Targeted immune therapies in heart transplantation

摘要 心脏移植已成为越来越多的患者的主要救生治疗策略 患有不可逆的晚期心脏病然而，必须应对许多挑战，以改善长期 心脏移植排斥反应虽然用于预防排斥反应的免疫疗法（IT）随着时间的推移而有所改善， 但仍不能有效地消除急性和慢性排斥反应。使用更密集、更有效的IT 移植项目通常采用的方案，可以通过以下方式降低心脏移植患者的存活率： 增加了他们患代谢综合征、移植后恶性肿瘤和严重感染的机会。 因此，存在开发新颖和创新的策略以增加药物治疗的功效的显著未满足的需求。 并降低其毒性。尽管使用纳米技术或抗体-药物靶向给药 尽管ADC在肿瘤领域引起了极大的兴趣，但其在移植中的应用仍有待进一步研究。 开发在过去几年中，我们取得了重大进展，推出了广泛的有针对性的 心脏移植研究领域的新进展。在移植中，将供体同种抗原呈递给 引流淋巴结（DLN）中的受体T细胞是产生同种异体反应性T细胞的基础， 移植物的运输导致排斥反应。本提案的总体假设是，有针对性地提供信息技术 DLN和同种异体移植物不仅增加了IT的疗效，而且还通过以下方式降低了它们的毒性： 减少全身剂量。在这个建议中，我们设计了一个临床上适用的主动靶向给药 在心脏移植的小鼠模型中，用于淋巴结和器官的IT促进同种异体移植物接受的方法。我们 我们还计划研究通过我们的活性药物延长心脏移植物存活的作用机制。 目标交付平台。这些实验将采用鼠心脏移植模型、纳米颗粒、纳米颗粒和纳米颗粒。 合成，先进的抗体-药物缀合，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细胞运输和有效载荷的动力学。支持我们的 这种多学科的合作具有广泛的专业知识以及成熟的模型、技术和数据 该方法首次提出了一种平衡、创新和临床适用的靶向递送 平台这里提出的研究有可能产生的结果，可能是范式转移，在我们的 移植中免疫抑制治疗的方法。

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.