Immuno-pathogenesis of Chronic Pancreatic Diseases Uncovered Applications expected for the treatment of pancreatic diseases and preventive measures for pancreatic cancer - Kindai University

Associate Professor Tomohiro Watanabe's research group of Clinical Internal Medicine (Gastroenterology) at the Faculty of Medicine of Kindai University (Osakasayama City, Osaka Prefecture) unraveled a part of the pathogenic immune response that is common to two different chronic pancreatic diseases, namely autoimmune pancreatitis and chronic pancreatitis. The results of this study are expected to be applied to the development of new treatments of pancreatic diseases and for the prevention of pancreatic cancer.

A paper relating to this study will be featured by the online edition of "Trends in Immunology", a United States-based scientific journal issued by Cell Press - the publisher of "Cell", a journal primarily focused on life sciences. The feature will begin 1:00 AM (JST) on October 26th, 2018 (Fri).

[Key aspects of this study]
- Until now, the barely understood immuno-pathogenesis for chronic inflammation of the pancreas has been uncovered.
- The pathogenic immune response that is common for both autoimmune pancreatitis and chronic pancreatitis was elucidated for the first time in the world.
- Applications are expected for new treatments of chronic pancreatic inflammation and new preventive measures for pancreatic cancer.

[Overview of the study]
Chronic inflammatory diseases of the pancreas can be largely categorized into two groups; autoimmune pancreatitis and chronic pancreatitis.

Autoimmune pancreatitis is thought to be triggered by the erroneous attack of pancreatic tissues in one's own body by the immune system. Many such instances are considered to be pancreatic manifestation of systemic IgG4-related diseases (*1), which are recognized as intractable diseases and are associated with concurrence of pancreatic, and various other types of cancer.

Chronic pancreatitis is a disease that arises from prolonged inflammation of the pancreas due to excessive intake of alcohol, which leads to loss of pancreatic functions as the condition progresses and involves a variety of symptoms, such as diarrhea, abdominal pain, malabsorption, and diabetes. The presence of chronic pancreatitis increases the incidence of pancreatic cancer. As immuno-pathogenesis has not been fully understood, definitive treatments for these two diseases have not existed.

The research group led by Watanabe discovered that the immuno-pathogenesis of these two different diseases involved two types of cytokines (*2), which are secreted by cells. One of these is type I Interferon (IFN) (*3) and the other is the Interleukin 33 (IL-33) (*4).

Unraveling the immuno-pathogenesis of autoimmune pancreatitis and chronic pancreatitis not only leads to the establishment of new treatments for patients suffering from chronic inflammation of the pancreas, but it can also potentially pave the way for the development of preventive measures of pancreatic cancer.

[Details of this study]
Name of journal: "Trends in Immunology", a scientific journal in the United States published by Cell Press, the publisher of "Cell", which is a journal primarily for the field of life science (impact factor: 14.188).

Research paper title: Mechanistic Insights into Autoimmune Pancreatitis and IgG4-Related Disease

Authors: Tomohiro Watanabe, Kosuke Minaga, Ken Kamata, Masatoshi Kudo and Warren Strober.

[Details of this study]
The research group led by Watanabe, in their search for the immuno-pathogenesis of autoimmune pancreatitis and chronic pancreatitis, discovered that two types of cytokines, type I IFN and IL-33, are involved in the development of two different types of diseases. Cells producing both type I IFN and IL-33 are different from each other, in that type I IFN and IL-33 are produced by the plasmacytoid dendritic cells (*5) in case of autoimmune pancreatitis, while type I IFN and IL-33 are produced by the pancreatic acinar cells (*6) in the case of chronic pancreatitis.

