Immunoregulatory Mechanisms of IL-33 in Heart Transplantation

早期移植物损伤是不可避免的移植相关事件的后果，如供者脑死亡， 缺血/再灌注损伤和外科创伤。受体对移植物同种异体抗原的反应也会产生移植物 在移植物的整个生命周期内都会受到损害。这些伤害和压力导致自身分子的释放。 包含与损伤相关的分子模式(阻尼值)。人们很好地理解，阻尼器支持亲 先天免疫系统的细胞，特别是单核细胞感觉到的炎症反应 和巨噬细胞。临床前啮齿动物心脏移植研究表明，这些释放的阻尼剂启动和 传播同种异体反应并针对炎症抑制，或它们激活的信号级联反应，减少 同种异体免疫和改善移植后的结果。然而，我们最近的研究提供了令人信服的 有证据表明，这些移植物损伤还会释放修复抑制物(RDAMPs)，如白细胞介素33(IL-33)，它 限制心脏移植后的局部炎症并启动免疫介导的组织修复。通过评估 儿科心脏移植受者样本和使用临床前小鼠心脏移植模型，我们确定 IL-33在移植物基质细胞中表达上调，限制了移植物血管病变和移植物的发展 纤维化，后来发展为慢性排斥反应(CR)。我们已公布的和初步的数据表明，IL-33 通过靶向浸润性单核细胞和巨噬细胞以及调节性T细胞来介导这种保护 (Treg)，以限制促炎巨噬细胞的产生，然后协调Treg和修复 巨噬细胞介导的损伤反应。虽然这些数据令人鼓舞，但我们的研究也表明， 在移植物的生命过程中，启动早期组织损伤修复的过程可能会变得不受调控。在预赛中 数据显示，当血管相关的Treg持续分泌修复因子时，它们就会变得病理性。 作为对IL-33的反应，IL-33促进局部成纤维细胞的增殖，从而促进CR。除了拥有他们的 由局部rDAMPs编程的功能，移植物浸润性受体单核细胞识别同种异体分子 使它们成熟为促炎症的髓系细胞，刺激T细胞增殖和干扰素γ的产生 在移植物中。我们已经证实单核细胞和巨噬细胞识别和发展同种异体特异性 通过配对的免疫球蛋白样受体-A对MHCI抗原的细胞毒性和记忆。这些数据让我们了解到 假设rDAMP信号启动心脏移植后早期组织损伤的修复 由于同种异体免疫的持续炎症反应，导致血管系统周围的调节失调 细胞。我们将在两个目标中检验这一假设：在目标1中，我们将定义rDAMP和免疫细胞如何相互作用 在CR发展过程中心脏移植微环境的进化。在《目标2》中，我们将确定先天是否 同种异体免疫阻止心脏移植后有效的损伤解决和修复。

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.