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.

项目摘要/摘要 器官移植是对不可逆器官损伤患者的关键疗法。短期结局是 出色，但大多数患者最终由于随着时间的流逝而慢性免疫介导的损伤，最终失去了器官。 缺血再灌注损伤（IRI）在移植中不可避免，并且是先天性的主要激活因子 移植后早期的免疫反应增强了急性和慢性同种异体移植率 拒绝随后。此外，存在可用于移植的器官的严重短缺， 这促使临床医生使用年龄较大或更合并症的捐助者的器官。这些 器官对缺血性损伤具有更大的敏感性。因此，IRI的关联随增加 同种异体移植免疫原性具有非常广泛的临床意义。出现了COTIMIMULATION BLOCKADE（CB） 最近，作为一种非常有前途的治疗方法，具有较高的微血管和 代谢安全性比钙调神经酶抑制剂。但是，CB与急性率提高有关 转移后早期的同种异移植排斥。我们的数据表明IRI废除了 CB的耐受作用。因此，移植的关键需求是更好地了解 IRI及其激活先天免疫反应增强移植排斥的机制，如 新型的治疗方案可预防或改善iri诱导的同种异体免疫性，可以帮助减少慢性 拒绝。我们的主要目标是揭示IRI增加移植拒绝的潜在机制。 根据我们的数据，我们的主要假设是，IRI通过a）增加早期内部 - 移植炎症反应和b）通过 独特的微解剖学变化。我们已经表明，早期移植内炎症反应的发挥作用 在增强同种免疫性方面的关键作用。我们还在这里提议首次使用纳米颗粒 将免疫疗法的靶向递送到DLN中，以减少iri诱导的同种免疫性。在AIM 1中， 我们将研究IRI在供体树突状细胞中自噬的诱导如何产生促炎的环境 在增强同种异体免疫力的器官中。在AIM 2中，我们将研究iri的机制 将DLN微型解剖学素数放大，以扩大同种免疫反应。在AIM 3中，我们将发展 纳米颗粒将CB靶向递送到DLN，以增强其耐受作用 减少IRI的有害影响。