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Nikoletta Argentou

Regulatory T cells and Apoptosis-Induced Inflammation. Nikoletta Argentou. D EPARTMENT OF I MMUNOLOGY & H ISTOCOMPATIBILITY – U NIVERSITY OF T HESSALY. Introduction. Medzhitov R. Nature 2008 ; 454: 428-435.

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Nikoletta Argentou

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  1. Regulatory T cells and Apoptosis-Induced Inflammation NikolettaArgentou DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  2. Introduction Medzhitov R. Nature 2008; 454: 428-435 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  3. Introduction Medzhitov R. Nature 2008; 454: 428-435 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  4. Regulatory T cells DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  5. Regulatory T cells Regulatory T cells (Treg) are an essential component of the immune system, balancing necessary aggressiveness against foes with tolerance for self-constituents Sakaguchi S. AnnuRevImmunol2004; 22: 531-562 Natural Tregs(FOXP3) Tregs Tr1 (IL10) Inducible Tregs Th3 (TGFB1) Dolganiuc A. J LeucBiol2008; 84: 614-622 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  6. Regulatory T cells- Foes? Chronic Hepatic Infection • Accumulation of Tregs in the liver of patients with chronic HBV infection Franzese et al, 2005 • Positive correlation between the HBV DNA level and the frequency of Tregsin the blood of chronically infected patients Stoop et al, 2007 • Presence of CD4+FOXP3+ T cells in the liver of chronically HCV infected persons Scott et al, 2007 Autoimmune Hepatic Diseases • Reduced levels of circulating CD4+CD25highTregs Longhi et al, 2004 • Reduced levels in correlation with higher disease activity or poorer prognosis Longhi et al, 2004; Boyer et al, 2004 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  7. Regulatory T cells- or Friends? Kim et al, Nature Immunol2007;8: 191-197 • CD4+CD25+Foxp3 regulatory T Cells protect against T Cell-mediated fulminant hepatitis in a TGF-β-dependent manner in mice Wei et al, 2008 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  8. Apoptosis and Liver DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  9. Aim Clarify the contribution of Tregs in pathogenesis of apoptosis-induced liver inflammation DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  10. Study Design Chronic liver diseases 1.chronic HBV infection at diagnosis; CHB/d 2. chronic HBV infection after treatment/relapse; CHB/nr 3. chronic HBV infection after treatment/remission; CHB/r 4. chronic HCV infection; CHC 5. Non Alcoholic Fatty Liver Disease; NAFLD 6. Autoimmune hepatic diseases; AD Control group (with minimal disease) DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  11. Biopsy Material DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  12. Study Design DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  13. Study Design RNA extraction from BIOPSY MATERIAL cDNA synthesis Real Time PCR Reference gene: b2M Relative expression analysis: ΔΔCT method Livak and Schmittgen, 2001 DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  14. Results-1 Liver Diseases vs control group AD DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  15. Conclusions-1 Liver Diseases vs control group • Apoptosis-induced inflammation, independently of the cause of tissue damage, may be responsible for the accumulation of Tregsin liver. DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  16. Hypothetic model apoptosis phagocytosis self-antigen presentation by APCs expansion of Tregs Prevention of catastrophic damage of self-tissues DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  17. Results-2 CHB at diagnosis vs CHB at remission Gene expressions with significant alteration of mRNA levels in the liver in CHB (Mann-Whitney U test) DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  18. Results-2 CHB at diagnosis vs CHB at remission Gene expressions in the liver in CHB, according to the intensity of liver inflammation and fibrosis DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  19. Results-2 CHB at diagnosis vs CHB at remission Correlations of FOXP3 and PD-1/PD-L1 with the other studied genes in the liver in CHB DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  20. Conclusions-2 • The immunosuppressive liver environment is down-regulated in the maintained on-treatment long-term remission state and correlates with the intensity