Inhibition of protein geranylgeranylation specifically interferes with cd40-dependent B cell activation, resulting in a reduced capacity to induce T cell immunity

Journal of Immunology

Volumn 193, Issue 10, 2014, Pages 5294-5305

  Shimabukuro Vornhagen, Alexander ^a   Zoghi, Shahram ^a   Liebig, Tanja M ^a   Wennhold, Kerstin ^a   Chemitz, Jens ^a   Draube, Andreas ^a   Kochanek, Matthias ^a   Blaschke, Florian ^b,c   Pallasch, Christian ^a   Holtick, Udo ^a   Scheid, Christof ^a   Theurich, Sebastian ^a   Hallek, Michael ^a   Von Bergwelt Baildon, Michael S ^a  

^a UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^c MAX DELBRÜCK CENTER FOR MOLECULAR MEDICINE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ATORVASTATIN; CD40 ANTIGEN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MEVALONIC ACID; SIMVASTATIN; HEPTANOIC ACID DERIVATIVE; PYRROLE DERIVATIVE; TRANSCRIPTOME;

ANTIGEN PRESENTATION; ARTICLE; B LYMPHOCYTE ACTIVATION; CELLULAR IMMUNITY; CONTROLLED STUDY; CYTOKINE PRODUCTION; ENZYME INHIBITION; GENE EXPRESSION REGULATION; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IMMUNOMODULATION; NORMAL HUMAN; PROTEIN GERANYLGERANYLATION; PROTEIN MODIFICATION; SIGNAL TRANSDUCTION; TRANSCRIPTOMICS; UPREGULATION; ANTAGONISTS AND INHIBITORS; B LYMPHOCYTE; DENDRITIC CELL; DRUG EFFECTS; ENZYMOLOGY; GENETICS; IMMUNOLOGY; LYMPHOCYTE ACTIVATION; METABOLISM; PRIMARY CELL CULTURE; PROTEIN PRENYLATION; T LYMPHOCYTE;

ANTIGEN PRESENTATION; ANTIGENS, CD40; B-LYMPHOCYTES; DENDRITIC CELLS; GENE EXPRESSION REGULATION; HEPTANOIC ACIDS; HUMANS; HYDROXYMETHYLGLUTARYL COA REDUCTASES; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; IMMUNITY, CELLULAR; LYMPHOCYTE ACTIVATION; MEVALONIC ACID; PRIMARY CELL CULTURE; PROTEIN PRENYLATION; PYRROLES; SIGNAL TRANSDUCTION; SIMVASTATIN; T-LYMPHOCYTES; TRANSCRIPTOME;

EID: 84910130913     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1203436     Document Type: Article

References (104)

1. DiLillo, D. J., M. Horikawa, and T. F. Tedder. 2011. B-lymphocyte effector functions in health and disease. Immunol. Res. 49: 281-292
2. Hikada, M., and M. Zouali. 2010. Multistoried roles for B lymphocytes in autoimmunity. Nat. Immunol. 11: 1065-1068
3. Shimabukuro-Vornhagen, A., M. J. Hallek, R. F. Storb, and M. S. Von Bergwelt-Baildon. 2009. The role of B cells in the pathogenesis of graft-versus-host disease. Blood 114: 4919-4927
4. Zarkhin, V., and M. M. Sarwal. 2012. The coin toss of B cells in rejection and tolerance: danger versus defense. Semin. Immunol. 24: 86-91
5. Von Bergwelt-Baildon, M., A. Shimabukuro-Vornhagen, A. Popov, N. Klein-Gonzalez, F. Fiore, S. Debey, A. Draube, B. Maecker, I. Menezes, L. M. Nadler, and J. L. Schultze. 2006. CD40-activated B cells express full lymph node homing triad and induce T-cell chemotaxis: potential as cellular adjuvants. Blood 107: 2786-2789
6. Mason, N. J., C. M. Coughlin, B. Overley, J. N. Cohen, E. L. Mitchell, T. A. Colligon, C. A. Clifford, A. Zurbriggen, K. U. Sorenmo, and R. H. Vonderheide. 2008. RNA-loaded CD40-activated B cells stimulate antigen-specific T-cell responses in dogs with spontaneous lymphoma. Gene Ther. 15: 955-965
7. Schultze, J. L., S. Grabbe, and M. S. Von Bergwelt-Baildon. 2004. DCs and CD40-activated B cells: current and future avenues to cellular cancer immunotherapy. Trends Immunol. 25: 659-664
