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This article explores the immunomodulatory effects of statins, particularly pravastatin, in heart transplant patients. Research indicates that statins not only improve lipid levels but also enhance survival rates and reduce the risk of severe rejection and cardiac allograft vasculopathy. Significant findings from trials show a decrease in natural killer cell activity when pravastatin is administered, suggesting its potential as an adjunct to conventional immunosuppressants like cyclosporine. The article discusses the broader immunomodulatory properties of statins, emphasizing their pleiotropic effects beyond cholesterol lowering.
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Statins and Immunomodulation Jon A. Kobashigawa, MD DSL/Thomas D. Gordon Chair in Heart Transplantation Medicine Associate Director, Cedars-Sinai Heart Institute Director, Advanced Heart Disease Section Director, Heart Transplant Program Cedars-Sinai Medical Center, Los Angeles, California Cedars-Sinai Heart Institute
Conflict of Interest/Affiliation Disclosure Statement Ihave the following relationship(s) to disclose: Research grants Name of Company/ies with which relationship exists: Novartis, XDx, TransMedics, Alexion Cedars-Sinai Heart Institute
Cardiac Allograft Vasculopathy Histology: Section of Affected Coronary Artery
Pravastatin in Heart Transplantation • The original paper1, “Outcomes of pravastatin in heart transplant patients” demonstrated benefit in survival, clinically severe rejection, and cardiac allograft vasculopathy at one year after transplant. • Inhibition of natural killer cells2 in the pravastatin treated patients suggested an added immunosuppressive effect when given concomitantly with cyclosporine. 1 Kobashigawa JA et al. N Engl J Med. 1995:333:621-627. 2 Wang M, Terasaki PI et al. Human Immunology 1993; 37: 264-270 Cedars-Sinai Heart Institute
Pravastatin Randomized Trial in Heart Transplantation • 97 heart transplant patients randomized to pravastatin (n=47) or no pravastatin (n=50) • Primary end points at 1 year included cholesterol levels, rejection, survival, and cardiac allograft vasculopathy by angiography and intravascular ultrasound (IVUS) Kobashigawa JA et al. N Engl J Med. 1995:333:621-627. Cedars-Sinai Heart Institute
First-year Results of Pravastatin Study NKC = natural killer cell IVUS = intravascular ultrasound Kobashigawa JA et al. N Engl J Med 1995:333:621-627
Terasaki Microtest Tray: Use of Calcein AM Vital Dye • Natural killer cells, lymphokine-activated killer cells and cytotoxic T-lymphocytes are readily detectable by this microtest. • The advantages of this microtest (1993) over the standard chromium-release assay are: • no radioactivity • tenfold fewer cells required • measurement time of 1 second per reading, which is about 60 times faster than with chromium release • ease in setting up multiple tests, numbering in the hundreds • results can be confirmed by microscopic examination. Wang M, Terasaki PI et al. Human Immunology 1993; 37: 264-270
Statins as Immunomodulators • Suppresses T-cell responses.1 • Reduces expression of class II MHC on APC’s due to suppression of CIITA promoter gene.2 • Reduces chemokine synthesis in PBM cells.3 • Blocks LFA-1 to decrease lymphocyte adhesion to ICAM-1 and impair T-cell costimulation.4 1. Kurakata, et al. Immunopharm 1996;34:51-61 2. Kwak, et al. Nature Med 2000;6:1399-1402 3. Romano, et al. Lab Invest 2000;80:1095-1100 4. Weitz, et al. Nature Med 2001;7:687-692 Cedars-Sinai Heart Institute
Cholesterol Synthesis Pathway HMG-CoA HMG-CoA Reductase Inhibitors Mevalonate Farnesyl P-P Farnesylated RAS Cholesterol
Farnesyltransferase Inhibition: A Novel Method of Immunomodulation • Farnesyltransferase inhibitors (FTIs) block farnesylation of proteins. • A new potent FTI, A228839, is analyzed for its effects on T cell proliferation, T cell polarized shape, intracellular calcium kinetics, cytokine production and apoptosis. • Si MS, Imagawa DK, et al. .Int Immunopharmacol 2003 Apr;3(4):475-483 Cedars-Sinai Heart Institute
A228839 Prevents Lectin-Induced Lymphocyte Proliferation Absorbance Lambda=490 nm A228839 ul PHA - + + + + + + + + • Si MS, Imagawa DK, et al. .Int Immunopharmacol 2003 Apr;3(4):475-483
A228839 Disrupts 1ES T cell Polarized Shape • Si MS, Imagawa DK, et al. .Int Immunopharmacol 2003 Apr;3(4):475-483
A228839 Promotes Apoptosis in PHA-Activated Lymphocytes A228839 treated lymphocytes (overlay) demonstrated greater FL-1 channel signals reflecting increased staining with annexin V. Approx 83% of A228839 treated lymphocytes were apoptotic as compared to 31% of untreated controls. Apoptotic Region A228839 Control • Si MS, Imagawa DK, et al. .Int Immunopharmacol 2003 Apr;3(4):475-483
Farnesyltransferase Inhibition: A Novel Method of Immunomodulation • Prevents lectin-induced lymphocyte proliferation. • Prevents APC-induced T cell proliferation. • Disrupts 1E5 T cell polarized shape. • Alters lymphocyte [Ca ++]i homeostasis. • Potently inhibits PBMC cytokine production. • Promotes apoptosis in lectin-activated lymphocytes. • Si MS, Imagawa DK, et al. .Int Immunopharmacol 2003 Apr;3(4):475-483 Cedars-Sinai Heart Institute
Summary • Benefit from statins are derived not only from lipid-lowering but also through the pleiotropic,cholesterol-independent effects which include: • vasculoprotective • anti-inflammatory • immunomodulatory properties • Statin therapy administered to patients after heart transplant on calcineurin inhibitor results in a decrease in rejection, cardiac allograft vasculopathy, and an increase in survival. • Various mechanistic studies of potential benefit of statins have been realized supporting its routine use in heart transplant recipients. Cedars-Sinai Heart Institute
