers of anti-laminin α5 (LAMA5) and anti-CD40L mAbs (Project 2 - Bromberg), as well as senolytic agents (SAs) (Project 1- Abdi). Core B will also synthesize dye-incorporating NPs (including infrared dye) to verify trafficking to LNs as well as to control the quality of the batches. This will be the first platform that targets LNs for drug delivery to reprogram their microenvironment towards immune tolerance. In addition, Core B will expand FRCs isolated from the LNs of healthy mice and will be fully characterized for FRC-specific markers. These cells will be provided to Project 1 for experiments that assess their impact on downregulating LN fibrosis and its deleterious effects on transplant tolerance. The specific aims of Core B are as follows: Aim 1. To characterize and provide antibody-conjugated NPs for targeted delivery of immune therapeutics to the LN to promote transplant tolerance. Aim 2. To characterize and provide healthy FRCs for in vivo administration to promote transplant tolerance by reprogramming the LN microenvironment.