Local and Systemic Analysis of Immune Responses in Pancreatitis Patients
Abstract
Pancreatitis is a progressive, inflammatory disease of the pancreas without cure or even effective approved treatments. The pancreas consists of exocrine (~95%) and endocrine (~5%) components. The exocrine pancreas secretes digestive enzymes necessary for digestion whereas the endocrine part secretes hormones such as insulin and glucagon that are necessary to regulate blood sugar levels. Acute pancreatitis (AP) begins with local injury to the exocrine pancreas leading to autodigestion of the gland and inflammation. Causes and risk factors include gallstones, alcoholism, heavy smoking, and hereditary factors or inherited genes. Patients who present with recurrent attacks of acute pancreatitis (RAP) are at increased risk for developing chronic pancreatitis (CP), and CP is a risk factor for pancreatic cancer. CP also predisposes individuals to developing diabetes, named Type3c or pancreatogenic diabetes. For unclear reasons, pancreatitis is increasing in our society and the economic impact approaches $10 billion annually. AP is the most common reason for hospital admission in those with gastrointestinal disease and the fifth most common nonmalignant cause of death from digestive diseases in the United States. Most therapeutic studies, although showing promise in experimental models, have not been successfully translated to clinical use. A major impediment for pancreatitis research has been a lack of understanding of the immune responses associated with the disease and how to stop these sequence of events once inflammation sets in place. In addition, patients can present with a spectrum of disease (AP, RAP, CP) as a result of multiple cause or factors and the huge hurdle associated with lack of access to human samples and studying human disease. The cellular and molecular mechanisms regulating the inflammatory response to pancreatitis are still emerging and represent a critical target for potential therapeutics. In our funded DOD grant using experimental models of pancreatitis, we identified distinct immune signatures in experimental model of mild AP, recovery and severe AP by a novel technology and method developed at Stanford University, which allows simultaneous analysis of many immune cells in depth (known as mass cytometry or CyTOF). Our current proposed expansion award research relates to the “Pancreatitis” area of FY20 PRMRP and aims to expand our mouse model findings to human disease using this novel CyTOF technology and accessing samples already collected by other DOD and NIH-funded studies that include pancreatitis patient sample collections. This study will focus on identifying distinct immune responses associated with the variety types and stages of pancreatitis (AP, RAP, CP, and also compared to that of healthy individuals). Understanding in-depth immune responses in heterogeneous human AP, RAP, and CP will likely lead to better understanding of disease, progression, and pathways that can be targeted in the future to alleviate the disease and prevent complications associated with disease progression. Such study has not been pursued to this magnitude and using human samples (blood and also pancreas tissue in those with CP undergoing resection due to disease progression, pain, and increased risk for pancreatic cancer through our collaboration with high volume center in the U.S. performing this surgery). The short-term impact of our proposed project is the gained understanding of immune mechanisms and responses that mediate human/clinical pancreatitis. Our preliminary results identify potential translatability of our current experimental model findings and likely to identify immune signatures in blood (without need to access the pancreas) that can inform human pancreatitis forms, stage, severity, progression, and give insight to potential future targets for therapy. The potential long-term impact is of great clinical significance in a disease where there is currently no active therapy or cure. If successful t
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110454
Entities
People
- Sohail Z Husain
Organizations
- Stanford University
- United States Army