Immunoregulatory Mechanisms of IL-33 in Heart Transplantation

IL-33在心脏移植中的免疫调节机制

• 批准号: 10680570
• 负责人: Heth R Turnquist
• 金额: $ 61.07万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680570
• 关键词: Alloantigen; Allogenic; Allografting; Antigens; Arteries; B-Lymphocytes; Blood Vessels; Brain Death; Cause of Death; Cell Communication; Cells; Cessation of life; Childhood; Chronic; Cicatrix; Clinical; Communication; Data; Development; Disease Resistance; Dissection; Event; Fibroblasts; Fibrosis; Generations; Graft Rejection; Growth Factor; Heart Transplantation; Immune; Immune response; Immune system; Immunoglobulins; Immunologics; Immunosuppressive Agents; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Interferon Type II; Interleukin-13; Interleukins; Ischemia; Life; Macrophage; Mediating; Memory; Metabolism; Modeling; Molecular; Mus; Myeloid Cells; Operative Surgical Procedures; Organ Transplantation; Pathologic; Pathway interactions; Pattern; Process; Production; Proliferating; Publishing; Regulatory T-Lymphocyte; Reperfusion Injury; Research; Resolution; Rodent; Sampling; Secondary to; Signal Transduction; Stress; Stromal Cells; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Tissues; Transgenic Mice; Transplant Recipients; Transplantation; Trauma; Vascular Diseases; arginase; chemokine; cytokine; cytotoxicity; directed differentiation; immunoregulation; improved outcome; insight; isoimmunity; monocyte; post-transplant; pre-clinical; prevent; promoter; receptor; repaired; response; response to injury; tissue repair; transcriptomics; transplant model; Alloantigen; Allogenic; Allografting; Antigens; Arteries; B-Lymphocytes; Blood Vessels; Brain Death; Cause of Death; Cell Communication; Cells; Cessation of life; Childhood; Chronic; Cicatrix; Clinical; Communication; Data; Development; Disease Resistance; Dissection; Event; Fibroblasts; Fibrosis; Generations; Graft Rejection; Growth Factor; Heart Transplantation; Immune; Immune response; Immune system; Immunoglobulins; Immunologics; Immunosuppressive Agents; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Innate Immune System; Interferon Type II; Interleukin-13; Interleukins; Ischemia; Life; Macrophage; Mediating; Memory; Metabolism; Modeling; Molecular; Mus; Myeloid Cells; Operative Surgical Procedures; Organ Transplantation; Pathologic; Pathway interactions; Pattern; Process; Production; Proliferating; Publishing; Regulatory T-Lymphocyte; Reperfusion Injury; Research; Resolution; Rodent; Sampling; Secondary to; Signal Transduction; Stress; Stromal Cells; T-Cell Proliferation; T-Lymphocyte; Technology; Testing; Tissues; Transgenic Mice; Transplant Recipients; Transplantation; Trauma; Vascular Diseases; arginase; chemokine; cytokine; cytotoxicity; directed differentiation; immunoregulation; improved outcome; insight; isoimmunity; monocyte; post-transplant; pre-clinical; prevent; promoter; receptor; repaired; response; response to injury; tissue repair; transcriptomics; transplant model

