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.

抽象的移植是治疗终末期器官疾病最有效的方法。临床上，有两个重要的危险因素移植结果不佳的原因是移植前受者体内存在供者反应性 T 细胞，而移植前移植物冷缺血储存（CIS）时间的长度。在肾移植患者中，预移植后循环供体反应性记忆 T 细胞的存在与急性急性白血病风险增加相关排斥反应、移植物功能延迟和下降以及长期移植物存活率较差。在未致敏的情况下对于受者来说，记忆 T 细胞的供体反应性是由于异源（交叉反应）免疫所致。然而，激活同种异体移植物内供体反应性内源性记忆 T 细胞介导急性移植物损伤的机制仍然知之甚少。长时间的 CIS 会增加缺血再灌注损伤 (IRI)，其特点是产生活性氧和促炎细胞因子，直接浸润受体白细胞进入移植物并引起移植物内这些细胞的激活。 IRI 还诱导移植物释放损伤受损和垂死细胞的相关分子模式 (DAMP) 会加剧炎症并促进导致高风险同种异体移植结果更差。我们之前表明，这两个导致移植不良的危险因素结果是相互关联的。心脏移植后持续的高炎症环境同种异体移植物经受长时间的 CIS 对于供体反应性记忆 T 细胞的充分激活是必要的介导未致敏受体的共刺激阻滞抵抗性急性排斥反应。多次临床移植研究表明，同种异体移植物损伤期间，循环中的一种 DAMP（无细胞 DNA）升高，代表了一种有前途的非侵入性生物标志物，用于早期检测急性排斥反应。另外，最近的工作我们的合作者发现了激活细胞游离 DNA 的先天免疫传感器，例如可以识别线粒体 DNA (mtDNA) 的 TLR9。这些研究结果和我们目前的初步数据使我们推测，持续的 CIS 和随后的 IRI 增加可增强 mtDNA 的释放，从而导致 TLR9 更大的激活和下游 I 型 IFN 产生，触发由内源性供体反应性记忆 T 细胞维持的促炎症循环介导急性移植物损伤。该假设将使用我们的血管化小鼠在两个特定目标上进行测试异位心脏移植模型：首先，我们将测试体内 TLR9 信号传导的调节，以评估对心脏移植的影响供体反应性记忆T细胞介导的急性移植物损伤；其次，我们将测试以下机制： I 型干扰素有助于早期移植后炎症和供体反应性 T 细胞的激活调解拒绝。我们预计这些研究将确定治疗策略的新目标，以改善通过抑制先天免疫介导的内源性供体的早期激活来实现实体器官移植的结果反应性记忆T细胞引起急性移植物损伤。