Targeted immune therapies in heart transplantation

摘要 心脏移植已成为越来越多患者的主要挽救生命的治疗策略 患有不可逆转的终末期心脏病。然而，必须应对众多挑战才能长期改善 心脏移植排斥反应。尽管用于预防排斥反应的免疫疗法(ITS)随着时间的推移而有所改进， 他们仍然无法有效地消除急性和慢性排斥反应。使用更密集、更强大的IT 移植项目通常采用的方案可以通过以下方式减少心脏移植患者的存活率 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，存在着一项尚未得到满足的重大需求，即开发新的和创新的战略，以提高防治艾滋病的效力。 并降低它们的毒性。尽管使用纳米技术或抗体药物的靶向给药 结合物(ADC)在肿瘤领域引起了极大的兴趣，其在移植中的应用尚待进一步研究 发展起来的。在过去的几年里，我们取得了重大进展，推出了广泛的有针对性的 治疗学走向心脏移植研究领域。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细胞是产生同种异体反应性T细胞的基础 交通到同种异体移植物并引起排斥反应。这项提议的总体假设是，有针对性地交付其 对于DLN和同种异体移植，不仅提高了其疗效，而且通过以下途径降低了其毒性 减少他们的全身剂量。在这项建议中，我们设计了一种临床适用的主动靶向递送 在小鼠心脏移植模型中促进同种异体移植接受性的方法。我们 还计划检查导致同种异体心脏移植物存活延长的操作机制 定向投放平台。这些实验将使用小鼠心脏移植模型，纳米颗粒 合成、先进的抗体-药物结合、全面的免疫表型分析和尖端技术 成像研究以了解T细胞在组织中的运输和有效载荷的动力学。由我们的 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 方法首次提出了一种平衡的、创新的和临床适用的定向递送 站台。这里提出的研究有可能产生可能改变我们的 移植中免疫抑制治疗的探讨。

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.