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Shinji Shimoda Last modified date:2020.06.22

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Academic Degree
Analysis of auto-immune T cells in primary billiary cihhrosis
Field of Specialization
 Infection and Immunity, Hepatology
Outline Activities
I investigate the etiology and pathology of autoimmune disease, I beliieve it makes possible to regulate immuno diseases. I choose primary billiary cihhrosis as one sample of autoimmune disases.
I investigate the pathology of infectious immunity, and try to regulate the infection. I choose chronic hepatitis, type B and C as one sample of infectious diseases.
And I investigate antibiotics resistant bacteria which causes febrile neutropenia.
Research Interests
  • Development of anti-fibrotic drug for patients with primary biliary cholangitis
    keyword : primary biliary cholangitis, anti-fibrotic treatment
  • Development of anti-fibrotic drug that block the CBP/B-catenine for liver cirrhosis with HCV
    keyword : Liver, fibrosis treatment
  • Development of new treatment of primary biliary cholangitis with informations of genome and lipids from disease mimic culture system
    keyword : genome analysis, lipid analysis, primary biliary cholangitis, disease mimic culture system, genome wide association study
  • The role of sinusoidal endothelial cells in the hepatic fibrosis
    keyword : liver sinusoidal endothelial cells, extra cellular magtrix
  • Chronic inflammation induced by infection or autoimmunity in the liver
    keyword : autophagy、inflammasomes
  • Analysis of Ag reactive T cells in chronic infection
    keyword : PD-1、exhausted T cell
  • The pathology of Autoimmune diseases
    keyword : autoimmune disease
Current and Past Project
  • Biliary epithelial cells (BEC) which established from disease liver in liver transplantation from Primary biliary cirrhosis expressed CD40 and Toll-like receptor (TLR)2,3 and 4. BEC were examined whether they have roles as antigen presenting cells.
    Auto antigen pyruvate dehydrogenase complex E2 component (PDC-E2) 163-176 peptide was pulsed to BEC, and PDC-E2 163-176 reactive T cell clones (TCC) were co-cultured with the peptide pulsed BEC, and TCC proliferation assay were performed. In some cases, BEC were pre-incubated with IFN-, CD40 ligand, TLR2, 3, or 4 ligand. In all cases BEC could not proliferate TCC. BEC could not express co-stimulation molecules, CD80 or CD86 even after stimulated with IFN-, CD40 ligand, TLR2, 3, or 4 ligand.
    Next BEC were examined whether sensitivity as target cells are increased after stimulated with IFN-, CD40 ligand, TLR2, 3, or 4 ligand. BEC have roles as target cells after stimulated with IFN-on the other hand BEC did not have roles as target cells with other stimulation.
    Finally chemokine CXCL8, CCL2, CXCL9, CXCL10, CX3CL1 and CXCL16 production from BEC were examined with or without the stimulation of IFN-, TLR2, 3, or 4 ligand. BEC produced CXCL8 and CCL2 spontaneously. CXCL10, CX3CL1 and CXCL16 were produced after the stimulation with TLR3 ligand. IFN-increased the production of such chemokines.
    In conclusion, BEC were clarified that they do not have roles as antigen presenting cells, that IFN-g stimulation turn BEC as target cells but other stimulation did not affect BEC as target cells, and that BEC produce chemokines spontaneously or uniquely with TLR3 ligand.
Academic Activities
1. Shinji Shimoda, It is time to change primary biliary cirrhosis (PBC): New nomenclature from cirrhosis to cholangitis, and upcoming treatment based on unveiling pathology, Hepatol Res., 2016.03.
