Role of lymphocytes in myocardial injury, healing, and remodeling after myocardial infarction

Circulation Research

Volumn 116, Issue 2, 2015, Pages 354-367

  Hofmann, Ulrich ^a   Frantz, Stefan ^b  

^a UNIVERSITY HOSPITAL WÜRZBURG   (Germany)

^b MARTIN LUTHER UNIVERSITÄT HALLE WITTENBERG   (Germany)

Author keywords

antigen; B cell; dendritic cell; myocardial infarction; T cell

Indexed keywords

ADENOSINE; AUTOANTIGEN;

B LYMPHOCYTE; CD4+ T LYMPHOCYTE; DENDRITIC CELL; HEALING; HEART ATRIUM REMODELING; HEART INFARCTION; HEART MUSCLE INJURY; HUMAN; INNATE IMMUNITY; LYMPHOCYTE ACTIVATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE SUBPOPULATION; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REPERFUSION INJURY; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE ACTIVATION; ANIMAL; HEART VENTRICLE REMODELING; IMMUNOLOGY; LYMPHOCYTE; PATHOLOGY; PHYSIOLOGY; WOUND HEALING;

ANIMALS; HUMANS; IMMUNITY, INNATE; LYMPHOCYTES; MYOCARDIAL INFARCTION; MYOCARDIAL REPERFUSION INJURY; VENTRICULAR REMODELING; WOUND HEALING;

EID: 84921973032     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.116.304072     Document Type: Review

References (116)

