Treg Alterations Lead To Systemic And Local Immune Deregulation In Idiopathic Pulmonary Fibrosis And Collagen Vascular Dis...
CD4 + CD25 +  T regulatory cells <ul><li>Essential for the maintenance of immunological tolerance </li></ul><ul><li>Preven...
Background <ul><li>ILDs are a heterogeneous group of lung diseases. </li></ul><ul><li>Imbalance of Th1/Th2 cytokine profil...
<ul><li>Evidence for immune system involvement in the pathogenesis of ILDs </li></ul><ul><li>Tregs  are the main regulator...
Experimental Design <ul><li>Patients & controls :   </li></ul><ul><li>Two groups of diseases  (CVD-IP n=10, IPF n=5)  </li...
<ul><li>IPF:  22% ±2.9% </li></ul><ul><li>CVD-IP:  18.6%±3% </li></ul><ul><li>Non-ILD:  7%±1.3%  </li></ul>Treg frequency ...
Treg frequency in BAL CD4 CD25 30% 28% 5.6% IPF Non ILD CVD-IP
<ul><li>The   absolute number   of   CD4 + CD25 hi  Tregs   in the periphery   is the same in all groups </li></ul>Absolut...
<ul><li>The   percentage of   CTLA-4   in   CD4 + CD25 hi  Tregs   of BAL   and   PB   is the same in all groups  </li></u...
<ul><li>Tregs in   PB   of   IPF and CVD-IP patients are  2  times less   suppressive in comparison with ND and non-ILDs  ...
CFSE-based proliferation assays in PB
CFSE-based proliferation assays in BAL <ul><li>Tregs in BAL of IPF and CVD-IP patients  exerted  comparable suppression  w...
Conclusions  <ul><li>In both IPF and CVD-IP Tregs exert impaired suppression in the  peripheral  blood , allowing  the ons...
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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

    1. 2. 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
    2. 3. CD4 + CD25 + T regulatory cells <ul><li>Essential for the maintenance of immunological tolerance </li></ul><ul><li>Prevent of autoimmunity by active suppression </li></ul><ul><li>High expression of a-chain of the IL-2 receptor (CD25) </li></ul><ul><li>Foxp3 is essential for their development and function </li></ul><ul><li>Suppression requires cell contact through CTLA-4 molecule </li></ul>T reg Foxp3 GITR CD4 CD25 CTLA-4
    3. 4. Background <ul><li>ILDs are a heterogeneous group of lung diseases. </li></ul><ul><li>Imbalance of Th1/Th2 cytokine profile </li></ul><ul><li>TGF- β : pro-fibrotic effect IFN- γ : anti-fibrotic effect </li></ul><ul><li>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). </li></ul><ul><li>Local and systemic immune activation remitting after steroids in IPF/UIP Homolka, J. et al. Respiration (2003) </li></ul><ul><li>Oligoclonal expansion of T cells </li></ul><ul><li>Shimizudani, N. et al Clin Exp Immunol (2002) </li></ul><ul><li>Yurovsky, V.V et al.Hum Immunol (1996) </li></ul>
    4. 5. <ul><li>Evidence for immune system involvement in the pathogenesis of ILDs </li></ul><ul><li>Tregs are the main regulatory subset responsible for the control of immunologic tolerance </li></ul><ul><li>Systemic and/or local, qualitative and/or quantitative Treg alterations are involved in the pathophysiology of ILDs </li></ul>Hypothesis - Objective
    5. 6. Experimental Design <ul><li>Patients & controls : </li></ul><ul><li>Two groups of diseases (CVD-IP n=10, IPF n=5) </li></ul><ul><li>24 Normal donors (ND only PB) </li></ul><ul><li>6 non-ILDs (as BAL controls) </li></ul><ul><li>Phenotypic analysis : </li></ul><ul><li>4-colour flow cytometry in PB and BAL </li></ul><ul><li>( CD4, CD25, CD152) </li></ul><ul><li>Modified MACS-isolation of </li></ul><ul><li>CD4 + CD25 High Tregs </li></ul><ul><li>CFSE-based proliferation assays </li></ul><ul><li>MACS-isolated PB and BAL </li></ul><ul><li>CD4 + CD25 + or – cells after polyclonal stimulation </li></ul>
    6. 7. <ul><li>IPF: 22% ±2.9% </li></ul><ul><li>CVD-IP: 18.6%±3% </li></ul><ul><li>Non-ILD: 7%±1.3% </li></ul>Treg frequency in BAL and PB P<0.03 P=0.01
    7. 8. Treg frequency in BAL CD4 CD25 30% 28% 5.6% IPF Non ILD CVD-IP
    8. 9. <ul><li>The absolute number of CD4 + CD25 hi Tregs in the periphery is the same in all groups </li></ul>Absolute number of Tregs in PB non-ILDs CVD-IP IPF ND
    9. 10. <ul><li>The percentage of CTLA-4 in CD4 + CD25 hi Tregs of BAL and PB is the same in all groups </li></ul><ul><li>Significant difference between BAL and PB in CVD-IP and IPF ( *p<0.05). </li></ul>* * CTLA-4 expression in Tregs
    10. 11. <ul><li>Tregs in PB of IPF and CVD-IP patients are 2 times less suppressive in comparison with ND and non-ILDs </li></ul><ul><li>(Τ reg:Teff = 1:2, *p<0.05 , n =5 ) . </li></ul>CFSE-based proliferation assays in PB * *
    11. 12. CFSE-based proliferation assays in PB
    12. 13. CFSE-based proliferation assays in BAL <ul><li>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) </li></ul>
    13. 14. Conclusions <ul><li>In both IPF and CVD-IP Tregs exert impaired suppression in the peripheral blood , allowing the onset of autoimmunity </li></ul><ul><li>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 </li></ul><ul><li>Our results indicate systemic and local immune system involvement in the pathophysiology of ILDs </li></ul>
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