Endogenous memory T cell mediated rejection of high-risk cardiac allografts

内源性记忆T细胞介导的高风险同种异体心脏移植排斥反应

基本信息

批准号：
10748492
负责人：
Erik Harrison Koritzinsky
金额：
$ 5.27万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10748492
关键词：
Acute Adoption Allogenic Allografting Antigens Blood Transfusion CD8-Positive T-Lymphocytes CTLA4-Ig Calcineurin inhibitor Cardiovascular system Cells Chronic Circulation Clinic Clinical Clinical Trials Complex Data Disease Endothelial Cells Environment Epidermal Growth Factor Receptor Event Exposure to Generations Goals Graft Survival Heart Transplantation IFNAR1 gene Immune Immunity Immunosuppression Incidence Infiltration Inflammation Inflammatory Inflammatory Response Injury Interferon Type I Interferon alpha Interferons Interleukin-1 beta Interleukin-6 Ischemia Kidney Kidney Transplantation Length Leukocytes Link Maintenance Mediating Memory Mitochondrial DNA Modeling Molecular Mus Myeloid Cell Activation Organ Organ Transplantation Outcome Pathway interactions Patient-Focused Outcomes Patients Pattern Phase Pregnancy Process Production Proliferating Reactive Oxygen Species Reperfusion Injury Reperfusion Therapy Resistance Risk Risk Factors Series Signal Transduction Solid T cell infiltration T memory cell T-Cell Activation T-Cell Proliferation T-Lymphocyte TNF gene Testing Time Tissue Grafts Tissues Toxic effect Transplant Recipients Transplantation Vascularization Work allograft rejection cell free DNA cell mediated immune response clinically relevant cohort cross reactivity cytokine early detection biomarkers effective therapy experimental study graft function heart allograft high risk immune activation improved improved outcome in vivo inflammatory milieu injured insight interest new therapeutic target novel novel strategies pathogen pharmacologic post-transplant response sensor side effect tissue injury transplant model type I interferon receptor

项目摘要

ABSTRACT Transplantation is the most effective treatment for end-stage organ diseases. Clinically, two important risk factors for poor transplant outcomes are the pre-transplant presence of donor-reactive T cells in the recipient and the length of graft cold ischemic storage (CIS) time prior to transplant. In kidney transplant patients, the pre- transplant presence of circulating donor-reactive memory T cells is associated with an increased risk of acute rejection episodes, delayed and decreased graft function and worse long-term graft survival. In unsensitized recipients, donor-reactivity of memory T cells is due to heterologous (cross-reactive) immunity. However, the mechanisms activating donor-reactive endogenous memory T cells within allografts to mediate acute graft injury remain poorly understood. Prolonged CIS increases ischemia-reperfusion injury (IRI), which is characterized by production of reactive oxygen species and proinflammatory cytokines that direct infiltration of recipient leukocytes into the graft and cause activation of these cells within the graft. IRI also induces the graft to release damage associated molecular patterns (DAMPs) from injured and dying cells that exacerbate inflammation and contribute to worse outcomes in higher risk allografts. We previously showed that these two risk factors for poor transplant outcomes are linked. The sustained high-inflammatory environment seen following transplant of cardiac allografts subjected to prolonged CIS is necessary for sufficient activation of donor-reactive memory T cells to mediate costimulatory blockade resistant acute rejection in unsensitized recipients. Multiple clinical transplant studies have shown that one DAMP, cell-free DNA is elevated in the circulation during allograft injury, representing a promising non-invasive biomarker for early detection of acute rejection. Additionally, recent work from our collaborators has found new, pharmacologically targetable signaling partners required for activation of innate immune sensors of cell free DNA, such as TLR9 which can recognize mitochondrial DNA (mtDNA). These findings and our current preliminary data have led us to hypothesize that prolonged CIS and subsequent increased IRI enhance the release of mtDNA, leading to greater TLR9 activation and downstream type I IFN production, triggering a pro-inflammatory cycle that is sustained by endogenous donor-reactive memory T cell mediated acute graft injury. This hypothesis will be tested in two specific aims using our vascularized mouse heterotopic heart transplant model: first, we will test modulation of TLR9 signaling in vivo to assess impact on donor-reactive memory T cell mediated acute graft injury; and second, we will test the mechanism(s) by which type I interferon contributes to early post-transplant inflammation and activation of donor-reactive T cells to mediate rejection. We anticipate that these studies will identify new targets for therapeutic strategies to improve solid organ transplant outcomes by inhibiting innate immune-mediated early activation of endogenous donor- reactive memory T cells to cause acute graft injury.

抽象的移植是终末期器官疾病的最有效治疗方法。临床上，两个重要的风险因素对于不良的移植预后，是移植前的前植物存在供体反应性T细胞和受体中的供体反应性T细胞移植前移植冷缺血储存（CI）的长度。在肾脏移植患者中，循环供体反应记忆T细胞的移植存在与急性风险增加有关排斥发作，移植功能延迟和降低以及长期移植物存活率较差。在未经敏感的情况下受体，记忆T细胞的供体反应性是由于异源（交叉反应性）免疫。但是，同种异体移植物中激活供体反应性内源性记忆T细胞以介导急性移植损伤的机制保持不当理解。长时间的顺式增加缺血 - 再灌注损伤（IRI），其特征是产生活性氧和促炎细胞因子，这些细胞因子直接浸润。进入移植物并在移植物中引起这些细胞的激活。 IRI还诱导移植物释放损坏来自受伤和垂死的细胞的相关分子模式（湿）加剧炎症并有助于在较高的同种异体移植中，结果更糟糕。我们先前表明，这两个差移植的危险因素结果是链接的。心脏移植后看到的持续高炎症环境经受长时间顺式的同种异体移植对于足够激活供体反应记忆T细胞是必要的介导未敏感的接受者中的抗刺激性阻滞性抗抑制作用。多次临床移植研究表明，在同种异体移植损伤期间，一个无细胞的DNA在循环中升高，代表有希望的非侵入性生物标志物，用于早期检测急性排斥。此外，最近的工作从我们的合作者那里发现，激活的新型，具有药理目标的信号合作伙伴无细胞DNA的先天免疫传感器，例如可以识别线粒体DNA（mtDNA）的TLR9。这些调查结果和我们当前的初步数据使我们假设延长顺式和随后的 IRI增加增强了mtDNA的释放，从而导致TLR9激活和下游I型IFN的释放生产，触发促炎周期，该周期由内源性供体反应记忆T细胞持续介导的急性移植损伤。该假设将使用我们的血管化小鼠以两个特定的目的进行检验异位心脏移植模型：首先，我们将测试体内TLR9信号传导的调制以评估对对的影响供体反应记忆T细胞介导的急性移植损伤；其次，我们将测试该机制 I型干扰素有助于早期移植后炎症和供体反应性T细胞的激活中介排斥。我们预计这些研究将确定用于改进治疗策略的新目标通过抑制先天免疫介导的内源供体的早期激活 - 反应性记忆T细胞会导致急性移植损伤。