Immuno-pathogenesis of Chronic Pancreatic Diseases Uncovered Applications expected for the treatment of pancreatic diseases and preventive measures for pancreatic cancer - Kindai University
Press Releases • Oct 25, 2018 16:00 GMT
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.
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.
Permeation Mechanism of Water through Polymeric Membrane; Clarified for the First Time in the World Expectations for Development of Membranes with Functions, Such As Seawater Desalination - Kindai University
Press Releases • Oct 14, 2018 23:00 GMT
Associate Professor Noriyoshi Arai and his research group at the Mechanical Engineering Department at the Faculty of Science and Engineering of Kindai University have elucidated the mechanism of permeation through polymeric membranes. The findings of this research will be featured in the Journal of Membrane Science , on October 15, 2018 at 8:00 AM (JST).
Successful Use of AI Technology for Efficient Prediction of Physical Properties of Substances with Complex Molecular Structures
Press Releases • Sep 14, 2018 23:00 GMT
- The study demonstrated that machine learning can be applied to predict physical properties of functional materials that have complex structures. - For the first time in the world, machine learning methodology has been applied to the analysis of complex molecular structures of surfactants that are used in our immediate surroundings, such as detergents and cosmetic products.
Press Releases • Aug 24, 2018 14:00 GMT
Bleeding in the digestive system occurs when patients have ulcers, inflammation and cancers. Therefore, an early sign of such diseases may be microscopic blood in stool, which doctors refer to as “fecal occult blood” (FOB). The luminol reaction, which has been used in forensics to detect trace amounts of concealed blood, can also be applied for detection of FOB, according to Kindai University researchers, led by Ah-Mee Park, Ph.D, Associate Professor in the Department of Microbiology, Faculty of Medicine.
1.Experiments have shown that the luminol reaction can be used to detect FOB in animals.
2.This is the first standard method to detect FOB in animal models for ulcers and cancers in the digestive system - which is simple, quick, economical and quantitative - making it applicable to use for any research laboratories.
3.It is hoped these findings will contribute to the furthering of research on gastric ulcers and colon cancer.
FOB, or microscopic blood in the stool, is a sign of gastrointestinal diseases, such as intestinal ulcers and colon cancers. To discover the precise cause and new treatments for such diseases requires animal models, in which the levels of FOB are measured to assess the severity of gastrointestinal bleeding. Unlike in clinical human stool samples, however, there is no standard method to detect FOB in experimental animals.
Kindai University researchers present a simple method to detect FOB in mice, using the luminol reaction, which has been used to detect bloodstains at crime scenes, like those often seen in detective stories and TV shows. By mixing feces with a luminol solution, hemoglobin-containing fecal samples produce visible blue light (chemiluminescence). The levels of FOB are measured by the hemoglobin content; a higher content corresponding to a higher brightness level of the chemiluminescence - as measured by a luminometer. This method is simple, quick, economical, and quantitative, allowing researchers to detect FOB in experimental animals. The application of the luminol reaction in clinical medicine is expected to contribute to furthering disease research.
Ah-Mee Park and Ikuo Tsunoda, “Forensic luminol reaction for detecting fecal occult blood in experimental mice” is published in the British scientific journal, BioTechniques, August 2018(Impact factor 2.030)
Details of the research
Bloody stool samples were collected from mice with intestinal ulcers, which were induced by injection of indomethacin, a non-steroidal anti-inflammatory drug. Fecal samples were mixed with a luminol solution and observed in dark field. The blue chemiluminescence became detectable 4 hours after the injection, and the intensity of the chemiluminescence was measured by a luminometer. The levels of FOB were calculated by the ratios of the chemiluminescence intensities of fecal samples to the chemiluminescence intensity of a luminol solution alone.
To detect FOB in human stool, there are two standard methods; the stool guaiac test and the hemoglobin antibody immunochemical test. The guaiac test using the colorimetric method is easy to operate, but lacks quantification and can be affected by other factors. On the contrary, the immunochemical test is expensive, but allows quantification of the hemoglobin content, is specifically for hemoglobin and is not affected by other factors. On the other hand, for experimental animal studies, researchers often assess the FOB levels by stool color and appearance since there is no standard method to detect and quantify FOB in animals.
Outlook for the future
Since this FOB detection method is simple, quick, economical, and quantitative, most researchers in the field of gastrointestinal diseases can use it easily in their laboratories as a gold standard method, allowing for more precise assessment of their experimental results, as well as comparison of reports between different laboratories and scientific articles. The limitations of the luminol reaction applying to human stool samples include several factors that affect the reaction, for example, food or bleach. Nevertheless, this discovery will help advance the field of research in gastrointestinal diseases.
Profiles of Researchers
Name: Ah-Mee Park, Ph.D.
