1. Academic Validation
  2. PD-1/PDL1 Blockade Exacerbates Pancreatic Damage and Immune Response in a Mouse Model of Acute Pancreatitis

PD-1/PDL1 Blockade Exacerbates Pancreatic Damage and Immune Response in a Mouse Model of Acute Pancreatitis

  • Inflammation. 2021 Aug;44(4):1441-1451. doi: 10.1007/s10753-021-01430-1.
Ting Xie  # 1 Ningzhi Wang  # 2 3 Guanghuai Yao  # 2 3 Songxin Xu 2 3 Dan Wang 4 Xinnong Liu 2 Lianghao Hu 4 Guotao Lu 2 3 Ruihua Shi 5 Yanbing Ding 6 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China.
  • 2 Pancreatic Center, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
  • 3 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China.
  • 4 Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai, China.
  • 5 Department of Gastroenterology, Zhongda Hospital, Southeast University, Nanjing, China. ruihuashi@126.com.
  • 6 Pancreatic Center, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China. ybding@yzu.edu.cn.
  • 7 Department of Gastroenterology, Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China. ybding@yzu.edu.cn.
  • # Contributed equally.
Abstract

Programmed necrosis factor 1 (PD-1) is significantly overexpressed in lymphocytes, neutrophils, and macrophages and has been studied in depth in tumors. As a member of the negative costimulatory family of immune regulatory molecules, expression of PD-1 and its primary regulatory pathway are related to immune cells. Recently, PD-1 was demonstrated to be clinically important in inflammatory diseases, such as multiple sclerosis, glomerulonephritis, and inflammatory bowel disease. PD-1, a negative regulator molecule, was recently found to protect tissues from the inflammatory response and inflammatory cell infiltration. Conversely, PD-1 deficiency may contribute to the occurrence of a diverse array of inflammatory diseases. However, whether PD-1 regulates the pathogenesis of acute pancreatitis (AP) is unclear. AP is a noninfectious inflammatory disease with primary pathological manifestations that include edema, inflammatory cell infiltration, and acinar cell necrosis. Among these features, costimulatory molecules including PD-1/PDL1 play a critical role in the regulation of immune response and immune activation. Here, we first found that PD-1 is notably upregulated in neutrophils and macrophages in peripheral blood and pancreatic injury tissue in AP mice. PD-1 gene deficiency exacerbated pancreatic injury in an experimental mouse model of AP. We observed more severe pancreatic injury in PD-1-deficient mice than in control mice, including increased pancreatic edema, inflammatory cells, infiltration, and acinar cell necrosis. We also found that PD-1-deficient mice exhibited higher levels of serum enzymology and inflammatory factors in AP. Furthermore, PD-1/PDL1 neutralizing Antibodies significantly aggravated pancreatic and lung injury and increased serum inflammatory cytokine levels. These findings were consistent with those in PD-1-deficient mice. In summary, PD-1 may protect against AP in mice and act as a potential target for the prevention of AP in the future.

Keywords

PD-1; acute pancreatitis; immunocyte; pancreatic injury.

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