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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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slide1

Regulatory T cells

and Apoptosis-Induced

Inflammation

NikolettaArgentou

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide2

Introduction

Medzhitov R. Nature 2008; 454: 428-435

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide3

Introduction

Medzhitov R. Nature 2008; 454: 428-435

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide4

Regulatory T cells

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide5

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

slide6

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

slide7

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

slide8

Apoptosis and Liver

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide9

Aim

Clarify the contribution of Tregs

in pathogenesis of apoptosis-induced liver inflammation

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide10

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

slide11

Biopsy Material

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide12

Study Design

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide13

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

slide14

Results-1

Liver Diseases vs control group

AD

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY

slide15

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

slide16

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

slide17

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

slide18

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

slide19

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

slide20

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

slide21

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

slide22

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

slide23

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

slide24

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

slide25

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

slide26

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

slide27

Thank you

for your attention…

DEPARTMENT OFIMMUNOLOGY & HISTOCOMPATIBILITY – UNIVERSITY OF THESSALY