1. Matzinger P. An innate sense of danger. Semin Immunol. 1998;10:399-415. doi: 10.1006/smim.1998.0143.
2. Frantz S, Bauersachs J, Kelly RA. Innate immunity and the heart. Curr Pharm Des. 2005;11:1279-1290.
3. Ertl G, Frantz S. Wound model of myocardial infarction. Am J Physiol Heart Circ Physiol. 2005;288:H981-H983. doi: 10.1152/ajpheart.00977.2004.
4. Frantz S, Bauersachs J, Ertl G. Post-infarct remodelling: contribution of wound healing and inflammation. Cardiovasc Res. 2009;81:474-481. doi: 10.1093/cvr/cvn292.
5. Leuschner F, Rauch PJ, Ueno T, et al. Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis. J Exp Med. 2012;209:123-137. doi: 10.1084/jem.20111009.
6. Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med. 2007;204:3037-3047. doi: 10.1084/jem.20070885.
7. Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure. Science. 2013;339:161-166. doi: 10.1126/science.1230719.
8. Frantz S, Hofmann U, Fraccarollo D, et al. Monocytes/macrophages prevent healing defects and left ventricular thrombus formation after myocardial infarction. FASEB J. 2013;27:871-881. doi: 10.1096/fj.12-214049.
9. Janeway CA Jr, Jason JM. How T lymphocytes recognize antigen. Crit Rev Immunol. 1980;1:133-164.
10. Janeway CA Jr, Bottomly K, Horowitz J, Kaye J, Jones B, Tite J. Modes of cell:cell communication in the immune system. J Immunol. 1985;135:739s-742s.
11. Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007;7:543-555. doi: 10.1038/nri2103.
12. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13:227-242. doi: 10.1038/nri3405.
13. Rochman Y, Spolski R, Leonard WJ. New insights into the regulation of T cells by gamma© family cytokines. Nat Rev Immunol. 2009;9:480-490. doi: 10.1038/nri2580.
14. Kuniyasu Y, Takahashi T, Itoh M, Shimizu J, Toda G, Sakaguchi S. Naturally anergic and suppressive CD25(+)CD4(+) T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation. Int Immunol. 2000;12:1145-1155.
15. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-1061. doi: 10.1126/science.1079490.
16. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic selftolerance maintained by activated T cells expressing IL-2 receptor alphachains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151-1164.
17. Killebrew JR, Perdue N, Kwan A, Thornton AM, Shevach EM, Campbell DJ. A self-reactive TCR drives the development of Foxp3+ regulatory T cells that prevent autoimmune disease. J Immunol. 2011;187:861-869. doi: 10.4049/jimmunol.1004009.
18. Yan X, Anzai A, Katsumata Y, Matsuhashi T, Ito K, Endo J, Yamamoto T, Takeshima A, Shinmura K, Shen W, Fukuda K, Sano M. Temporal dynamics of cardiac immune cell accumulation following acute myocardial infarction. J Mol Cell Cardiol. 2013;62:24-35. doi: 10.1016/j. yjmcc.2013.04.023.
19. Zouggari Y, Ait-Oufella H, Bonnin P, et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med. 2013;19:1273-1280. doi: 10.1038/nm.3284.
20. Hofmann U, Beyersdorf N, Weirather J, Podolskaya A, Bauersachs J, Ertl G, Kerkau T, Frantz S. Activation of CD4+ T lymphocytes improves wound healing and survival after experimental myocardial infarction in mice. Circulation. 2012;125:1652-1663. doi: 10.1161/CIRCULATIONAHA.111.044164.
21. Weirather J, Hofmann U, Beyersdorf N, Ramos GC, Vogel B, Frey A, Ertl G, Kerkau T, Frantz S. Foxp3+cd4+ t cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res. 2014
22. Yang Z, Day YJ, Toufektsian MC, Xu Y, Ramos SI, Marshall MA, French BA, Linden J. Myocardial infarct-sparing effect of adenosine A2A receptor activation is due to its action on CD4+ T lymphocytes. Circulation. 2006;114:2056-2064. doi: 10.1161/CIRCULATIONAHA.106.649244.
23. Decking UK, Schlieper G, Kroll K, Schrader J. Hypoxia-induced inhibition of adenosine kinase potentiates cardiac adenosine release. Circ Res. 1997;81:154-164.
24. Romio M, Reinbeck B, Bongardt S, Hüls S, Burghoff S, Schrader J. Extracellular purine metabolism and signaling of CD73-derived adenosine in murine Treg and Teff cells. Am J Physiol Cell Physiol. 2011;301:C530-C539. doi: 10.1152/ajpcell.00385.2010.