8. Shimabukuro-Vornhagen, A., T. Liebig, and M. Von Bergwelt-Baildon. 2008. Statins inhibit human APC function: implications for the treatment of GVHD. Blood 112: 1544-1545
9. Chodick, G., H. Amital, Y. Shalem, E. Kokia, A. D. Heymann, A. Porath, and V. Shalev. 2010. Persistence with statins and onset of rheumatoid arthritis: A population-based cohort study. PLoS Med. 7: e1000336
10. Debey, S., U. Schoenbeck, M. Hellmich, B. S. Gathof, R. Pillai, T. Zander, and J. L. Schultze. 2004. Comparison of different isolation techniques prior gene expression profiling of blood derived cells: impact on physiological responses, on overall expression and the role of different cell types. Pharmacogenomics J. 4: 193-207
11. + T cells in Hodgkin lymphoma. Blood 110: 3226-3233
12. Li, C., and W. H. Wong. 2001. Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98: 31-36
13. Reich, M., T. Liefeld, J. Gould, J. Lerner, P. Tamayo, and J. P. Mesirov. 2006. GenePattern 2.0. Nat. Genet. 38: 500-501
14. Huang, W., B. T. Sherman, Q. Tan, J. Kir, D. Liu, D. Bryant, Y. Guo, R. Stephens, M. W. Baseler, H. C. Lane, and R. A. Lempicki. 2007. DAVID bioinformatics resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 35: W169-75
15. Huang, W., B. T. Sherman, and R. A. Lempicki. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4: 44-57
16. Merico, D., R. Isserlin, O. Stueker, A. Emili, and G. D. Bader. 2010. Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5: e13984
17. Shannon, P., A. Markiel, O. Ozier, N. S. Baliga, J. T. Wang, D. Ramage, N. Amin, B. Schwikowski, and T. Ideker. 2003. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res. 13: 2498-2504
18. Zambon, A. C., S. Gaj, I. Ho, K. Hanspers, K. Vranizan, C. T. Evelo, B. R. Conklin, A. R. Pico, and N. Salomonis. 2012. GO-Elite: A flexible solution for pathway and ontology over-representation. Bioinformatics 28: 2209-2210
19. Salomonis, N., K. Hanspers, A. C. Zambon, K. Vranizan, S. C. Lawlor, K. D. Dahlquist, S. W. Doniger, J. Stuart, B. R. Conklin, and A. R. Pico. 2007. GenMAPP 2: new features and resources for pathway analysis. BMC Bioinformatics 8: 217
20. Liebig, T. M., A. Fiedler, S. Zoghi, A. Shimabukuro-Vornhagen, and M. S. Von Bergwelt-Baildon. 2009. Generation of human CD40-activated B cells. J. Vis. Exp. 32: 1373
21. Shimabukuro-Vornhagen, A., T. M. Liebig, T. Koslowsky, S. Theurich, and M. S. Von Bergwelt-Baildon. 2013. The ratio between dendritic cells and T cells determines whether prostaglandin E2 has a stimulatory or inhibitory effect. Cell. Immunol. 281: 62-67
22. Postmus, I., J. J. W. Verschuren, A. J. M. de Craen, P. E. Slagboom, R. G. J. Westendorp, J. W. Jukema, and S. Trompet. 2012. Pharmacogenetics of statins: Achievements, whole-genome analyses and future perspectives. Pharmacogenomics 13: 831-840
23. Shimabukuro-Vornhagen, A., A. Draube, T. M. Liebig, A. Rothe, M. Kochanek, and M. S. Von Bergwelt-Baildon. 2012. The immunosuppressive factors IL-10, TGF-b, and VEGF do not affect the antigen-presenting function of CD40-activated B cells. J. Exp. Clin. Cancer Res. 31: 47
24. Fecteau, J. F., and S. Néron. 2003. CD40 stimulation of human peripheral B lymphocytes: distinct response from naive and memory cells. J. Immunol. 171: 4621-4629