1. Ueno K, Aiba Y, Hitomi Y, Shimoda S, Nakamura H, Gervais O, Kawai Y, Kawashima M, Nishida N, Kohn SS, Kojima K, Katsushima S, Naganuma A, Sugi K, Komatsu T, Mannami T, Matsushita K, Yoshizawa K, Makita F, Nikami T, Nishimura H, Kouno H, Kouno H, Ohta H, Komura T, Tsuruta S, Yamauchi K, Kobata T, Kitasato A, Kuroki T, Abiru S, Nagaoka S, Komori A, Yatsuhashi H, Migita K, Ohira H, Tanaka A, Takikawa H, Nagasaki M, Tokunaga K, Nakamura M; PBC‐GWAS Consortium in Japan., Integrated GWAS and mRNA Microarray Analysis Identified IFNG and CD40L as the Central Upstream Regulators in Primary Biliary Cholangitis., Hepatol Commun., 4, 5, 724-738, 2020.03.
2. Ogawa E, Toyoda H, Iio E, Jun DW, Huang CF, Enomoto M, Hsu YC, Haga H, Iwane S, Wong G, Lee DH, Tada T, Liu CH, Chuang WL, Hayashi J, Cheung R, Yasuda S, Tseng CH, Takahashi H, Tran S, Yeo YH, Henry L, Barnett SD, Nomura H, Nakamuta M, Dai CY, Huang JF, Yang HI, Lee MH, Jung Jun M, Kao JH, Eguchi Y, Ueno Y, Tamori A, Furusyo N, Yu ML, Tanaka Y, Nguyen MH; REAL-C Investigators, Ahn SB, Azuma K, Dohmen K, Yoon Jeong J, Jung JH, Kajiwara E, Kato M, Kawano A, Koyanagi T, Ooho A, Park SH, Satoh T, Shimoda S, Song DS, Takahashi K, Yeh ML, Yoon EL., HCV Cure Rates are Reduced in Patients with Active but not Inactive Hepatocellular Carcinoma- A Practice Implication., Clin Infect Dis., 2019.11.
3. Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D, Vierling JM, Adams D, Alpini G, Banales JM, Beuers U, Björnsson E, Bowlus C, Carbone M, Chazouillères O, Dalekos G, De Gottardi A, Harada K, Hirschfield G, Invernizzi P, Jones D, Krawitt E, Lanzavecchia A, Lian ZX, Ma X, Manns M, Mavilio D, Quigley EM, Sallusto F, Shimoda S, Strazzabosco M, Swain M, Tanaka A, Trauner M, Tsuneyama K, Zigmond E, Gershwin ME., The challenges of primary biliary cholangitis: What is new and what needs to be done., J Autoimmun., 8, 10, 1157, 2019.09.
4. Shinji Shimoda, Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis., 75, 150-160, 2016.12.
5. Shinji Shimoda, Natural killer cells regulate T cell immune responses in primary biliary cirrhosis., 62, 6, 1817-1827, 2015.06.
6. Shimoda S, Harada K, Niiro H, Yoshizumi T, Soejima Y, Taketomi A, Maehara Y, Tsuneyama K, Nakamura M, Komori A, Migita K, Nakanuma Y, Ishibashi H, Selmi C, Gershwin ME., Biliary epithelial cells and primary biliary cirrhosis: the role of liver-infiltrating mononuclear cells., Hepatology, 47(3):958-65., 2008.03.
7. Shimoda S, Miyakawa H, Nakamura M, Ishibashi H, Kikuchi K, Kita H, Niiro H, Arinobu Y, Ono N, Mackay IR, Gershwin ME, Akashi K., CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis, J Autoimmun., 31(2):110-5, 2008.09.
8. Kawano A, Shimoda S, Kamihira T, Ishikawa F, Niiro H, Soejima Y, Taketomi A, Maehara Y, Nakamura M, Komori A, Migita K, Ishibashi H, Azuma M, Gershwin ME, Harada M. , Peripheral tolerance and the qualitative characteristics of autoreactive T cell clones in primary biliary cirrhosis., J Immunol. , 2007.09.
9. Kamihira T, Shimoda S, Nakamura M, Yokoyama T, Takii Y, Kawano A, Handa M, Ishibashi H, Gershwin ME, Harada M, Biliary epithelial cells regulate autoreactive T cells: implications for biliary-specific diseases., Hepatology., 10.1002/hep.20494, 41, 1, 151-159, 41(1):151-9, 2005.01.
10. Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, Tsuneyama K, Nakamura M, Ishibashi H, Nakanuma Y, Gershwin ME, Harada M, Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis., Gastroenterology. , 10.1053/S0016-5085(03)01359-3, 125, 5, 1379-1387, 1379-87, 2003.11.
11. Shimoda S, Nakamura M, Ishibashi H, Hayashida K, Niho Y., HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases., J Exp Med, 10.1084/jem.181.5.1835, 181, 5, 1835-1845, 1;181(5):1835-45., 1995.05.
1. Shinji Shimoda, Kenichi Harada, Minoru Nakamura, M Eric Gershwin, Identification of new biomarkers of biliary epithelial cells in primary biliary cholangitis (PBC), アメリカ肝臓学会(AASLD), 2019.11, Many patients with primary biliary cirrhosis (PBC) who are refractory for standard UDCA therapy progress to fibrosis. Then it is urgent to detect the new biomarkers for UDCA refraction and new therapy target molecules. The hallmark of PBC is the presence of chronic non-suppurative destructive cholangitis. Main target for PBC is biliary epithelial cell (BEC).
We have previously demonstrated that toll like receptors ligands (TLRLs) and hydrophobic bile acids induce inflammation in PBC mimic ex vivo culture system that contains immune cells and autologous BEC. We have taken advantage of our ability to isolate relatively pure viable preparations of liver-derived BEC and spleen-derived immune cells, and isolated total RNA from BEC and immune-cells in PBC mimic ex vivo culture system and performed gene expression microarrays. We found immune cells after the contact with the TLRLs and hydrophobic bile acids stimulated BEC produce IFNG. Then next we stimulate BEC in the presence of IFNG or in the presence of TLRLs and hydrophobic bile acid. We integrated these data with the array data from liver biopsy samples. Eleven genes from BEC were up regulated and one gene is down regulated in common from PBC mimic culture system and from liver biopsy samples. All 12 genes are coded proteins and immune staining from liver biopsy samples were available for 4 (IFIT2, IFIT3, IDO1, RTP4) out of total 12 proteins. We prepared samples from untreated PBC (n=22), UDCA treated PBC (n=12) and HCV hepatitis (n=19). Expression patterns of all four proteins in BEC are similar to each other one. The expression from untreated PBC is high when compared to that from HCV hepatitis (all of four: p<0.05) and the expression from treated PBC is low when compared to that from untreated PBC (all of four: p<0.05). Then now we conclude that the expression of these four proteins from BEC might be predict the response of UDCA treatment in patients with PBC.
2. Shimoda Shinji, Liver Immunology and Genetics, Autoimmune target cells in primary biliary cholangitis, The Asian Pacific Association for the Study of the Liver, 2019.04.
3. Shinji Shimoda, Kenichi Harada, Minoru Nakamura, Molecular mechanism of autoimmune liver diseases, especially PBC, JSH-EASL Joint Session (第54回日本肝臓学会総会), 2018.06.
4. 下田 慎治, Hydrophobic Bile Acids Suppress Expression of AE2 in Biliary Epithelial Cells and, American association for the study of liver diseases, 2016.11.
5. 下田 慎治, Natural killer cells regulate T cell immunity in primary biliary cirrhosis
, American Association for the Study of Liver Diseases 2015, 2015.11.
Membership in Academic Society
  • The Japanese Society for Mucosal Immunology
  • The Japan society for Clinical Immunology
  • The role of NK cells for destruction of bile ducts in primary biliary cirrhosis
Educational Activities
Lecture of medical school students and resident physicians.
Other Educational Activities
  • 2018.04.
  • 2017.04.
  • 2016.06.
Professional and Outreach Activities
Fukuoka Medical doctor Training program coordination commission
Fukuoka Intractable disease management commission.