25. Bönner F, Borg N, Jacoby C, Temme S, Ding Z, Flögel U, Schrader J. Ecto-5'-nucleotidase on immune cells protects from adverse cardiac remodeling. Circ Res. 2013;113:301-312. doi: 10.1161/CIRCRESAHA.113.300180.
26. Linden J, Cekic C. Regulation of lymphocyte function by adenosine. Arterioscler Thromb Vasc Biol. 2012;32:2097-2103. doi: 10.1161/ATVBAHA.111.226837.
27. Linfert D, Chowdhry T, Rabb H. Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando). 2009;23:1-10. doi: 10.1016/j. trre.2008.08.003.
28. Reynolds JM, Dong C. Toll-like receptor regulation of effector T lymphocyte function. Trends Immunol. 2013;34:511-519. doi: 10.1016/j. it.2013.06.003.
29. Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301-305. doi: 10.1126/science.1071059.
30. Imanishi T, Hara H, Suzuki S, Suzuki N, Akira S, Saito T. Cutting edge: TLR2 directly triggers Th1 effector functions. J Immunol. 2007;178:6715-6719.
31. Park JS, Svetkauskaite D, He Q, Kim JY, Strassheim D, Ishizaka A, Abraham E. Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem. 2004;279:7370-7377. doi: 10.1074/jbc.M306793200.
32. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191-195. doi: 10.1038/nature00858.
33. Van Tassell BW, Toldo S, Mezzaroma E, Abbate A. Targeting interleukin-1 in heart disease. Circulation. 2013;128:1910-1923. doi: 10.1161/CIRCULATIONAHA.113.003199.
34. Ke D, Fang J, Fan L, Chen Z, Chen L. Regulatory T cells contribute to rosuvastatin-induced cardioprotection against ischemia-reperfusion injury. Coron Artery Dis. 2013;24:334-341. doi: 10.1097/MCA.0b013e3283608c12.
35. Forero-Penã DA, Gutierrez FR. Statins as modulators of regulatory T-cell biology. Mediators Inflamm. 2013;2013:167086. doi: 10.1155/2013/167086.
36. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol. 2006;7:401-410. doi: 10.1038/ni1318.
37. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2007;8:191-197. doi: 10.1038/ni1428.
38. Feng M, Wang Q, Zhang F, Lu L. Ex vivo induced regulatory T cells regulate inflammatory response of Kupffer cells by TGF-beta and attenuate liver ischemia reperfusion injury. Int Immunopharmacol. 2012;12:189-196. doi: 10.1016/j.intimp.2011.11.010.
39. Lai LW, Yong KC, Lien YH. Pharmacologic recruitment of regulatory T cells as a therapy for ischemic acute kidney injury. Kidney Int. 2012;81:983-992. doi: 10.1038/ki.2011.412.
40. Lewkowicz N, Klink M, Mycko MP, Lewkowicz P. Neutrophil-CD4+CD25+ T regulatory cell interactions: a possible new mechanism of infectious tolerance. Immunobiology. 2013;218:455-464. doi: 10.1016/j. imbio.2012.05.029.
41. Liao YH, Xia N, Zhou SF, Tang TT, Yan XX, Lv BJ, Nie SF, Wang J, Iwakura Y, Xiao H, Yuan J, Jevallee H, Wei F, Shi GP, Cheng X. Interleukin-17A contributes to myocardial ischemia/reperfusion injury by regulating cardiomyocyte apoptosis and neutrophil infiltration. J Am Coll Cardiol. 2012;59:420-429. doi: 10.1016/j.jacc.2011.10.863.
42. Vantourout P, Hayday A. Six-of-the-best: unique contributions of T cells to immunology. Nat Rev Immunol. 2013;13:88-100. doi: 10.1038/nri3384.
43. Zhang X. Regulatory functions of innate-like B cells. Cell Mol Immunol. 2013;10:113-121. doi: 10.1038/cmi.2012.63.
44. Zhang M, Alicot EM, Chiu I, Li J, Verna N, Vorup-Jensen T, Kessler B, Shimaoka M, Chan R, Friend D, Mahmood U, Weissleder R, Moore FD, Carroll MC. Identification of the target self-antigens in reperfusion injury. J Exp Med. 2006;203:141-152. doi: 10.1084/jem.20050390.
45. Haas MS, Alicot EM, Schuerpf F, Chiu I, Li J, Moore FD, Carroll MC. Blockade of self-reactive IgM significantly reduces injury in a murine model of acute myocardial infarction. Cardiovasc Res. 2010;87:618-627. doi: 10.1093/cvr/cvq141.
46. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Köhl J. The role of the anaphylatoxins in health and disease. Mol Immunol. 2009;46:2753-2766. doi: 10.1016/j.molimm.2009.04.027.
