Elucidation of the immune system in human normal and diseased liver

The liver is constantly exposed to substances from the intestine through the portal vein. While the immune system in the liver must be activated to fight against various pathogens draining into the liver, the immune system must be suppressed against harmless or even beneficial substances, such as gut microflora and nutrients. The liver is generally considered an organ where immune suppression is dominant (immune tolerant), and there are quite a few cases where immunosuppressive drugs can be successfully withdrawn after liver transplantation. However, little is known regarding the local immune system in the human liver, partly because blood samples have been commonly used for immunology research of human liver diseases.

We conduct basic and clinical immunological research using human normal as well as diseased liver specimens. The samples are obtained in collaboration with multiple departments of Kyoto University Hospital, including Hepato-Biliary-Pancreatic Surgery and Transplantation, Gastroenterology, Pathology, etc. Our research includes: 1) To elucidate the immune tolerance mechanism by which HBs antibody remains unproduced in patients with chronic hepatitis B virus infection, 2) To define the pathogenesis of hepato-biliary autoimmune diseases, such as primary biliary cholangitis and primary sclerosing cholangitis. We are also interested in the immune system in congenital biliary atresia, where the involvement of the immune system is poorly characterized.

Elucidation of the immune response in the human cancer microenvironment

Cancer immunotherapy represents a treatment approach aiming at shifting the balance of anti-tumor and pro-tumor immunity towards anti-tumor. In the last ten years, inhibition of immune checkpoint molecules such as CTLA-4 and PD-1 has been proven effective in treating cancer patients. Prof. Tasuku Honjo at Kyoto University, who discovered PD-1, was awarded the Nobel Physiology and Medicine Award in 2018 together with Dr. JP Allison. However, the effectiveness of immune checkpoint inhibition is limited to some cases, and the development of new approaches which can induce a more robust anti-cancer immune response is desired. In collaboration with multiple departments at Kyoto University Hospital, including Obstetrics and Gynecology, Hepato-Biliary and Pancreatic Surgery and Transplantation, Urology, Pediatrics, Pediatric Surgery, Pathology etc., we are dissecting the immune cells in-depth in the tumor microenvironment of endometrial cancer, hepatocellular carcinoma, intrahepatic bile duct cancer, hepatoblastoma, neuroblastoma, and urothelial cancer. We aim to establish potent novel approaches that promote anti-cancer immunity and release cancer-induced immunosuppression.

In addition, we are trying to elucidate the mechanism by which primary sclerosing cholangitis transforms into cholangiocarcinoma through an interdisciplinary approach that combines genomic biology and immunology, in collaboration with Prof. Seishi Ogawa, Department of Pathology and Tumor Biology.

Breakdown of the immune tolerance in human autoimmune diseases

Autoimmune diseases are caused by the breakdown of the immune tolerance mechanism and the promotion of the development of auto-antibodies and autoreactive T cells. There is a gap in our knowledge regarding the interactions of pathogenic immune cells in inflamed human tissues. In collaboration with multiple departments at Kyoto University Hospital, including Clinical Immunology, Orthopedic Surgery, Neurology etc., we conduct basic and clinical immunology research using tissue, blood, and spinal fluid specimens obtained from patients with diseases, such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and neuromyelitis optica. Our goals are to identify the pathogenic immune cells and molecular mechanisms directly related to tissue inflammation, to establish new biomarkers, and to develop new treatments. In addition, we are conducting joint research with the Department of Neurology on the involvement of the immune system in Parkinson's disease.

Pediatric allergy and T follicular helper cell subset

Allergy is one of the national diseases in Japan that affect more than half of the population. Pediatric allergy is a type I allergic disease mediated by allergen-specific IgE, which causes a severe anaphylactic reaction in severe cases. Studies in mice over the last few years have shown that T follicular helper (Tfh) cells play a central role in allergen-specific IgE production. However, It remains unclear whether the findings in mice can be applied to humans. In collaboration with the department of Pediatrics, Respiratory Medicine, Otolaryngology etc., we aim to define the subset of T follicular helper cells directly involved in human pediatric allergy and their differentiation mechanisms. We are particularly interested in egg allergy. Furthermore, in collaboration with Prof. Hiroaki Hiraoka (ASHBi), we are developing a novel method to determine the human T cell differentiation pathway using a mathematical model from single-cell RNAseq data obtained from human tissue, such as tonsils.

Adaptive immune responses in severe and mild COVID-19

The pandemic of COVID-19 caused by SARS-CoV-2 infection has dramatically affected our life in many aspects. While COVID-19 tends to cause severe and critical conditions in the elderly, young people are often asymptomatic. It remains unclear what immune responses cause such differences in clinical symptoms. We are analyzing the quality and quantity of SARS-CoV-2 specific T cells and B cells in depth to clarify the mechanism responsible for different symptoms in COVID-19, with a hypothesis that T cells induced by the infection of common cold coronaviruses are highly involved. We are collaborating with researchers in Vietnam (Nagasaki University Institute of Tropical Medicine) and the United States (University of California, San Diego) to compare the type of SARS-CoV-2 specific immune responses among residents from different continents. The per capita mortality rate of COVID-19 is low in Asia and high in Europe and the Americas, and we hypothesize that this is due to at least partly differences in the quality and quantity of the specific immune responses.

In addition, COVID-19 can cause many sequelae (post-acute sequelae of SARS-CoV-2; PASC), but the mechanism has not been elucidated. Several reports have shown that sequelae symptoms can be alleviated by COVID-19 vaccination. We are conducting research on PASC under the hypothesis that different types of SARS-CoV-2 specific T cells are associated with different symptoms of sequelae.

Basic human immunology research

There are still many mysteries and unknowns in human immune cells. We aim at elucidating the phenotypical and functional heterogeneity of human naïve CD4+ T cells. We are also analyzing the functional consequence of PD-1 signals on human CD4 + T cells by using multiple different approaches.

Owing to advances in molecular genetics, many specific gene mutations that cause diseases have been recently discovered. We aim to clarify how specific gene mutations result in the development of diseases, for example by using patient-derived iPS cells. Our target diseases include adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP; CSF1R mutation) and familial Mediterranean fever (MEFV mutation).