25. Kuhrt, D., S. Faith, A. Hattemer, A. Leone, D. Sodora, L. Picker, L. Borghesi, and K. S. Cole. 2011. Naïve and memory B cells in the rhesus macaque can be differentiated by surface expression of CD27 and have differential responses to CD40 ligation. J. Immunol. Methods 363: 166-176
26. Weitz-Schmidt, G., K. Welzenbach, V. Brinkmann, T. Kamata, J. Kallen, C. Bruns, S. Cottens, Y. Takada, and U. Hommel. 2001. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat. Med. 7: 687-692
27. Kurakata, S., M. Kada, Y. Shimada, T. Komai, and K. Nomoto. 1996. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology 34: 51-61
28. Tanaka, T., C. M. Porter, J. A. Horvath-Arcidiacono, and E. T. Bloom. 2007. Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis. Int. Immunol. 19: 163-173
29. Kalliokoski, A., and M. Niemi. 2009. Impact of OATP transporters on pharmacokinetics. Br. J. Pharmacol. 158: 693-705
30. Sharma, P., C. J. Butters, V. Smith, R. Elsby, and D. Surry. 2012. Prediction of the in vivo OATP1B1-mediated drug-drug interaction potential of an investigational drug against a range of statins. Eur. J. Pharm. Sci. 47: 244-255
31. Niemi, M., M. K. Pasanen, and P. J. NeuVonen. 2006. SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin. Clin. Pharmacol. Ther. 80: 356-366
32. Lund, F. E. 2008. Cytokine-producing B lymphocytes-key regulators of immunity. Curr. Opin. Immunol. 20: 332-338
33. Pistoia, V. 1997. Production of cytokines by human B cells in health and disease. Immunol. Today 18: 343-350
34. Ghia, P., P. Transidico, J. P. Veiga, C. Schaniel, F. Sallusto, K. Matsushima, S. E. Sallan, A. G. Rolink, A. Mantovani, L. M. Nadler, and A. A. Cardoso. 2001. Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemiaspecific T cells. Blood 98: 533-540
35. Liao, J. K. 2002. Isoprenoids as mediators of the biological effects of statins. J. Clin. Invest. 110: 285-288
36. Getts, D. R., S. Shankar, E. M. L. Chastain, A. Martin, M. T. Getts, K. Wood, and S. D. Miller. 2011. Current landscape for T-cell targeting in autoimmunity and transplantation. Immunotherapy 3: 853-870
37. Shimoni, A., N. Shem-Tov, A. Chetrit, Y. Volchek, E. Tallis, A. Avigdor, S. Sadetzki, R. Yerushalmi, and A. Nagler. 2013. Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced. Leukemia 27: 829-835
38. Fishman, J. A. 2007. Infection in solid-organ transplant recipients. N. Engl. J. Med. 357: 2601-2614
39. Chakraverty, R., and M. Sykes. 2007. The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia. Blood 110: 9-17
40. + T cell immunity. Nat. Rev. Immunol. 10: 236-247
41. Ng, Y.-H., M. H. Oberbarnscheidt, H. C. K. Chandramoorthy, R. Hoffman, and G. Chalasani. 2010. B cells help alloreactive T cells differentiate into memory T cells. Am. J. Transplant. 10: 1970-1980
42. Zarkhin, V., G. Chalasani, and M. M. Sarwal. 2010. The yin and yang of B cells in graft rejection and tolerance. Transplant. Rev. (Orlando) 24: 67-78
43. Crocchiolo, R., L. Castagna, J. El-Cheikh, A. Helvig, S. Fürst, C. Faucher, A. Vazquez, A. Granata, D. Coso, R. Bouabdallah, and D. Blaise. 2011. Prior rituximab administration is associated with reduced rate of acute GVHD after in vivo T-cell depleted transplantation in lymphoma patients. Exp. Hematol. 39: 892-896
44. Cutler, C., D. Miklos, H. T. Kim, N. Treister, S. B. Woo, D. Bienfang, L. B. Klickstein, J. Levin, K. Miller, C. Reynolds, et al. 2006. Rituximab for steroid-refractory chronic graft-versus-host disease. Blood 108: 756-762