47. van der Laan AM, Nahrendorf M, Piek JJ. Healing and adverse remodelling after acute myocardial infarction: role of the cellular immune response. Heart. 2012;98:1384-1390. doi: 10.1136/heartjnl-2012-301623.
48. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612-616. doi: 10.1126/science.1175202.
49. Maisel A, Cesario D, Baird S, Rehman J, Haghighi P, Carter S. Experimental autoimmune myocarditis produced by adoptive transfer of splenocytes after myocardial infarction. Circ Res. 1998;82:458-463.
50. Anzai A, Anzai T, Nagai S, et al. Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling. Circulation. 2012;125:1234-1245. doi: 10.1161/CIRCULATIONAHA.111.052126.
51. Dobaczewski M, Xia Y, Bujak M, Gonzalez-Quesada C, Frangogiannis NG. CCR5 signaling suppresses inflammation and reduces adverse remodeling of the infarcted heart, mediating recruitment of regulatory T cells. Am J Pathol. 2010;176:2177-2187. doi: 10.2353/ajpath.2010.090759.
52. Tang TT, Yuan J, Zhu ZF, et al. Regulatory T cells ameliorate cardiac remodeling after myocardial infarction. Basic Res Cardiol. 2012;107:232. doi: 10.1007/s00395-011-0232-6.
53. Matsumoto K, Ogawa M, Suzuki J, Hirata Y, Nagai R, Isobe M. Regulatory T lymphocytes attenuate myocardial infarction-induced ventricular remodeling in mice. Int Heart J. 2011;52:382-387.
54. Saxena A, Dobaczewski M, Rai V, Haque Z, Chen W, Li N, Frangogiannis NG. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol. 2014;307:H1233-H1242. doi: 10.1152/ajpheart.00328.2014.
55. Curato C, Slavic S, Dong J, Skorska A, Altarche-Xifró W, Miteva K, Kaschina E, Thiel A, Imboden H, Wang J, Steckelings U, Steinhoff G, Unger T, Li J. Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury. J Immunol. 2010;185:6286-6293. doi: 10.4049/jimmunol.0903681.
56. Yan X, Shichita T, Katsumata Y, et al. Deleterious effect of the IL-23/IL-17A axis and T cells on left ventricular remodeling after myocardial infarction. J Am Heart Assoc. 2012;1:e004408. doi: 10.1161/JAHA.112.004408.
57. Sobirin MA, Kinugawa S, Takahashi M, Fukushima A, Homma T, Ono T, Hirabayashi K, Suga T, Azalia P, Takada S, Taniguchi M, Nakayama T, Ishimori N, Iwabuchi K, Tsutsui H. Activation of natural killer T cells ameliorates postinfarct cardiac remodeling and failure in mice. Circ Res. 2012;111:1037-1047. doi: 10.1161/CIRCRESAHA.112.270132.
58. Goodchild TT, Robinson KA, Pang W, Tondato F, Cui J, Arrington J, Godwin L, Ungs M, Carlesso N, Weich N, Poznansky MC, Chronos NA. Bone marrow-derived B cells preserve ventricular function after acute myocardial infarction. JACC Cardiovasc Interv. 2009;2:1005-1016. doi: 10.1016/j.jcin.2009.08.010.
59. Lv H, Havari E, Pinto S, Gottumukkala RV, Cornivelli L, Raddassi K, Matsui T, Rosenzweig A, Bronson RT, Smith R, Fletcher AL, Turley SJ, Wucherpfennig K, Kyewski B, Lipes MA. Impaired thymic tolerance to ?-myosin directs autoimmunity to the heart in mice and humans. J Clin Invest. 2011;121:1561-1573. doi: 10.1172/JCI44583.
60. Pummerer CL, Luze K, Grässl G, Bachmaier K, Offner F, Burrell SK, Lenz DM, Zamborelli TJ, Penninger JM, Neu N. Identification of cardiac myosin peptides capable of inducing autoimmune myocarditis in BALB/c mice. J Clin Invest. 1996;97:2057-2062. doi: 10.1172/JCI118642.
61. Rizzo LV, Cunha-Neto E, Teixeira AR. Autoimmunity in Chagas' disease: specific inhibition of reactivity of CD4+ T cells against myosin in mice chronically infected with Trypanosoma cruzi. Infect Immun. 1989;57:2640-2644.
62. Elahi AW, Vijayakumar AN, Lichstein E, Mokhtarian F. Interplay of antibody and T cell responses in acute myocardial infarction. J Lab Clin Med. 2001;138:112-118. doi: 10.1067/mlc.2001.116489.
63. Smith SC, Allen PM. Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis. Proc Natl Acad Sci USA. 1992;89:9131-9135.
64. Rose ML, Page C, Hengstenberg C, Yacoub MH. Identification of antigen presenting cells in normal and transplanted human heart: importance of endothelial cells. Hum Immunol. 1990;28:179-185.
