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ISFA Vienna 2011 8th International Society for Apheresis Congress

Extracorporeal (pro- and anti-inflammatory) cytokine removal: beyond lipid-apheresis? Claudia Stefanutti. ISFA Vienna 2011 8th International Society for Apheresis Congress 3rd Wiener Aphereseseminar (Educational Program) September 14th – 17th University Hospital, Vienna - Austria.

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ISFA Vienna 2011 8th International Society for Apheresis Congress

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  1. Extracorporeal (pro- and anti-inflammatory) cytokine removal: beyond lipid-apheresis?Claudia Stefanutti ISFA Vienna 2011 8th International Society for Apheresis Congress 3rd Wiener Aphereseseminar (Educational Program) September 14th – 17th University Hospital, Vienna - Austria

  2. Chemokines (Cytokines) and inflammation Over the last decade we have come to understand that atherosclerotic plaque formation is a process of ongoing inflammation Atherogenesis is characterized by endothelial damage, recruitment of mononuclear cells and vascular smooth muscle cell (VSMC) proliferation Many of these processes are driven by chemokines Evidence implicating chemokines in the development of ATS lesions: • Experimental animal models • Primary cell culture systems • Immunohistochemistry of atherosclerotic plaques • Genetic association studies

  3. Chemokine function in atherosclerosis 1 Monocyte exposure to oxLDL leads to loss of MCP-1 R (which is pro-migratory) and gain of fractalkineR (which is pro-adhesive), facilitating plaque progression Macrophages exposed to oxLDL express higher levels of fractalkine R, which enables adhesion to SMCs, providing a credible retention mechanism in the ATS lesions The Chemokine ligand 1 receptor (the ligands: MIP-1α, RANTES, MCP-3, MPIF-1), and RANTES R have been implicated in the development of ATS RANTES, MIP-1α and MIP-1β, can be detected in ATS plaques Barlic, J. et al., Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor gamma-dependent pathway; Circulation(2006); 114: 807-819

  4. Chemokine function in atherosclerosis 2 Th1 cells secrete IFN-γ, leading to macrophage activation, which can lead to ATS plaque destabilisation(e.g., by increased MMP-9 expression).The Chemokine ligand 1 receptor is highly expressed on monocytes, while levels of RANTES Rexpression are highest on Th1-like cells (CD4+subset) accumulating in developing ATS plaques Interestingly, MCP-1has been shown to be a direct target for statin therapy; Treatment of normocholesterolemic patients for 2 weeks with simvastatin led to a reduction in MCP-1 Rexpression on circulating monocytes without a reduction in plasma LDL In a study involving over 2000 patients at high CVD risk, MCP-1acting via MCP-1 R, atorvastatin treatment resulted in a small (4%) but significant drop in plasma levels of MCP-1

  5. APHERESIS ?

  6. Cytokine2011 Aug;55(2):245-50. Epub 2011 May 10. Cytokines profile in serum of homozygous familial hypercholesterolemia is changed by LDL-apheresis. Stefanutti C, Vivenzio A, Di Giacomo S, Ferraro PM. Source Extracorporeal Therapeutic Techniques Unit, Immunohematology and Transfusion Medicine, Department of Molecular Medicine University of Rome "La Sapienza", "Umberto I" Hospital, Rome, Italy.

  7. Stefanutti C et al., Cytokine 2011; 55(2):245-50

  8. Stefanutti C et al., Cytokine 2011; 55(2):245-50

  9. Stefanutti C et al., Cytokine 2011; 55(2):245-50

  10. Study outcome In this study LDL-apheresis changed several circulating cytokines and their receptors inducing anti-inflammatory and anti-atherogenic changes in cytokines plasma profile in HozFH patients with/without pre-existing angiographically demonstrated coronary heart disease (CHD) and aortic valvular disease (AVD).

  11. Discussion (1) Given the key role of chemokines and their receptors in inflammatory cell recruitment and activation, chemokine network has emerged as an attractive target for the development of new anti-inflammatory drugs in a wide range of chronic inflammatory diseases Several studies looking for novel biomarkers of increased risk of CVD have been performed and a number of CC chemokines have been identified as promising candidates for further studies An obvious question that arises from this impressive body of experimental work is - will any of these therapeutic approaches find clinical application in the treatment of ATS and CVD?

  12. Discussion & future prospects (2) Experimental animal models of arterial injury strongly suggest that short- term intervention to prevent inflammatory cell recruitment to sites of vascular injury can have beneficial effects on the resultant vascular remodeling, providing that they do not prevent the recruitment of endothelial progenitor cells Rather than thinking about life-long anti chemokine therapy perhaps we should consider if short-term, high intensity blockadeor inhibition of chemokine activity could offer a significant benefit to patients undergoing percutaneous angioplasty or coronary artery bypass surgery Lipid- or LDL-apheresis can do this? Yes, presumably! To be furtherly investigated

  13. Chronic inflammatory diseases (suggested to be treated by therapeutic apheresis) Rheumatoid Arthritis Cardiovascular Disease Asthma and COPD Multiple Sclerosis (MS) Chronic Neuropathic Pain Inflammatory Bowel Disease Age Related Macular Degeneration Charo and Ransohoff, The many roles of chemokines and chemokine receptors in inflammation; N Engl J Med (2006) 354: 610-62 OPEN QUESTIONS Another important question to address is will anti-chemokine drugs and extracorporeal treatments such as LDL-apheresis offer a significant increased benefit to patients affected by severe dyslipidemia genetically determined taking cholesterol-lowering drugs (e.g. statins) ? If safe small molecule inhibitors of chemokine receptors are developed for other inflammatory diseases it will be possible to test the ability of these drugs to act synergistically with cholesterol-lowering agents (LDL-apheresis, statins) in clinical trials in subgroups of patients at enhanced risk of developing CVD complications ?

  14. MIP-1αmacrophage inflammatory proteins 1α MIP-1βmacrophage inflammatory proteins 1β MCP-1 monocyte chemoattractant protein-1 RANTESRegulated upon Activation, Normal T-cell Expressed, and Secreted GCSFgranulocyte–colony stimulating factor GM-CSF granulocyte macrophage-colony stimulating factor IL-1α interleukin-1α IL-1β interleukin-1β IL-2 interleukin-2 IL-6 interleukin-6 IFN-γ interferon-γ Apheresis-inducible cytokine pattern change in severe, genetic dyslipidemias Stefanutti C, Vivenzio A, Ferraro PM*, Morozzi Claudia, Belotherkovsky Dany Extracorporeal Therapeutic Techniques Unit Immunohematology and Transfusion Medicine, Department of Molecular Medicine - University of Rome ‘La Sapienza’ - ‘Umberto I’ Hospital Renal Unit - Catholic University of the Sacred Heart of  Rome (*)

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