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.

摘要 移植领域取得了许多重大突破，包括发展 免疫调节分子(IRMS)是器官移植成功的关键。然而， IRMS的使用因缺乏有效性和毒性而受到阻碍，并与器官的发病有关。 失败和加速的心血管疾病，这是移植受者死亡的主要原因。 因此，存在着大量未得到满足的医疗需求，以开发新的策略来提高疗效和 降低IRMS的毒性。现有的药物通常是足够有效的，当专门针对他们的 目标部位，因此靶向给药方法可以增强其安全性和有效性 值得注意的是，在减少开发新药的需求的同时，这一过程可能非常昂贵，劳动力- 强度大、耗时长。尽管使用纳米技术的靶向给药代表着高度的 有希望的和创新的局部给药策略，其在移植中的应用仍有待于 发展起来的。 这项提案的总体目标是为移植中的IRMS开发一种靶向给药系统， 最终目标是提高它们的疗效，减少它们的毒性。在移植中，提出 引流淋巴结(DLN)中受者T细胞的供体同种异体抗原是产生DLN的基础 同种异体反应性T细胞进入同种异体移植物并引起同种异体移植物排斥反应。对此的总体假设是 建议有针对性地向DLN提供IRMS不仅会增加它们的疗效，而且还会减少 通过显著减少全身用药量来降低其毒性。 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IRMS递送到DLN 促进同种异体心脏移植的接受度。我们将主要关注小鼠同种异体心脏移植的存活，通过设计一种 与我们的靶向递送平台相结合的治疗策略，以解决当前未得到满足的 移植中更安全、更有效的治疗方法。在目标2中，我们计划评估 我们的主动靶向递送平台可延长同种异体心脏移植物的存活时间。机械论研究将 还允许改进我们的定向递送方法的设计。这些实验将使用小鼠 心脏移植模型，成熟的功能分析和复杂的成像研究，以更好地了解 IRMS及其纳米载体的生物分布。在目标3中，我们计划继续我们的初步数据，以产生 在设计一种针对非人类灵长类动物DLN的IRMS靶向方法中的概念验证数据。这 多学科、协作的方法提出了一个新的定向交付平台，该平台可能会 移植中免疫抑制治疗方法的范例。