45. Cutler, C., H. T. Kim, B. Bindra, S. Sarantopoulos, V. T. Ho, Y.-B. Chen, J. Rosenblatt, S. McDonough, P. Watanaboonyongcharoen, P. Armand, et al. 2013. Rituximab prophylaxis prevents corticosteroid-requiring chronic GVHD after allogeneic peripheral blood stem cell transplantation: results of a phase 2 trial. Blood 122: 1510-1517
46. Arai, S., B. Sahaf, B. Narasimhan, G. L. Chen, C. D. Jones, R. Lowsky, J. A. Shizuru, L. J. Johnston, G. G. Laport, W.-K. Weng, et al. 2012. Prophylactic rituximab after allogeneic transplantation decreases B-cell alloimmunity with low chronic GVHD incidence. Blood 119: 6145-6154
47. Nozaki, T., J. M. Rosenblum, D. Ishii, K. Tanabe, and R. L. Fairchild. 2008. CD4 T cell-mediated rejection of cardiac allografts in B cell-deficient mice. J. Immunol. 181: 5257-5263
48. Noorchashm, H., A. J. Reed, S. Y. Rostami, R. Mozaffari, G. Zekavat, B. Koeberlein, A. J. Caton, and A. Naji. 2006. B cell-mediated antigen presentation is required for the pathogenesis of acute cardiac allograft rejection. J. Immunol. 177: 7715-7722
49. Schultz, K. R., J. Paquet, S. Bader, and K. T. HayGlass. 1995. Requirement for B cells in T cell priming to minor histocompatibility antigens and development of graft-versus-host disease. Bone Marrow Transplant. 16: 289-295
50. Young, J. S., T. Wu, Y. Chen, D. Zhao, H. Liu, T. Yi, H. Johnston, J. Racine, X. Li, A. Wang, et al. 2012. Donor B cells in transplants augment clonal expansion and survival of pathogenic CD4+ T cells that mediate autoimmune-like chronic graft-versus-host disease. J. Immunol. 189: 222-233
51. Burns, A. M., L. Ma, Y. Li, D. Yin, J. Shen, J. Xu, and A. S. Chong. 2009. Memory alloreactive B cells and alloantibodies prevent anti-CD154-mediated allograft acceptance. J. Immunol. 182: 1314-1324
52. Kirk, A. D., N. A. Turgeon, and N. N. Iwakoshi. 2010. B cells and transplantation tolerance. Nat. Rev. Nephrol. 6: 584-593
53. Redfield, R. R., III, E. Rodriguez, R. Parsons, K. Vivek, M. M. Mustafa, H. Noorchashm, and A. Naji. 2011. Essential role for B cells in transplantation tolerance. Curr. Opin. Immunol. 23: 685-691
54. Carter, N. A., R. Vasconcellos, E. C. Rosser, C. Tulone, A. Muñoz-Suano, M. Kamanaka, M. R. Ehrenstein, R. A. Flavell, and C. Mauri. 2011. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J. Immunol. 186: 5569-5579
55. Ray, A., S. Basu, C. B. Williams, N. H. Salzman, and B. N. Dittel. 2012. A novel IL-10-independent regulatory role for B cells in suppressing autoimmunity by maintenance of regulatory T cells via GITR ligand. J. Immunol. 188: 3188-3198
56. Cascalho, M. I., B. J. Chen, M. Kain, and J. L. Platt. 2013. The paradoxical functions of B cells and antibodies in transplantation. J. Immunol. 190: 875-879
57. Ahmadi, T., A. Flies, Y. Efebera, and D. H. Sherr. 2008. CD40 ligand-activated, antigen-specific B cells are comparable to mature dendritic cells in presenting protein antigens and major histocompatibility complex class I-and class IIbinding peptides. Immunology 124: 129-140
58. Rodríguez-Pinto, D., and J. Moreno. 2005. B cells can prime naive CD4+ T cells in vivo in the absence of other professional antigen-presenting cells in a CD154-CD40-dependent manner. Eur. J. Immunol. 35: 1097-1105