of liver inflammation, but not liver T-cell restoration. • The completion of Immunohistochemistry experiments for the analysis of FOXP3, CD8, CD4, PD-1, and PD-L1 protein expression “Liver FOXP3 and PD1/PDL1 expression is down-regulated in chronic HBV hepatitis on maintained remission, related to the degree of inflammation”. Frontiers in Immunology DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  21. Results-3 TGFb/Activin pathway in CHB and NAFLD Glasgow ECI 2012 Immunology 2012;137 (Suppl 1):506 (poster) Manuscript in preparation Error bar diagrams presenting the expression of genes, for which a significant alteration of their mRNA levels was observed. pvalues in each diagram refer to Mann-Whitney U test. DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  22. Results-3 TGFb/Activin pathway in CHB and NAFLD Glasgow ECI 2012 Immunology 2012;137 (Suppl 1):506 (poster) Manuscript in preparation Inflammation intensity Inflammation intensity p=0.029 p=0.040 p=0.001 p=0.035 SMAD7 mRNA expression ALK4 mRNA expression ALK5 mRNA expression INHBC mRNA expression absent absent marked minimal absent marked marked absent minimal moderate minimal marked minimal moderate moderate moderate mild mild mild mild Boxplot diagrams presenting the expression of mediators of the TGFb/Activin signaling pathway according to the intensity of liver inflammation. p values in each diagram refer to Kruskal-Wallis H test. DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  23. Coclusions-3 Glasgow ECI 2012 Immunology 2012;137 (Suppl 1):506 (poster) Manuscript in preparation • SMAD7overexpression might be a mechanism limiting the fibrogenic effect of TGFb suggesting that its induction may provide a target for novel therapeutic approaches. • The completion of Immunohistochemistry experiments for the analysis of TGF-b(-b1,-b2,-b3), and SMAD7 protein expression DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  24. Perspectives Examination of the hypothesis in another model of Chronic Inflammation • Osteoarthritis of hip • 6 patients (2M/4F); median age 73 years • Osteoarthritis of knee • 21 patients (1M/20F); median age 74 years • Control group • 5patients (3M/2F); median age 85 years DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  25. Collaborating Groups • A’Department of Internal Medicine, A.H.E.P.A Hospital, Aristotle University of Thessaloniki • Gastroenterology and Hepatology Division, Hippokration Hospital, Aristotle University of Thessaloniki • Department of Pathology, AHEPA Hospital, Aristotle University of Thessaloniki • Center of Immunology and Transplantation, Biomedical Research Foundation, Academy of Athens • A’ Department of Internal Medicine, Medical School, Democritus University of Thrace, • Department of Orthopaedic Surgery and Musculoskeletal Trauma, University General Hospital of Larissa, University of Thessalia DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  26. Ελληνικά Συνέδρια H έκφραση του FOXP3 στο ήπαρ σχετίζεται με το βαθμό αλλά όχι με το αίτιο της φλεγμονής. 12ο ΠανελλήνιοΗπατολογικόΣυνέδριο, Μάιος 2011, Χανιά Τα ηπατικά επίπεδα του FOXP3 mRNA στη Χρόνια Ηπατίτιδα Β εξαρτώνται από την έκφραση των οδών FAS/FASL και PD-1/PD-L1. 31ο ΠανελλήνιοΣυνέδριο Γαστρεντερολογίας, Οκτώβριος 2011, Θεσσαλονίκη, Annals of Gastroenterology, 2011;24:S13. Η ηπατική έκφραση FOXP3 και PD1/PDL1 ελαττώνεται στη Χρόνια Ηπατίτιδα Β σε διατηρούμενη ύφεση, σχετιζόμενη με το βαθμό της φλεγμονής. 32ο ΠανελλήνιοΣυνέδριο Γαστρεντερολογίας, Νοέμβριος 2012, Αθήνα. Η υπερέκφραση του SMAD7 προστατεύει το ήπαρ από την TGF-β/SMAD-μεσολαβούμενηινογένεση. 32ο ΠανελλήνιοΣυνέδριο Γαστρεντερολογίας, Αθήνα, Νοέμβριος 2012. InternationalCongresses Foxp3 expression in liver correlates with the degree but not the cause of inflammation. The Liver Meeting AASLD, October 2010, Boston, Massachusets. Liver PD-1/PDL-1/PDL-2 mRNA expression quantitative analysis in patients with chronic HBV and HCV hepatitis. The International Liver Congress, 45th annual meeting of the European Association for the Study of the Liver, April 2010 Vienna, Austria, J Hepatol, 52; S506. Overexpression of SMAD7 protects liver from TGFb/Smad-mediated fibrogenesis. European Congress of Immunology, September 2012, Glasgow, Scotland, Immunology, 137; S506. DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

  27. Thank you for your attention… DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

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