Core B

核心 B - 摘要/摘要 Core B 将提供抗体包被的纳米颗粒 (NP) 和 FRC，用于体内给药以重新编程 LN 微环境朝向促进移植耐受的调节环境。这些策略 代表了仅由这里的团队提出的尖端方法，因此它们 代表了与诱导耐受的传统方法的根本背离。这些技术提供 Core B 为开发旨在重新编程的一流疗法奠定了基础 LN 的微环境。这些数据除了应用于移植之外，还可以有 对 LN 在发病机制中发挥核心作用的其他免疫疾病产生重大影响（例如， 自身免疫性疾病和肿瘤免疫）。该核心将充分表征并合成大量 抗层粘连蛋白 α5 (LAMA5) 和抗 CD40L mAb 的 MECA-79 缀合载体（项目 2 - Bromberg），如 以及抗衰老剂 (SA)（项目 1- Abdi）。核心 B 还将合成掺入染料的纳米颗粒（包括 红外染料）来验证向 LN 的运输并控制批次的质量。这将是第一个 该平台针对 LN 进行药物输送，以重新编程其微环境以实现免疫耐受。在 此外，Core B 将扩展从健康小鼠 LN 中分离出的 FRC，并将对其进行全面表征 FRC 特定标记。这些细胞将提供给项目 1 进行实验，评估其对 下调淋巴结纤维化及其对移植耐受的有害影响。 Core B的具体目标如下： 目标 1. 表征并提供抗体缀合的纳米粒子，用于靶向递送免疫 对 LN 进行治疗以促进移植耐受。 目标 2. 表征并提供健康的 FRC 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.