59. Carpenter, E. L., R. Mick, J. Rüter, and R. H. Vonderheide. 2009. Activation of human B cells by the agonist CD40 antibody CP-870,893 and augmentation with simultaneous Toll-like receptor 9 stimulation. J. Transl. Med. 7: 93
60. Bennett, S. R., F. R. Carbone, F. Karamalis, R. A. Flavell, J. F. Miller, and W. R. Heath. 1998. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393: 478-480
61. Rheumatoid Arthritis Consortium International (RACI). 2013. Human genetics in rheumatoid arthritis guides a high-Throughput drug screen of the CD40 signaling pathway. PLoS Genet. 9: e1003487
62. Raychaudhuri, S., E. F. Remmers, A. T. Lee, R. Hackett, C. Guiducci, N. P. Burtt, L. Gianniny, B. D. Korman, L. Padyukov, F. A. S. Kurreeman, et al. 2008. Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat. Genet. 40: 1216-1223
63. Förster, E., W. Krenger, J. Joergensen, R. Hof, R. S. Geha, and G. A. Holländer. 1999. Contribution of CD40-CD154-mediated costimulation to an alloresponse in vivo. Transplantation 67: 1284-1287
64. Elgueta, R., M. J. Benson, V. C. de Vries, A. Wasiuk, Y. Guo, and R. J. Noelle. 2009. Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol. Rev. 229: 152-172
65. Néron, S., P. J. Nadeau, A. Darveau, and J.-F. Leblanc. 2011. Tuning of CD40-CD154 interactions in human B-lymphocyte activation: A broad array of in vitro models for a complex in vivo situation. Arch. Immunol. Ther. Exp. (Warsz.) 59: 25-40
66. Wang, J., A. Ioan-Facsinay, E. I. H. van der Voort, T. W. J. Huizinga, and R. E. M. Toes. 2007. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37: 129-138
67. Pattison, J., P. J. Nelson, P. Huie, I. Von Leuttichau, G. Farshid, R. K. Sibley, and A. M. Krensky. 1994. RANTES chemokine expression in cell-mediated transplant rejection of the kidney. Lancet 343: 209-211
68. Fleury, S., J. Li, E. Simeoni, E. Fiorini, L. K. Von Segesser, L. Kappenberger, and G. Vassalli. 2006. Gene transfer of RANTES and MCP-1 chemokine antagonists prolongs cardiac allograft survival. Gene Ther. 13: 1104-1109
69. Dikow, R., L. E. Becker, M. Schaier, R. Waldherr, M.-L. Gross, and M. Zeier. 2010. In renal transplants with delayed graft function chemokines and chemokine receptor expression predict long-Term allograft function. Transplantation 90: 771-776
70. Choi, S. W., G. C. Hildebrandt, K. M. Olkiewicz, D. A. Hanauer, M. N. Chaudhary, I. A. Silva, C. E. Rogers, D. T. Deurloo, J. M. Fisher, C. Liu, et al. 2007. CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation. Blood 110: 3447-3455
71. Reshef, R., S. M. Luger, E. O. Hexner, A. W. Loren, N. V. Frey, S. D. Nasta, S. C. Goldstein, E. A. Stadtmauer, J. Smith, S. Bailey, et al. 2012. Blockade of lymphocyte chemotaxis in visceral graft-versus-host disease. N. Engl. J. Med. 367: 135-145
72. Snowden, N., A. Hajeer, W. Thomson, and B. Ollier. 1994. RANTES role in rheumatoid arthritis. Lancet 343: 547-548
73. Pavkova Goldbergova, M., J. Lipkova, N. Pavek, J. Gatterova, A. Vasku, M. Soucek, and P. Nemec. 2012. RANTES, MCP-1 chemokines and factors describing rheumatoid arthritis. Mol. Immunol. 52: 273-278
74. Ogliari, A. C., R. Caldara, C. Socci, V. Sordi, N. Cagni, M. P. Moretti, A. Dell'acqua, A. Mercalli, M. Scavini, A. Secchi, et al. 2008. High levels of donor CCL2/MCP-1 predict graft-related complications and poor graft survival after kidney-pancreas transplantation. Am. J. Transplant. 8: 1303-1311