Affiliation: Dept. Microbiology, Kindai University Faculty of Medicine
Specialty: Microbiology, Free radicals
Metropolitan DC Thoracic Society Annual Meeting: First Prize
Annual Meeting of American Thoracic Society: Travel Award
1.Experiments have shown that the luminol reaction can be used to detect FOB in animals. 2.This is the first standard method to detect FOB in animal models for ulcers and cancers in the digestive system - which is simple, quick, economical and quantitative - making it applicable to use for any research laboratories.
Japanese High School Students Set the World as the Stage Proposing a Project for Contributing to Society -Entrepreneurship World Competition-
Press Releases • Aug 09, 2018 05:30 GMT
[Time and Date] August 8th - August 14th
[Location] Durban, South Africa
[Sponsored] SAGE Global
[Participated Countries] USA, Ukraine, Canada, Chile, China, India, Iran, Ireland, Nigeria, Korea, Russia, Pakistan, Australia, Japan, etc. Around 30 countries and regions
A domestic event held in March (sponsored by SAGE JAPAN CUP・Tokyo Metropolitan Government Board of Education etc.) the first place team H.O.P.E from Tokyo Metropolitan Kokusai High School will participate in the Sage World Cup held in South Africa.
SAGE was established in the United States of America in 2002, and this year will the 16th year of the World Cup and high school teams from around 30 countries and regions will participate this year. Japan will send a high school team for the third straight year. Two years ago at the Philippines World Cup, Tokyo Metropolitan Ryogoku High School represented Japan and last year at the Ukraine World Cup, Yokohama Science Frontier High School represented Japan. This year, Tokyo Metropolitan Kokusai High School will challenge themselves to make a presentation, aiming to claim the top prize.
During the World Cup, high schools from each country will participate in culture exchanges.
<Contact in regard to the event>
Professor Takeshi Miyazaki, Soka University: Iwaki
*For more information please visit the homepage
[Time and Date] August 8th - August 14th [Location] Durban, South Africa [Sponsored] SAGE Global [Participated Countries] USA, Ukraine, Canada, Chile, China, India, Iran, Ireland, Nigeria, Korea, Russia, Pakistan, Australia, Japan, etc. Around 30 countries and regions
World’s First Demonstration on Efficacy of Drug for Lung Cancer Genetic Mutation Diagnosed with Blood sample using cobas EGFR mutation test v2.Alleviating burden on patients through diagnosis with blood tests
Press Releases • Jul 31, 2018 07:09 GMT
[Key aspects of this study] - World’s first research findings that demonstrate efficacy and safety of a drug which is administered based on genetic screening results. - Efficacy demonstrated by a response rate of 55.1%, which represents the ratio of people whose tumor shrunk. - Potential for partial transition to blood test from endoscopic biopsy, which places a heavy burden on patients.
Ritsumeikan University to Establish the College of Global Liberal Arts in April 2019 on Osaka Ibaraki Campus
Press Releases • Jun 18, 2018 05:00 GMT
Ritsumeikan University will establish the College of Global Liberal Arts in April 2019, a new undergraduate dual degree program with The Australian National University to offer border-spanning Asia Pacific-centered liberal arts education for a global era.
Soka University is holding a Kickoff Symposium for MEXT's "Private University Research Branding Project" titled "Establishment of a Recycling-oriented Society in African Countries - Interdisciplinary Collaboration between Ethiopia and Japan -"
Press Releases • May 09, 2018 03:09 GMT
Soka University will hold a Kickoff Symposium entitled, "Establishment of a Recycling-oriented Society in African Countries - Interdisciplinary Collaboration with Ethiopia -" at Room 201, S Building, Soka University on 12th May (Sat).
Joined by 250 universities in 25 Countries and Regions worldwide, The Association of Southeast Asian Institutions of Higher Learning's (ASAIHL) annual conference will be held at Soka University - Held in Japan for the first time -
Press Releases • Mar 16, 2018 05:38 GMT
The 2018 ASAIHL Conference will be held from March 26th to March 28th (Supported by: MEXT, Hachioji City) at Soka University (Hachioji City, Tokyo / President: Yoshihisa Baba).
Bringing you the latest news - in English - from Japanese universities: "Japan University News" launches!
Press Releases • Mar 15, 2018 03:57 GMT
With the goal of increasing global awareness for Japanese universities as well as building a platform for pro-actively building relationships with international media, Daigaku Tsushin will commence "Japan University News" in April of 2018.
About Japan University News
“Japan University News” is an English-language news portal that provides an outlet for the latest news of Japanese Universities for a global audience. It provides an overview of the unique culture, prominent research and contributions to the global society of Japanese Universities for international media, stakeholders and other interested parties.