Core B

核心B

基本信息

批准号：
10662309
负责人：
Reza Abdi
金额：
$ 17.94万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-27 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662309
关键词：
Alloantigen Anti-Inflammatory Agents Antibodies Area Autoimmune Diseases Biology Biomedical Engineering Blood Capsid Proteins Cell Separation Cells Characteristics Collagen Conjugated Carrier Data Dimensions Drug Delivery Systems Drug Targeting Dyes Engineering Equilibrium Fibronectins Fibrosis Goals High Endothelial Venule Immune Immune Tolerance Immune response Immunity Immunotherapeutic agent Inflammatory Inflammatory Response L-Selectin Lymphatic Lymphocyte Microanatomy Molecular Monoclonal Antibodies Mus Myofibroblast Nanodelivery Nature Organ Organ Transplantation Pathogenesis Peripheral Phenotype Play Quality Control Reaction Regulation Regulatory T-Lymphocyte Reticular Cell Role Shapes Signal Transduction Signaling Molecule Stromal Cells Sulfate Surface T-Lymphocyte TNFSF5 gene Techniques Therapeutic Time Tissues Transplantation Transplantation Tolerance Tumor Immunity absorption allograft rejection antibody conjugate cytokine design experience experimental study fiber cell immune activation immune modulating agents immunoregulation in vivo innovation insight intradermal injection laminin alpha5 lymph nodes lymphocyte trafficking migration multidisciplinary nanoformulation nanoparticle nanoparticle delivery novel particle prevent programs receptor response sialyl Lewis x stem sugar targeted delivery trafficking venule virtual

项目摘要

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.

核心B-摘要/摘要核心B将提供抗体涂覆的纳米颗粒（NP）和FRC，以进行体内给药以重新编程 LN微环境朝着促进移植耐受性的监管环境。这些策略代表只有在这里团队提出的尖端方法，因此代表与传统方法诱发宽容的根本性。提供了这些技术核心B为开发旨在重新编程的一流理论的基础奠定了基础 LN的微环境。除了这些数据用于移植的应用外，它们还可以 LN在发病机理中起着核心作用的其他免疫条件中的主要影响（例如自身免疫性疾病和肿瘤免疫史）。该核心将充分表征和合成大量 MECA-79抗层胺α5（LAMA5）和抗CD40L mAb（项目2-Bromberg）的MECA-79载体，AS 以及塞溶剂剂（SAS）（项目1-ABDI）。核心B还将合成染料与NP的染料（包括红外染料）以验证运输到LNS以及控制批次的质量。这将是第一个针对LNS进行药物输送的平台，以重新编程其微环境以降低免疫耐受性。在此外，Core B将扩展与健康小鼠LN分离的FRC，并将完全表征特定于FRC的标记。这些单元将提供给项目1的实验，以评估它们对下调LN纤维化及其对移植耐受性的有害影响。核心B的具体目的如下：目标1。表征和提供抗体偶联的NP，以靶向免疫递送对LN的疗法，以促进移植耐受性。目标2。表征并提供健康的FRC，以供体内给药以促进移植通过重新编程LN微环境来容忍。