75. Kwak, B., F. Mulhaupt, S. Myit, and F. Mach. 2000. Statins as a newly recognized type of immunomodulator. Nat. Med. 6: 1399-1402
76. Yilmaz, A., C. Reiss, A.Weng, I. Cicha, C. Stumpf, A. Steinkasserer,W. G. Daniel, and C. D. Garlichs. 2006. Differential effects of statins on relevant functions of human monocyte-derived dendritic cells. J. Leukoc. Biol. 79: 529-538
77. Yilmaz, A., C. Reiss, O. Tantawi, A. Weng, C. Stumpf, D. Raaz, J. Ludwig, T. Berger, A. Steinkasserer, W. G. Daniel, and C. D. Garlichs. 2004. HMG-CoA reductase inhibitors suppress maturation of human dendritic cells: new implications for atherosclerosis. Atherosclerosis 172: 85-93
78. Thibault, A., D. Samid, A. C. Tompkins, W. D. Figg, M. R. Cooper, R. J. Hohl, J. Trepel, B. Liang, N. Patronas, D. J. Venzon, et al. 1996. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin. Cancer Res. 2: 483-491
79. Jain, M. K., and P. M. Ridker. 2005. Anti-inflammatory effects of statins: clinical evidence and basic mechanisms. Nat. Rev. Drug Discov. 4: 977-987
80. Khan, M. A., R. M. Gallo, G. J. Renukaradhya, W. Du, J. Gervay-Hague, and R. R. Brutkiewicz. 2009. Statins impair CD1d-mediated antigen presentation through the inhibition of prenylation. J. Immunol. 182: 4744-4750
81. NeuVonen, P. J., M. Niemi, and J. T. Backman. 2006. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin. Pharmacol. Ther. 80: 565-581
82. Vanhaecke, J., J. Van Cleemput, J. Van Lierde, W. Daenen, and H. De Geest. 1994. Safety and efficacy of low dose simvastatin in cardiac transplant recipients treated with cyclosporine. Transplantation 58: 42-45
83. Marzoa-Rivas, R., M. G. Crespo-Leiro, M. J. Paniagua-Marin, D. Llinares-García, J. Muñiz-Garcia, G. Aldama-López, P. Piñón-Esteban, R. Campo-Pérez, and A. Castro-Beiras. 2005. Safety of statins when response is carefully monitored: A study of 336 heart recipients. Transplant. Proc. 37: 4071-4073
84. Pallasch, C. P., J. Schwamb, S. Königs, A. Schulz, S. Debey, D. Kofler, J. L. Schultze, M. Hallek, A. Ultsch, and C. M. Wendtner. 2008. Targeting lipid metabolism by the lipoprotein lipase inhibitor orlistat results in apoptosis of Bcell chronic lymphocytic leukemia cells. Leukemia 22: 585-592
85. El-Jawahri, A., and Y.-B. Chen. 2013. Pleiotropic approach to graft-versus-host disease. J. Clin. Oncol. 31: 4462-4464
86. Jameel, A., K. G.-J. Ooi, N. R. Jeffs, G. Galatowicz, S. L. Lightman, and V. L. Calder. 2013. Statin modulation of human T-cell proliferation, IL-1b and IL-17 production, and IFN-g T cell expression: synergy with conventional immunosuppressive agents. Int. J. Inflamm. 2013: 434586
87. Lisik, W., L. Schoenberg, R. E. Lasky, and B. D. Kahan. 2007. Statins benefit outcomes of renal transplant recipients on a sirolimus-cyclosporine regimen. Transplant. Proc. 39: 3086-3092
88. Kobashigawa, J. A., S. Katznelson, H. Laks, J. A. Johnson, L. Yeatman, X. M.Wang, D. Chia, P. I. Terasaki, A. Sabad, G. A. Cogert, et al. 1995. Effect of pravastatin on outcomes after cardiac transplantation. N. Engl. J. Med. 333: 621-627
89. Khatri, P., S. Roedder, N. Kimura, K. De Vusser, A. A. Morgan, Y. Gong, M. P. Fischbein, R. C. Robbins, M. Naesens, A. J. Butte, andM.M. Sarwal. 2013. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation. J. Exp. Med. 210: 2205-2221