65. Spencer SC, Fabre JW. Characterization of the tissue macrophage and the interstitial dendritic cell as distinct leukocytes normally resident in the connective tissue of rat heart. J Exp Med. 1990;171:1841-1851.
66. Kornete M, Piccirillo CA. Functional crosstalk between dendritic cells and Foxp3(+) regulatory T cells in the maintenance of immune tolerance. Front Immunol. 2012;3:165. doi: 10.3389/fimmu.2012.00165.
67. Caforio AL, Grazzini M, Mann JM, Keeling PJ, Bottazzo GF, McKenna WJ, Schiaffino S. Identification of alpha-and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathy. Circulation. 1992;85:1734-1742.
68. Kaya Z, Leib C, Katus HA. Autoantibodies in heart failure and cardiac dysfunction. Circ Res. 2012;110:145-158. doi: 10.1161/CIRCRESAHA.111.243360.
69. Leuschner F, Li J, Göser S, Reinhardt L, Ottl R, Bride P, Zehelein J, Pfitzer G, Remppis A, Giannitsis E, Katus HA, Kaya Z. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction. Eur Heart J. 2008;29:1949-1955. doi: 10.1093/eurheartj/ehn268.
70. Boivin-Jahns V, Schlipp A, Hartmann S, Panjwani P, Klingel K, Lohse MJ, Ertl G, Jahns R. Antibodies to cardiac receptors. Herz. 2012;37:843-848. doi: 10.1007/s00059-012-3699-5.
71. Deubner N, Berliner D, Schlipp A, Gelbrich G, Caforio AL, Felix SB, Fu M, Katus H, Angermann CE, Lohse MJ, Ertl G, Störk S, Jahns R; Etiology, Titre-Course, and Survival-Study Group. Cardiac beta1-adrenoceptor autoantibodies in human heart disease: rationale and design of the Etiology, Titre-Course, and Survival (ETiCS) Study. Eur J Heart Fail. 2010;12:753-762. doi: 10.1093/eurjhf/hfq072.
72. Lichtman AH. The heart of the matter: protection of the myocardium from T cells. J Autoimmun. 2013;45:90-96. doi: 10.1016/j.jaut.2013.05.004.
73. Zhai S, Zhang L, Dang S, Yu Y, Zhao Z, Zhao W, Liu L. The ratio of Th-17 to Treg cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure. Viral Immunol. 2011;24:303-310. doi: 10.1089/vim.2010.0135.
74. Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol. 2005;45:1939-1945. doi: 10.1016/j. jacc.2005.03.040.
75. Cheng X, Yu X, Ding YJ, Fu QQ, Xie JJ, Tang TT, Yao R, Chen Y, Liao YH. The Th17/Treg imbalance in patients with acute coronary syndrome. Clin Immunol. 2008;127:89-97. doi: 10.1016/j.clim.2008.01.009.
76. Mor A, Luboshits G, Planer D, Keren G, George J. Altered status of CD4(+)CD25(+) regulatory T cells in patients with acute coronary syndromes. Eur Heart J. 2006;27:2530-2537. doi: 10.1093/eurheartj/ehl222.
77. Dumitriu IE, Araguás ET, Baboonian C, Kaski JC. CD4+ CD28 null T cells in coronary artery disease: when helpers become killers. Cardiovasc Res. 2009;81:11-19. doi: 10.1093/cvr/cvn248.
78. Nakajima T, Schulte S, Warrington KJ, Kopecky SL, Frye RL, Goronzy JJ, Weyand CM. T-cell-mediated lysis of endothelial cells in acute coronary syndromes. Circulation. 2002;105:570-575.
79. Pawlik A, Ostanek L, Brzosko I, Brzosko M, Masiuk M, Machalinski B, Gawronska-Szklarz B. The expansion of CD4+CD28-T cells in patients with rheumatoid arthritis. Arthritis Res Ther. 2003;5:R210-R213. doi: 10.1186/ar766.
80. Liuzzo G, Goronzy JJ, Yang H, Kopecky SL, Holmes DR, Frye RL, Weyand CM. Monoclonal T-cell proliferation and plaque instability in acute coronary syndromes. Circulation. 2000;101:2883-2888.
81. Liuzzo G, Biasucci LM, Trotta G, Brugaletta S, Pinnelli M, Digianuario G, Rizzello V, Rebuzzi AG, Rumi C, Maseri A, Crea F. Unusual CD4+CD28null T lymphocytes and recurrence of acute coronary events. J Am Coll Cardiol. 2007;50:1450-1458. doi: 10.1016/j.jacc.2007.06.040.
82. Dumitriu IE, Baruah P, Finlayson CJ, Loftus IM, Antunes RF, Lim P, Bunce N, Kaski JC. High levels of costimulatory receptors OX40 and 4-1BB characterize CD4+CD28null T cells in patients with acute coronary syndrome. Circ Res. 2012;110:857-869. doi: 10.1161/CIRCRESAHA.111.261933.
83. Zal B, Kaski JC, Arno G, Akiyu JP, Xu Q, Cole D, Whelan M, Russell N, Madrigal JA, Dodi IA, Baboonian C. Heat-shock protein 60-reactive CD4+CD28null T cells in patients with acute coronary syndromes. Circulation. 2004;109:1230-1235. doi: 10.1161/01. CIR.0000118476.29352.2A.
