IL-18诱导的Breg细胞介导慢性胰腺炎向胰腺癌转化及其机制的研究

Chronic pancreatitis is an independent risk factor for pancreatic cancer. However, the mechanism of the transformation from chronic pancreatitis to pancreatic cancer remains controversial and needs further study. Previously we successfully established the malignant transformation model of chronic pancreatitis in KC mice. We found that IL-18 and Breg cells were gradually increased in wild mice, chronic pancreatitis(CP) mice and pancreatic cancer(PC) mice. In addition, IL-18 and Breg cells increased in the Peripheral blood of CP patients and PC patients, and Breg cells proportion were positively correlative with IL-18 levels. The differentiation of naïve B lymphocytes into Breg was disrupted in IL-18-/- mice. Ex vivo rmIL-18 facilitated B lymphocytes differentiating into IL10+ B cells (Breg cells). Therefore, we propose a hypothesis that IL-18 induces Breg cells that interact with pancreatic acinar cells and promote chronic pancreatitis transforming into pancreatic cancer. We plan to verify the hypothesis through the following experiments. By building animal models with KC mice and gene knockout mice, we will explicit the role of IL-18/Breg in pancreatic cancer tumorigenesis. We will clear the marker characteristics and immune regulation mechanism of Breg(IL-18) through the animal models, ex vivo culture, cell sorting and chip analysis. Through separation and ex vivo culture of pancreatic acinar cells, we will determine whether Breg(IL-18) affect pancreatic acinar cells and its mechanism. This study is expected to further reveal the mechanism of pancreatic carcinogenesis.

慢性胰腺炎是胰腺癌的独立危险因素，但慢性胰腺炎向胰腺癌转化的机制尚存争议。我们前期通过KC小鼠慢性胰腺炎恶性转化模型，发现IL-18和Breg细胞在慢性胰腺炎向胰腺癌转化过程中逐渐升高。IL-18和Breg细胞在慢性胰腺炎和胰腺癌患者血液中升高且表达量成正比。体外实验表明IL-18促进B淋巴细胞分化为Breg细胞。由此我们假设：IL-18诱导B淋巴细胞分化为Breg细胞，介导慢性胰腺炎向胰腺癌转化。并计划：利用KC、IL-18-/-、IL-18R-/-和CD19-/-小鼠构建动物模型，明确IL-18和Breg细胞在慢性胰腺炎向胰腺癌转化过程中的作用，以及IL-18相关Breg细胞的标记特点及免疫调控机制；体内外实验明确Breg细胞是否直接作用于胰腺腺泡及其机制。本研究有望进一步揭示慢性胰腺炎进展为胰腺癌的机制。

胰腺癌作为恶性程度最高的肿瘤之一，其五年生存率不足5%，其中，慢性胰腺炎是胰腺癌发生的独立危险因素，但是慢性胰腺炎介导的胰腺癌的恶性转化机制尚不明确。调节B细胞(Bregs)是一种免疫抑制的淋巴细胞，其调节异常与自身免疫性疾病和癌症的发生有关。Bregs产生诱导免疫耐受的细胞表面分子和产生耐受的细胞因子(白介素-10和转化生长因子- β)。我们的研究显示，炎症因子白介素-18和Breg细胞在胰腺癌患者体内水平均升高。通过动物实验验证，白介素-18可以促进B细胞比例的升高，而白介素-18结合蛋白会抑制B细胞的产生。进一步体内实验研究显示，白介素-18会促进B细胞转化为Breg细胞。在CD19敲除的小鼠模型中，我们观察到B细胞比例显著下降，而胰腺炎症程度和胰腺癌恶性程度均明显减轻，在腹腔注射给药重组小鼠白介素-18后，B细胞比例上升，胰腺炎症程度和胰腺癌恶性程度均加重。通过本次研究，我们发现并证明了白介素-18会诱导B淋巴细胞分化为Breg细胞，介导慢性胰腺炎向胰腺癌转化，这为胰腺癌的临床治疗提供了新的策略，为恶性肿瘤在免疫治疗领域的研究开辟了新的思路与方法。