Lymph Node Delivery in Transplantation

移植中的淋巴结输送

• 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
• 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

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 移植领域取得了许多重大突破，其中包括 免疫调节分子（IRM）是器官移植成功的关键。然而， IRM 的使用因缺乏效率和毒性而受到阻碍，并且与器官的发病机制有关 衰竭和加速心血管疾病，这是移植受者死亡的主要原因。 因此，存在大量未满足的医疗需求来开发新的策略来提高疗效和 降低 IRM 的毒性。现有的药物在专门针对其目标时通常具有足够的效力。 预定位点，因此靶向药物输送方法可以增强其安全性和有效性 显着，同时减少了创造新药的需求，这一过程可能非常昂贵，劳动力 密集且耗时。尽管使用纳米技术的靶向药物输送代表了高度 定点药物递送的前景广阔且创新的策略，其在移植中的应用仍有待研究 发达。 该提案的总体目标是为移植中的 IRM 开发靶向药物递送系统， 最终目标是提高其功效并减少其毒性。在移植中，呈现 引流淋巴结 (DLN) 中受体 T 细胞的供体同种异体抗原是产生 同种异体反应性 T 细胞运输至同种异体移植物并引起同种异体移植物排斥。本次的总体假设 建议将 IRM 定向递送至 DLN 不仅会提高其功效，还会降低 通过显着降低全身剂量来降低其毒性。 在目标 1 中，我们计划设计一种临床适用的主动靶向方法，将 IRM 递送至 DLN 促进心脏同种异体移植的接受。我们将主要关注小鼠心脏同种异体移植物的存活，通过设计 与我们的靶向递送平台的组合治疗策略，以满足当前未满足的需求 移植治疗更安全、更有效。在目标 2 中，我们计划评估以下机制： 通过我们的 DLN 主动靶向递送平台延长心脏同种异体移植物的存活率。机理研究将 还可以改进我们有针对性的交付方法的设计。这些实验将使用小鼠 心脏移植模型、已建立的功能测定和复杂的成像研究，以更好地了解 IRM 及其纳米载体的生物分布。在目标 3 中，我们计划追求初步数据以生成 设计一种在非人类灵长类动物中将 IRM 靶向 DLN 的方法的概念验证数据。这 多学科协作方法提出了一个新颖的有针对性的交付平台，该平台可能会改变 移植中免疫抑制治疗方法的范例。