Targeted immune therapies in heart transplantation

心脏移植中的靶向免疫治疗

• 批准号: 10573846
• 负责人: Reza Abdi
• 金额: $ 105.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2030-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573846
• 关键词: Acute; Adopted; Alloantigen; Allografting; Antibody-drug conjugates; Biological Assay; Chronic; Data; Drug Delivery Systems; Drug Targeting; Generations; Goals; Heart Diseases; Heart Transplantation; Immune; Immune Targeting; Immunotherapeutic agent; Immunotherapy; Infection; Kinetics; Life; Malignant Neoplasms; Metabolic syndrome; Methods; Modeling; Mus; Nanotechnology; Organ; Patients; Phenotype; Research; T-Lymphocyte; Techniques; Therapeutic; Therapeutic Uses; Therapeutic immunosuppression; Time; Tissues; Toxic effect; Transplant Recipients; Transplantation; allograft rejection; clinical application; collaborative approach; dosage; draining lymph node; experimental study; heart allograft; imaging study; improved; improved outcome; innovation; interest; mouse model; multidisciplinary; nanoparticle; novel; post-transplant; prevent; programs; targeted delivery; targeted treatment; trafficking; transplant model

Abstract Heart transplantation has become the mainstay lifesaving therapeutic strategy for a growing number of patients with irreversible, end-stage heart disease. However, numerous challenges must be met to improve long term heart allograft rejection. Although immune therapeutics (ITs) used to prevent rejection have improved over time, they are still unable to eliminate acute and chronic rejection effectively. The use of more intense and potent IT regimens, adopted commonly by transplant programs, can reduce the survival of heart transplant patients by increasing their chances of developing metabolic syndrome, post-transplant malignancy, and serious infection. Therefore, a significant unmet need exists to develop novel and innovative strategies to increase the efficacy of ITs and to reduce their toxicity. Although targeted drug delivery using nanotechnology or antibody-drug conjugates (ADCs) has sparked great interest in the cancer field, its application to transplantation remains to be developed. Over the past several years, we have made major strides to introduce a wide range of targeted therapeutics to the heart transplantation research field. In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLN) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause rejection. The overall hypothesis of this proposal is that targeted delivery of ITs to the DLN and allografts not only increases the efficacy of ITs, but it also decreases their toxicity through reduction of their systemic dosage. In this proposal, we devise a clinically applicable active targeted delivery method for ITs to LNs and organs to promote allograft acceptance in murine models of heart transplantation. We also plan to examine the operating mechanisms that result in prolongation of heart allograft survival by our active targeted delivery platform. These experiments will employ murine heart transplant models, nanoparticle synthesis, advanced antibody-drug conjugation, comprehensive immune phenotyping assays, and sophisticated imaging studies to understand the kinetics of T cell trafficking and payloads in the tissue. Supported by our extensive expertise, as well as established models, techniques, and data, this multidisciplinary collaborative approach sets forth for the first time a well-balanced, innovative, and clinically applicable targeted delivery platform. The studies proposed here have the potential to yield results that could be paradigm-shifting in our approach to immunosuppressive therapy in transplantation.

抽象的 心脏移植已成为越来越多患者的主要救生治疗策略 患有不可逆转的终末期心脏病。然而，要改善长期发展，必须应对众多挑战 同种异体心脏移植排斥反应。尽管用于预防排斥反应的免疫疗法（IT）随着时间的推移而得到改善， 他们仍然无法有效消除急性和慢性排斥反应。使用更密集、更有效的 IT 移植计划普遍采用的治疗方案可以通过以下方式降低心脏移植患者的生存率： 增加他们患代谢综合征、移植后恶性肿瘤和严重感染的机会。 因此，开发新颖和创新的策略以提高疗效的需求存在重大未满足的需求。 IT 并降低其毒性。尽管使用纳米技术或抗体药物进行靶向药物输送 偶联物（ADC）引起了癌症领域的极大兴趣，其在移植中的应用仍有待进一步研究 发达。在过去的几年里，我们取得了重大进展，推出了一系列有针对性的 心脏移植治疗研究领域。在移植中，将供体同种异体抗原呈递给 引流淋巴结 (DLN) 中的受体 T 细胞是同种异体反应性 T 细胞生成的基础， 运输到同种异体移植物并导致排斥反应。该提案的总体假设是有针对性地交付 IT DLN 和同种异体移植物不仅增加了 IT 的功效，而且还通过降低其毒性 减少其全身剂量。在这个提案中，我们设计了一种临床适用的主动靶向递送 一种将 IT 应用于 LN 和器官以促进小鼠心脏移植模型中同种异体移植物接受的方法。我们 还计划通过我们的积极研究来检查导致同种异体心脏移植物存活时间延长的操作机制 有针对性的交付平台。这些实验将采用小鼠心脏移植模型、纳米颗粒 合成、先进的抗体-药物偶联、全面的免疫表型分析以及复杂的 成像研究，以了解组织中 T 细胞运输和有效负载的动力学。由我们的支持 广泛的专业知识以及已建立的模型、技术和数据，这种多学科协作 该方法首次提出了一种均衡、创新且临床适用的靶向给药方法 平台。这里提出的研究有可能产生可能改变我们的范式的结果 移植中免疫抑制治疗的方法。