Role of immune cells in chronic pancreatitis

 描述（由申请人提供）：慢性胰腺炎（CP）的特征是炎症、纤维化和胰腺细胞丢失。CP可导致充分的组织破坏，并导致外分泌和内分泌功能不全以及难以治疗的慢性腹痛。CP的管理具有挑战性，因为没有有效的方法可以阻止疾病进展或逆转疾病。此外，CP是胰腺癌发展的危险因素。CP治疗缺乏进展的部分原因是对可能逆转或阻止疾病的机制缺乏了解。最近的体内外研究客观地表明，活化的胰腺星状细胞（PSC）在CP纤维化中的作用。PSC通过调节细胞外基质蛋白的合成和降解在疾病进展中发挥核心作用。PSC的活化通过来自受损腺泡细胞和浸润白细胞（例如巨噬细胞）的细胞因子而增加。然而，巨噬细胞触发和维持纤维化过程的机制尚未完全了解。我们的初步研究表明，巨噬细胞亚群（称为M2）在CP中占主导地位，而急性胰腺炎（AP）则由不同的巨噬细胞亚型（M1）主导。我们推测，与M1不同，M2巨噬细胞通过持续激活PSC促进胰腺纤维化，反过来激活的PSC增强巨噬细胞向M2的极化，并提出参与巨噬细胞-PSC相互作用以促进CP进展的机制。为了实现目标1中的这一目标，我们使用急性和慢性胰腺炎的动物模型来表征与CP相关的免疫应答。根据目标2，我们将确定巨噬细胞亚群在CP中的作用和来源。具体来说，我们建议测试和研究的亚型巨噬细胞和细胞因子是必不可少的CP的发展。在目标3下，我们将确定巨噬细胞影响PSC功能的机制，以及PSC如何反过来影响巨噬细胞极化和行为，使用各种共培养系统和体内转基因动物，允许测试免疫应答中的相关途径。如可能，将使用人PSC（从手术标本中分离）和单核细胞/巨噬细胞确认和识别相关途径。我们提出的研究是新颖的，因为它们专注于与CP，巨噬细胞可塑性相关的免疫反应，并有可能通过提出可以停止或逆转CP的机制来改变该领域的范式，从而改变疾病的自然进程。除了对介导和/或允许CP进展的免疫机制的理解外，该项目的潜在影响具有重要的临床意义，因为我们的研究可能导致开发新的治疗方法，从而改变我们管理CP患者的方式。

 DESCRIPTION (provided by applicant): Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and loss of pancreatic cells. CP can lead to sufficient tissue destruction and result in exocrine and endocrine insufficiency as well as difficult to treat chronic abdominal pain. The management of CP is challenging as there are no effective methods that can stop progression or reverse the disease. In addition, CP is a risk factor for the development of pancreatic cancer. Absence of progress in CP therapy in part is due to lack of understanding in mechanisms that potentially can either reverse or halt the disease. Recent in vitro and in vivo studies have shown objectively the role of activated pancreatic stellate cells (PSCs) in fibrogenesis in CP. PSCs play a central role in disease progression by regulating the synthesis and degradation of extracellular matrix proteins. Activation of PSCs is increased by cytokines from injured acinar cell and infiltrating leukocytes (e.g. macrophages). However, the mechanisms by which macrophages trigger and sustain the fibrotic processes are not fully understood. Our initial studies show that subset of macrophages (known as M2) are dominant in CP as compared to acute pancreatitis (AP), which is dominated by a different subtype of macrophages (M1). We hypothesize that unlike M1, M2 macrophages promote pancreatic fibrosis through sustained activation of PSCs, and in turn the activated PSCs enhance macrophage polarization towards M2 and propose mechanisms involved in macrophage-PSCs interaction to promote progression of CP. To achieve this goal in aim 1, we use animal models of acute and chronic pancreatitis in order to characterize immune responses associated with CP. Under aim 2, we will determine the role and source of macrophage subpopulation in CP. Specifically, we propose to test and study subtypes of macrophages and cytokines that are essential in the development of CP. Under aim 3, we will identify mechanisms via which macrophages affect PSC function and how PSCs in turn affect macrophage polarization and behavior using various co-culture systems and in vivo using transgenic animals that allow testing of pertinent pathways in the immune responses. When possible human PSCs (isolated from surgical specimens) and monocyte/macrophages will be used to confirm and identify pathways involved. Our proposed studies are novel because they focus on the immune responses associated with CP, macrophage plasticity, and have the potential to shift paradigm in the field by proposing mechanisms that can either halt or reverse CP, and thus alter the natural course of the disease. In addition to the gained understanding of immune mechanisms that mediate and/or allow progression of CP, the potential impact of this project is of great clinical significance, as our studies may lead to development of novel therapies that can change how we manage patients with CP.