Lymph Node Delivery in Transplantation

移植中的淋巴结输送

基本信息

批准号：
10650172
负责人：
Reza Abdi
金额：
$ 46.3万
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：
2022
资助国家：
美国
起止时间：
2022-06-18 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650172
关键词：
Acceleration Achievement Address Affinity Alloantigen Allograft Tolerance Allografting Antibody-drug conjugates Antigens Biodistribution Biological Assay CD3 Antigens Cardiovascular Diseases Cardiovascular system Cause of Death Cells Consumption Data Development Dose Drug Delivery Systems Drug Kinetics Drug Targeting Encapsulated Engineering Equilibrium Failure Family Formulation Future Generations Goals Graft Rejection Heart Transplantation High Endothelial Venule Immune Immunobiology Lymphatic Malignant Neoplasms Mammals Medical Membrane Proteins Metabolic syndrome Methods Molecular Monoclonal Antibodies Morbidity - disease rate Mus Nanodelivery Nanotechnology Organ Organ Transplantation Organ failure Outcome Pathogenesis Patients Peripheral Pharmaceutical Preparations Process Regulatory T-Lymphocyte Research Safety Shapes Sirolimus Site Skin Transplantation Surface System T-Lymphocyte Techniques Testing Therapeutic Therapeutic immunosuppression Time Toxic effect Transplant Recipients Transplantation absorption allograft rejection clinical application collaborative approach combinatorial design dosage draining lymph node effector T cell efficacious treatment experimental study heart allograft imaging study immunoregulation improved in vivo innovation intradermal injection lymph nodes multidisciplinary nanocarrier nanoparticle nonhuman primate novel novel strategies novel therapeutics success sugar surface coating targeted delivery transplant model virtual

Acceleration Achievement Address Affinity Alloantigen Allograft Tolerance Allografting Antibody-drug conjugates Antigens Biodistribution Biological Assay CD3 Antigens Cardiovascular Diseases Cardiovascular system Cause of Death Cells Consumption Data Development Dose Drug Delivery Systems Drug Kinetics Drug Targeting Encapsulated Engineering Equilibrium Failure Family Formulation Future Generations Goals Graft Rejection Heart Transplantation High Endothelial Venule Immune Immunobiology Lymphatic Malignant Neoplasms Mammals Medical Membrane Proteins Metabolic syndrome Methods Molecular Monoclonal Antibodies Morbidity - disease rate Mus Nanodelivery Nanotechnology Organ Organ Transplantation Organ failure Outcome Pathogenesis Patients Peripheral Pharmaceutical Preparations Process Regulatory T-Lymphocyte Research Safety Shapes Sirolimus Site Skin Transplantation Surface System T-Lymphocyte Techniques Testing Therapeutic Therapeutic immunosuppression Time Toxic effect Transplant Recipients Transplantation absorption allograft rejection clinical application collaborative approach combinatorial design dosage draining lymph node effector T cell efficacious treatment experimental study heart allograft imaging study immunoregulation improved in vivo innovation intradermal injection lymph nodes multidisciplinary nanocarrier nanoparticle nonhuman primate novel novel strategies novel therapeutics success sugar surface coating targeted delivery transplant model virtual

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项目摘要

Abstract The transplantation field has witnessed many major breakthroughs, including the development of immunoregulatory molecules (IRMs), which have been key to the success of organ transplantation. However, the use of IRMs is hindered by lack of efficiency and toxicity, and it is implicated in the pathogenesis of organ failure and accelerated cardiovascular disease, which is the leading cause of death in transplant recipients. Therefore, a substantial unmet medical need exists to develop novel strategies to increase the efficacy and reduce the toxicity of IRMs. The existing drugs are often adequately potent when directed specifically to their intended sites, so methods of targeted drug delivery could potentiate their safety and efficacy profiles significantly, while reducing the need for creating new drugs, a process that can be extremely expensive, labor- intensive, and time-consuming. Although targeted drug delivery using nanotechnology represents a highly promising and innovative strategy for site-specific drug delivery, its application to transplantation remains to be developed. The overall goal of this proposal is to develop a targeted drug delivery system for IRMs in transplantation, with the ultimate goal of increasing their efficacy and diminishing their toxicity. In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLNs) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause allograft rejection. The overall hypothesis of this proposal is that targeted delivery of IRMs to the DLN would not only increase their efficacy, but also decrease their toxicity by significantly reducing systemic dosage. In Aim 1, we plan to devise a clinically applicable active targeted method of delivering IRMs to the DLNs to promote heart allograft acceptance. We will focus primarily on murine heart allograft survival by devising a combinatorial therapeutic strategy with our targeted delivery platform to address the immediate unmet need for safer and more efficacious therapies in transplantation. In Aim 2, we plan to evaluate the mechanism of prolongation of heart allograft survival by our active targeted delivery platform to DLNs. Mechanistic studies will also permit improvement of the design of our targeted delivery method. These experiments will employ murine heart transplant models, established functional assays, and sophisticated imaging studies to understand better the biodistribution of IRMs and their nanocarriers. In Aim 3, we plan to pursue our preliminary data to generate proof-of-concept data in devising a method of targeting IRMs to DLNs in non-human primates. This multidisciplinary, collaborative approach sets forth a novel targeted delivery platform that could potentially shift the paradigm of the approach to immunosuppressive therapy in transplantation.

抽象的移植场见证了许多重大突破，包括发展免疫调节分子（IRMS），这是器官移植成功的关键。然而，缺乏效率和毒性阻碍了IRM的使用，这与器官的发病机理有关失败和加速心血管疾病，这是移植受者死亡的主要原因。因此，存在着巨大的未满足医疗需求，以制定新的策略来提高功效和降低IRM的毒性。专门针对其其专门针对其的现有药物通常是足够的预期的地点，因此有针对性的药物输送方法可以增强其安全性和有效性。值得注意的是，同时减少了创建新药的需求，这一过程可能非常昂贵，劳动力 - 密集和耗时。尽管使用纳米技术的有针对性的药物输送代表了高度特定于现场药物的有前途和创新的策略，其在移植中的应用仍然是发达。该提案的总体目标是开发针对IRMS移植的目标药物输送系统，以提高其疗效并降低其毒性的最终目标。在移植中，表示排水淋巴结（DLNS）中对受体T细胞的供体同种抗原是生成的基础同种异体传播并引起同种异体移植排斥的同种异体T细胞。总体假设建议是，将IRM的目标交付到DLN不仅会提高其疗效，而且还会降低它们的毒性通过大大降低全身剂量。在AIM 1中，我们计划设计一种临床适用的主动靶向方法，将IRM传递到DLNS 促进心脏同种异体的接受。我们将通过设计一个组合治疗策略与我们的目标交付平台，以满足直接未满足的需求在移植方面更安全，更有效的疗法。在AIM 2中，我们计划评估我们的主动靶向输送平台向DLN延长心脏同种异体移植的生存。机械研究将还允许改进目标交付方法的设计。这些实验将采用鼠心脏移植模型，已建立的功能测定和复杂的成像研究，以更好地理解 IRMS及其纳米载体的生物分布。在AIM 3中，我们计划追求初步数据以生成概念验证数据在设计一种将IRM靶向非人类灵长类动物中的DLN的方法。这多学科的协作方法提出了一个新颖的目标交付平台，可能会改变移植中免疫抑制治疗方法的范例。