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1957.ppt
 

1957.ppt

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  • METRAS: 4/25/FOXP3 % KAI ABS NO STO BAL, EPISHS: 4/25 STO PB ALLAZEIS KAI KANEIS CD152 STA OLIKA CD4+ SE PB KAI BAL
  • … as it is shown by both the proliferation assays and CTLA-4 expression. Potentially

1957.ppt 1957.ppt Presentation Transcript

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  • Treg Alterations Lead To Systemic And Local Immune Deregulation In Idiopathic Pulmonary Fibrosis And Collagen Vascular Disease-Associated Interstitial Pneumonia Nakou E 1 , Tzouvelekis A 1 , Bouchliou I 2 , Kouliatsis G 1 , Froudarakis M 1 , Steiropoulos P 1 , Kotsianidis I 2 and Bouros D 1 1 Dep of Pneumonology and 2 Dep of Haematology, Democritus Thrace University Hospital Alexandroupolis, Greece
  • CD4 + CD25 + T regulatory cells
    • Essential for the maintenance of immunological tolerance
    • Prevent of autoimmunity by active suppression
    • High expression of a-chain of the IL-2 receptor (CD25)
    • Foxp3 is essential for their development and function
    • Suppression requires cell contact through CTLA-4 molecule
    T reg Foxp3 GITR CD4 CD25 CTLA-4
  • Background
    • ILDs are a heterogeneous group of lung diseases.
    • Imbalance of Th1/Th2 cytokine profile
    • TGF- β : pro-fibrotic effect IFN- γ : anti-fibrotic effect
    • Krein et al,Chest ,(2002). Strieter et al, Am J Respir Crit Care Med(2004). Burdick et al. Am J Respir Crit Care Med,(2005).
    • Local and systemic immune activation remitting after steroids in IPF/UIP Homolka, J. et al. Respiration (2003)
    • Oligoclonal expansion of T cells
    • Shimizudani, N. et al Clin Exp Immunol (2002)
    • Yurovsky, V.V et al.Hum Immunol (1996)
    • Evidence for immune system involvement in the pathogenesis of ILDs
    • Tregs are the main regulatory subset responsible for the control of immunologic tolerance
    • Systemic and/or local, qualitative and/or quantitative Treg alterations are involved in the pathophysiology of ILDs
    Hypothesis - Objective
  • Experimental Design
    • Patients & controls :
    • Two groups of diseases (CVD-IP n=10, IPF n=5)
    • 24 Normal donors (ND only PB)
    • 6 non-ILDs (as BAL controls)
    • Phenotypic analysis :
    • 4-colour flow cytometry in PB and BAL
    • ( CD4, CD25, CD152)
    • Modified MACS-isolation of
    • CD4 + CD25 High Tregs
    • CFSE-based proliferation assays
    • MACS-isolated PB and BAL
    • CD4 + CD25 + or – cells after polyclonal stimulation
    • IPF: 22% ±2.9%
    • CVD-IP: 18.6%±3%
    • Non-ILD: 7%±1.3%
    Treg frequency in BAL and PB P<0.03 P=0.01
  • Treg frequency in BAL CD4 CD25 30% 28% 5.6% IPF Non ILD CVD-IP
    • The absolute number of CD4 + CD25 hi Tregs in the periphery is the same in all groups
    Absolute number of Tregs in PB non-ILDs CVD-IP IPF ND
    • The percentage of CTLA-4 in CD4 + CD25 hi Tregs of BAL and PB is the same in all groups
    • Significant difference between BAL and PB in CVD-IP and IPF ( *p<0.05).
    * * CTLA-4 expression in Tregs
    • Tregs in PB of IPF and CVD-IP patients are 2 times less suppressive in comparison with ND and non-ILDs
    • (Τ reg:Teff = 1:2, *p<0.05 , n =5 ) .
    CFSE-based proliferation assays in PB * *
  • CFSE-based proliferation assays in PB
  • CFSE-based proliferation assays in BAL
    • Tregs in BAL of IPF and CVD-IP patients exerted comparable suppression with the non-ILD BAL Treg (Τ reg:Teff = 1:2, n=5)
  • Conclusions
    • In both IPF and CVD-IP Tregs exert impaired suppression in the peripheral blood , allowing the onset of autoimmunity
    • In contrast, Tregs are expanded and also functionally normal in the lung of the above diseases, potentially resulting in aberrant oversuppression of the local immune response
    • Our results indicate systemic and local immune system involvement in the pathophysiology of ILDs