IRI, innate immunity and transplant rejection

项目摘要/摘要 器官移植是治疗不可逆器官损伤的关键疗法。短期结果是 很好，但随着时间的推移，大多数患者最终会因为慢性免疫介导的损伤而失去器官。 缺血再灌注损伤(IRI)是移植过程中不可避免的，也是先天的主要激活物 移植后早期的免疫反应提高了急性和慢性同种异体移植物的发生率 随后拒绝。此外，世界范围内可供移植的器官严重短缺， 这促使临床医生使用年龄较大或合并疾病较多的捐赠者的器官。这些 器官对缺血性损伤的易感性要大得多。因此，与IRI的关联性增加 同种异体移植物的免疫原性具有非常广泛的临床意义。共刺激阻断(CB)已经出现 近年来，作为一种非常有希望的治疗方法，移植的微血管和远端优势 比钙调神经磷酸酶抑制剂的代谢安全性概况。然而，慢性支气管炎与急性心肌梗塞的发生率增加有关。 移植后早期的同种异体排斥反应。我们的数据表明，IRI废除了 CB的致耐受作用。因此，移植中一个尚未得到满足的关键需求是更好地了解 IRI及其对先天免疫反应的激活增强移植排斥反应的机制 预防或改善IRI诱导的同种免疫的新治疗方案可能有助于减少慢性 拒绝。我们的主要目标是揭示IRI增强移植排斥反应的潜在机制。 根据我们的数据，我们的主要假设是，IRI通过以下方式激活同种免疫：A)增加早期内- 移植物炎症反应和B)通过以下途径启动移植受体的引流淋巴(DLN) 独特的显微解剖变化。我们已经证明，移植物内的早期炎症反应在 在增强同种异体免疫中的关键作用。我们还首次在这里提议使用纳米颗粒来 向DLN靶向递送免疫治疗药物以降低IRI诱导的同种免疫。在目标1中， 我们将研究IRI诱导供者树突状细胞自噬是如何创造促炎环境的。 在增强同种异体免疫的器官内。在目标2中，我们将研究IRI的机制 移植物在显微解剖上启动DLN，以放大同种免疫反应。在AIM 3中，我们将开发 靶向向DLN递送CB的纳米粒增强其耐受作用 减少IRI的有害影响。

Project Summary/Abstract Organ transplantation is a critical therapy for patients with irreversible organ damage. Short-term outcomes are excellent, but most patients lose their organs eventually due to chronic immune-mediated injury over time. Ischemia reperfusion injury (IRI) is unavoidable in transplantation and the primary activator of the innate immune response in the early post-transplant period, which enhances the rates of acute and chronic allograft rejection subsequently. Furthermore, a critical worldwide shortage of organs available for transplant exists, which has prompted clinicians to use organs from donors who are older or have greater comorbidity. These organs have much greater susceptibility to ischemic injuries. Therefore, the association of IRI with increased allograft immunogenicity has very broad clinical implications. Costimulatory blockade (CB) has emerged recently as a highly promising therapeutic approach in transplantation with far superior microvascular and metabolic safety profile than calcineurin inhibitors. However, CB is associated with increased rates of acute allograft rejection during the early post-transplantation phase. Our data indicate that IRI abrogates the tolerogenic effect of CB. Therefore, a key unmet need in transplantation is to understand better the mechanisms by which IRI and its activation of the innate immune response potentiates transplant rejection, as novel therapeutic regimens to prevent or ameliorate IRI-induced alloimmunity could assist in reducing chronic rejection. Our main goal is to reveal the underlying mechanisms of augmentation of transplant rejection by IRI. Pursuant to our data, our main hypothesis is that IRI activates alloimmunity by A) increasing the early intra- graft inflammatory response and B) priming the draining lymph node (DLN) of the graft recipient through distinctive microanatomical changes. We have shown that early intra-graft inflammatory responses play a critical role in augmenting alloimmunity. We also propose here for the first-time the use of nanoparticles for targeted delivery of immune therapeutics to the DLN for the reduction of IRI-induced alloimmunity. In AIM 1, we will examine how induction of autophagy in donor dendritic cells by IRI creates a pro-inflammatory milieu within the organs that augments alloimmunity. In AIM 2, we will examine the mechanism by which IRI of the grafts primes the DLN microanatomically to amplify the alloimmune response. In AIM 3, we will develop nanoparticles for the targeted delivery of CB to the DLN for augmentation of their tolerogenic effects in reducing the deleterious effects of IRI.