90. Hamadani, M., F. T. Awan, and S. M. Devine. 2008. The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation. Blood 111: 3901-3902
91. Rotta, M., B. E. Storer, R. F. Storb, P. J. Martin, S. Heimfeld, A. Peffer, D. G. Maloney, H. J. Deeg, B. M. Sandmaier, F. R. Appelbaum, and M. Mielcarek. 2010. Donor statin treatment protects against severe acute graftversus-host disease after related allogeneic hematopoietic cell transplantation. Blood 115: 1288-1295
92. Rotta, M., B. E. Storer, R. Storb, P. J. Martin, M. E. D. Flowers, M. S. Vernon, A. Peffer, D. G. Maloney, H. J. Deeg, B. M. Sandmaier, et al. 2010. Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 16: 1463-1466
93. Hori, A., Y. Kanda, S. Goyama, Y. Onishi, Y. Komeno, K. Mitani, Y. Kishi, S. Ogawa, O. Imataki, S. Chiba, et al; Japan Hematology and Oncology Clinical Study Group. 2005. A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease. Transplantation 79: 372-374
94. Hamadani, M., L. F. Gibson, S. C. Remick, S. Wen, W. Petros, W. Tse, K. M. Brundage, J. A. Vos, A. Cumpston, P. Bunner, and M. D. Craig. 2013. Sibling donor and recipient immune modulation with atorvastatin for the prophylaxis of acute graft-versus-host disease. J. Clin. Oncol. 31: 4416-4423
95. Shimabukuro-Vornhagen, A., H. Schlösser, T. Kisner, D. L. Stippel, and M. Von Bergwelt-Baildon. 2013. The use of statins in hematopoietic stem cell transplantation and solid organ transplantation. Curr. Stem Cell Res. Ther. In press
96. Blaser, B. W., H. T. Kim, E. P. Alyea III, V. T. Ho, C. Cutler, P. Armand, J. Koreth, J. H. Antin, J. Plutzky, and R. J. Soiffer. 2012. Hyperlipidemia and statin use after allogeneic hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 18: 575-583
97. Gill, J. S. 2008. Cardiovascular disease in transplant recipients: current and future treatment strategies. Clin. J. Am. Soc. Nephrol. 3(Suppl. 2): S29-S37
98. Rosch, J. W., A. R. Boyd, E. Hinojosa, T. Pestina, Y. Hu, D. A. Persons, C. J. Orihuela, and E. I. Tuomanen. 2010. Statins protect against fulminant pneumococcal infection and cytolysin toxicity in a mouse model of sickle cell disease. J. Clin. Invest. 120: 627-635
99. Tleyjeh, I. M.,T.Kashour, F.A. Hakim, V.A.Zimmerman, P. J. Erwin, A. J. Sutton, and T. Ibrahim. 2009. Statins for the prevention and treatment of infections: A systematic review and meta-analysis. Arch. Intern. Med. 169: 1658-1667.
100. Shachaf, C. M., O. D. Perez, S. Youssef, A. C. Fan, S. Elchuri, M. J. Goldstein, A. E. Shirer, O. Sharpe, J. Chen, D. J. Mitchell, et al. 2007. Inhibition of HMGcoA reductase by atorvastatin prevents and reverses MYC-induced lymphomagenesis. Blood 110: 2674-2684.
101. Demierre, M.-F., P. D. R. Higgins, S. B. Gruber, E. Hawk, and S. M. Lippman. 2005. Statins and cancer prevention. Nat. Rev. Cancer 5: 930-942.
102. Fröhlich, G. M., K. Rufibach, F. Enseleit, M. Wolfrum, M. Von Babo, M. Frank, R. Berli, M. Hermann, J. Holzmeister, M. Wilhelm, et al. 2012. Statins and the risk of cancer after heart transplantation. Circulation 126: 440-447. 103
103. van der Weide, K., P. M. Korthuis, F. Kuipers, E. G. E. de Vries, and E. Vellenga. 2012. Heterogeneity in simvastatin-induced cytotoxicity in AML is caused by differences in Ras-isoprenylation. Leukemia 26: 845-848
104. Ashburn, T. T., and K. B. Thor. 2004. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3: 673-683.