IRI, innate immunity and transplant rejection

项目总结/摘要 器官移植是治疗不可逆性器官损伤的重要手段。短期结果是 很好，但大多数患者最终由于长期慢性免疫介导的损伤而失去器官。 缺血再灌注损伤（Ischemia reperfusion injury，IRI）是移植过程中不可避免的，是移植器官先天性缺血再灌注损伤的主要激活因子。 移植后早期的免疫反应，这提高了急性和慢性同种异体移植的比率 随后拒绝。此外，全世界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症较重的捐赠者的器官。这些 器官对缺血性损伤的敏感性更高。因此，IRI与增加 同种异体移植免疫原性具有非常广泛的临床意义。共刺激阻断（CB） 最近，作为一种非常有前途的治疗方法，在具有远为上级的微血管和 代谢安全性比钙调磷酸酶抑制剂。然而，CB与急性胰腺炎的发生率增加有关。 在移植后早期阶段的同种异体移植物排斥。我们的数据表明，IRI废除了 CB的致耐受作用。因此，移植中一个关键的未满足的需求是更好地理解 IRI及其激活先天免疫应答增强移植排斥反应的机制，如 预防或改善IRI诱导的同种异体免疫的新治疗方案可以帮助减少慢性免疫缺陷。 排斥反应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A）增加早期细胞内 移植物炎症反应和B）通过以下途径引发移植物受体的引流淋巴结（DLN 独特的显微解剖学变化。我们已经证明，早期移植物内炎症反应在移植物的存活中起着重要作用。 在增强同种免疫中的关键作用。我们还首次提出使用纳米粒子 将免疫治疗剂靶向递送至DLN以减少IRI诱导的同种异体免疫。在AIM 1中， 我们将研究IRI如何诱导供体树突状细胞的自噬， 增强同种免疫力的器官在AIM 2中，我们将研究IRI的机制。 移植物在显微解剖学上引发DLN以放大同种免疫应答。在AIM 3中，我们将开发 用于将CB靶向递送至DLN以增强其致耐受性作用的纳米颗粒， 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.