IRI, innate immunity and transplant rejection

IRI、先天免疫和移植排斥

• 批准号: 10371989
• 负责人: Reza Abdi
• 金额: $ 46.34万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10371989
• 关键词: Acute; Address; Alloantigen; Allografting; Anatomy; Autophagocytosis; Binding; Calcineurin inhibitor; Chronic; Clinical; Data; Dendritic Cells; Disease; Dose; Equilibrium; Extracellular Matrix; Goals; Graft Rejection; Heart; Heart Transplantation; High Endothelial Venule; Homing; Hour; IL6 gene; ITGAX gene; Immune; Immune response; Immunity; Immunomodulators; Immunotherapeutic agent; Inflammatory; Inflammatory Response; Injections; Injury; Innate Immune Response; Interleukin-6; Knowledge; Life; Lymphoid Tissue; Mediating; Metabolic; Methods; Monoclonal Antibodies; Mus; Nano delivery; Natural Immunity; Organ; Organ Donor; Organ Transplantation; Outcome; Patients; Phase; Play; Predisposition; Production; Regimen; Regulatory T-Lymphocyte; Reperfusion Injury; Reticular Cell; Role; Safety; Savings; Site; Stromal Cells; T-Lymphocyte; Testing; Therapeutic; Time; Transgenic Mice; Transplant Recipients; Transplantation; allograft rejection; chemokine; clinical efficacy; comorbidity; conditional knockout; draining lymph node; effector T cell; experimental study; immune activation; immunogenicity; immunoregulation; improved; inflammatory milieu; ischemic injury; isoimmunity; lymph nodes; lymphatic vessel; nanocarrier; nanoparticle; novel; novel therapeutics; operation; optimal treatments; post-transplant; prevent; response; surface coating; targeted delivery; time use; trafficking; transplant model

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.

项目概要/摘要 器官移植是治疗不可逆器官损伤患者的重要疗法。短期结果是 很好，但随着时间的推移，大多数患者最终会由于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，也是先天性损伤的主要激活因素。 移植后早期的免疫反应，提高急性和慢性同种异体移植的发生率 随后拒绝。此外，全球范围内可用于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多的捐献者的器官。这些 器官对缺血性损伤的敏感性要高得多。因此，IRI 与增加的关联 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）已经出现 最近作为一种非常有前途的移植治疗方法，具有远远优越的微血管和 代谢安全性优于钙调神经磷酸酶抑制剂。然而，CB 与急性发病率增加有关 移植后早期阶段的同种异体移植排斥反应。我们的数据表明 IRI 废除了 CB的致耐受作用。因此，移植中一个关键的未满足的需求是更好地了解 IRI 及其对先天免疫反应的激活增强移植排斥的机制，如 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) 增加早期体内免疫 移植物炎症反应和 B) 通过以下方式启动移植受者的引流淋巴结 (DLN) 独特的显微解剖变化。我们已经证明早期移植物内炎症反应起着 在增强同种免疫中发挥关键作用。我们还首次在此提出使用纳米颗粒 将免疫治疗药物靶向递送至 DLN，以减少 IRI 诱导的同种免疫。在目标 1 中， 我们将研究 IRI 如何诱导供体树突状细胞自噬，从而创造促炎环境 在增强同种免疫的器官内。在 AIM 2 中，我们将研究 IRI 的机制 移植物在显微解剖学上启动 DLN，以增强同种免疫反应。在AIM 3中，我们将开发 纳米颗粒用于将 CB 靶向递送至 DLN，以增强其耐受性作用 减少 IRI 的有害影响。