[Expectations for the future]
Animal experiments as well as observations of human patients revealed that autoimmune pancreatitis and chronic pancreatitis share the abnormal immune responses, excessive production of type I IFN and IL-33. The cells that produce type I IFN and IL-33 for these two diseases, on the other hand, are fundamentally different. In cases of the autoimmune pancreatitis, plasmacytoid dendritic cells produce type I IFN and IL-33, while the pancreatic acinar cells produce type I IFN and IL-33 to trigger chronic pancreatitis. It is hoped in the future that the mechanisms accounting for the findings that different cells producing the two cytokines (type I IFN and IL-33) lead to the development of different diseases can be elucidated. From the perspective of applications for patients, there are expectations for the effectiveness of a drug that can inhibit the actions of type I IFN and IL-33 for both autoimmune pancreatitis and chronic pancreatitis.

[Notes on research paper]
The research group led by Watanabe has been trying for last ten years to uncover the immuno-pathogenesis of autoimmune pancreatitis and chronic pancreatitis. The results of their study at various stages were presented in a number of scientific journals. The research paper presented this time will be featured in "Trends in Immunology" as a review article for the results of the study. This research paper is the fruit of a joint study conducted with Dr. Warren Strober, a Senior Investigator of Mucosal Immunity at the National Institute of Health in the United States.
Results of the study so far are introduced on the next page.

First of all, this research group demonstrated that type I IFN and IL-33 produced by the plasmacytoid dendritic cells are essential for the onset of the autoimmune pancreatitis, based on their study that used model animals (Figure A). The development of the autoimmune pancreatitis can be prevented by administering antibodies that reduce the number of plasmacytoid dendritic cells, as well as those that suppress signals from type I IFN and IL-33. Furthermore, pancreatic localization of the plasmacytoid dendritic cells producing both the type I IFN and the IL-33 has been confirmed in patients suffering from autoimmune pancreatitis. These series of findings were published in "Journal of Immunology 2015: 195:3033-44" and "Journal of Immunology 2017: 198:3886-96".

The research group also demonstrated that the type I IFN and IL-33 produced by pancreatic acinar cells were essential for the development of chronic pancreatitis, by using model animals for pancreatitis they have established (Figure B). This was demonstrated by an experiment that involved mice deficient in type I IFN-mediated signaling pathways and an experiment that involved the use of antibodies inhibiting IL-33-mediated signaling pathways. Furthermore, pancreatic localization of the acinar cells producing the IL-33 was confirmed in the patients suffering from chronic pancreatitis. These series of findings were published in "Immunity 2012;37:326-38", "Mucosal Immunology 2016;9:1234-49" and "Mucosal Immunology 2017;10:283-298".

These studies directed the research group led by Watanabe to the discovery that the production of the type I IFN and the IL-33 by the plasmacytoid dendritic cells leads to the development of the autoimmune pancreatitis, while the production of the type I IFN and the IL-33 by the pancreatic acinar cells leads to the development of the chronic pancreatitis.

[Glossary of terms]
*1: IgG4 related diseases: An autoimmune disease that is chracterized by increase of IgG4, which is one of antibodies. Such diseases trigger multiple organ injury including pancreas, salivary glands, lungs, kidneys and a variety of other organs. This is a new disease entity proposed by researchers in Japan and is currently attracting much attention.

*2: Cytokines: Proteins secreted by cells. It is one of factors that determine immune responses.
Excessive secretion of cytokines can trigger autoimmune diseases.

*3: type I IFN: One of cytokines. It is produced upon exposure to microbial infections, particularly virus infections and plays an important role in host defense against microbial infections. Production in large amounts without presence of infection, on the other hand, triggers autoimmune diseases, represented by systemic lupus erythematosus.

*4: IL-33: A cytokine . It plays an important role for inflammations, allergies and fibrosis of tissues.

*5: Plasmacytoid dendritic cell: A type of immune cells; a dendritic cell with the ability to produce a large amount of type I interferons (IFN).

*6: Pancreatic acinar cell: A type of cell in the pancreas that secrets digestive enzymes necessary for digestion and absorption in gastrointestinal tracts.