Early graft injury is the consequence of unavoidable transplant-associated events, such as donor brain death, ischemia/reperfusion injury, and surgical trauma. Recipient responses to graft alloantigens will also produce graft damage throughout the life of the graft. These injuries and stresses cause the release of self-molecules containing damage-associated molecular patterns (DAMPs). It is well appreciated that DAMPs support pro- inflammatory responses when they are sensed by cells of the innate immune system, particularly monocytes and macrophages. Preclinical rodent heart transplant studies reveal that these released DAMPs initiate and propagate alloresponses and targeting inflammatory DAMPs, or the signaling cascades they activate, reduce alloimmunity and improve outcomes after transplantation. Yet, our recent research has provided compelling evidence that these graft injuries also release reparative DAMPs (rDAMPs), such as Interleukin-33 (IL-33), which limits local inflammation and initiates immune-mediated tissue repair after heart transplant. By assessing pediatric heart transplant recipient samples and using a preclinical mouse heart transplant model, we identified that IL-33 is upregulated in graft stromal cells and limits the development of allograft vasculopathy and graft fibrosis that later culminates in chronic rejection (CR). Our published and preliminary data suggest that IL-33 mediates this protection by targeting infiltrating monocytes and macrophages, as well as regulatory T cells (Tregs), to limit the generation of pro-inflammatory macrophages and then coordinate a Treg and reparative macrophage-mediated response to injury. While these data are encouraging, our studies also suggest that the processes that initiate repair of early tissue damage may become dysregulated over the graft's life. In preliminary data, we show that vessel-associated Tregs become pathologic when their sustained secretion of repair factors in response to IL-33 promotes the proliferation of local fibroblasts contributing to CR. In addition to having their functions programmed by local rDAMPs, graft infiltrating recipient monocytes recognize allogenic molecules causing them to mature into pro-inflammatory myeloid cells that stimulate T cell proliferation and IFNγ production in the graft. We have established that monocytes and macrophages recognize and develop allospecific cytotoxicity and memory to MHCI antigens via paired immunoglobulin-like receptors-A. These data lead us to HYPOTHESIZE that rDAMP signals initiating the repair of tissue damage early after heart transplantation become dysregulated around the vasculature due to a sustained inflammatory response by alloreactive immune cells. We will test this hypothesis in two aims: In AIM 1, we will define how rDAMP and immune cell interactions evolve in heart transplant microenvironments during CR development. In AIM 2, we will establish if innate alloimmunity prevents effective injury resolution and repair after heart transplantation.

早期草伤是不可避免的移植相关事件的结果，例如供体脑死亡， 缺血/再灌注损伤和手术创伤。接受者对移植物同种剂的反应也将产生移植物 在移植生命中的损害。这些伤害和压力导致自分子的释放 包含与损伤相关的分子图案（湿）。非常感谢潮湿支持支持 当炎症反应被先天免疫系统的细胞感测时，尤其是单核细胞 和巨噬细胞。临床前啮齿动物心脏移植研究表明，这些释放的潮湿启动和 传播同种酶和靶向炎症湿或激活的信号级联 同种免疫力和移植后改善结果。但是，我们最近的研究提供了引人注目的 这些移植物损伤还释放了修复性潮湿（RDAMP），例如白介素33（IL-33） 限制局部炎症并引发心脏移植后免疫介导的组织修复。通过评估 小儿心脏移植受者样本并使用临床前小鼠心脏移植模型，我们确定了 IL-33在移植基质细胞中进行了更新，并限制了同种异体血管病和移植物的发展 纤维化后来在慢性排斥（CR）中达到高潮。我们发布的初步数据表明IL-33 通过靶向浸润的单核细胞和巨噬细胞以及调节性T细胞来介导这种保护 （Tregs），限制促炎性巨噬细胞的产生，然后协调treg并修复 巨噬细胞介导的对损伤的反应。尽管这些数据令人鼓舞，但我们的研究也表明 启动早期组织损伤修复的过程可能会在移植物的生活中失调。在初步 数据，我们表明，当血管相关的Treg持续分泌修复因子时，Treg会成为病理 对IL-33的响应促进了导致CR的局部成纤维细胞的扩散。除了拥有他们的 由局部rdamps编程的功能，移植浸润的受体单核细胞识别同源分子 使它们成熟成促炎性髓样细胞，刺激T细胞增殖和IFNγ产生 我们已经确定，单核细胞和巨噬细胞认可并发展了同种类繁殖 通过成对的免疫球蛋白样受体-A对MHCI抗原的细胞毒性和记忆。这些数据导致我们进入 假设RDAMP信号会启动心脏移植后早期修复组织损伤 由于同种异体免疫的持续炎症反应，在脉管系统周围变得失调 细胞。我们将以两个目的检验该假设：在AIM 1中，我们将定义RDAMP和免疫细胞相互作用 CR发育过程中心脏移植微环境的进化。在AIM 2中，我们将确定是否天生 同种异体免疫可防止有效的损伤解决和心脏移植后修复。