84. Hoffmann J, Fiser K, Weaver J, Dimmick I, Loeher M, Pircher H, Martin-Ruiz C, Veerasamy M, Keavney B, von Zglinicki T, Spyridopoulos I. High-throughput 13-parameter immunophenotyping identifies shifts in the circulating T-cell compartment following reperfusion in patients with acute myocardial infarction. PLoS One. 2012;7:e47155. doi: 10.1371/journal.pone.0047155.
85. Förster R, Schubel A, Breitfeld D, Kremmer E, Renner-Müller I, Wolf E, Lipp M. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell. 1999;99:23-33.
86. Abbate A, Bussani R, Liuzzo G, et al. Sudden coronary death, fatal acute myocardial infarction and widespread coronary and myocardial inflammation. Heart. 2008;94:737-742. doi: 10.1136/hrt.2007.115329.
87. Backteman K, Andersson C, Dahlin LG, Ernerudh J, Jonasson L. Lymphocyte subpopulations in lymph nodes and peripheral blood: a comparison between patients with stable angina and acute coronary syndrome. PLoS One. 2012;7:e32691. doi: 10.1371/journal.pone.0032691.
88. Doesch AO, Mueller S, Nelles M, Konstandin M, Celik S, Frankenstein L, Goeser S, Kaya Z, Koch A, Zugck C, Katus HA. Impact of troponin I-autoantibodies in chronic dilated and ischemic cardiomyopathy. Basic Res Cardiol. 2011;106:25-35. doi: 10.1007/s00395-010-0126-z.
89. Jahns R, Boivin V, Lohse MJ. beta(1)-Adrenergic receptor function, autoimmunity, and pathogenesis of dilated cardiomyopathy. Trends Cardiovasc Med. 2006;16:20-24. doi: 10.1016/j.tcm.2005.11.002.
90. Jahns R, Boivin V, Siegmund C, Inselmann G, Lohse MJ, Boege F. Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure. Circulation. 1999;99:649-654.
91. Spor A, Koren O, Ley R. Unravelling the effects of the environment and host genotype on the gut microbiome. Nat Rev Microbiol. 2011;9:279-290. doi: 10.1038/nrmicro2540.
92. Gill N, Finlay BB. The gut microbiota: challenging immunology. Nat Rev Immunol. 2011;11:636-637. doi: 10.1038/nri3061.
93. Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz TV, Phillips LK, Goldstein MJ, Bhat R, Raine CS, Sobel RA, Steinman L. Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1-and TH17-mediated autoimmunity. Proc Natl Acad Sci USA. 2009;106:14948-14953. doi: 10.1073/pnas.0903958106.
94. Chow SC. Immunomodulation by statins: mechanisms and potential impact on autoimmune diseases. Arch Immunol Ther Exp (Warsz). 2009;57:243-251. doi: 10.1007/s00005-009-0038-5.
95. Bujak M, Kweon HJ, Chatila K, Li N, Taffet G, Frangogiannis NG. Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction. J Am Coll Cardiol. 2008;51:1384-1392. doi: 10.1016/j.jacc.2008.01.011.
96. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. N Engl J Med. 2008;359:473-481. doi: 10.1056/NEJMoa071142.
97. Riley JL, June CH, Blazar BR. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity. 2009;30:656-665. doi: 10.1016/j.immuni.2009.04.006.
98. Kanellakis P, Dinh TN, Agrotis A, Bobik A. Cd4(+)cd25(+)foxp3(+) regulatory t cells suppress cardiac fibrosis in the hypertensive heart. J Hypertens. 2011;29:1820-1828.
99. Hippen KL, Riley JL, June CH, Blazar BR. Clinical perspectives for regulatory T cells in transplantation tolerance. Semin Immunol. 2011;23:462-468. doi: 10.1016/j.smim.2011.07.008.
100. Tacke M, Hanke G, Hanke T, Hünig T. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. Eur J Immunol. 1997;27:239-247. doi: 10.1002/eji.1830270136.
101. Hünig T. Manipulation of regulatory T-cell number and function with CD28-specific monoclonal antibodies. Adv Immunol. 2007;95:111-148. doi: 10.1016/S0065-2776(07)95004-X.
102. Langenhorst D, Gogishvili T, Ribechini E, Kneitz S, McPherson K, Lutz MB, Hünig T. Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells. PLoS One. 2012;7:e50080. doi: 10.1371/journal.pone.0050080.
103. Hünig T. The storm has cleared: lessons from the CD28 superagonist TGN1412 trial. Nat Rev Immunol. 2012;12:317-318. doi: 10.1038/nri3192.
104. Pallardy M, Hünig T. Primate testing of TGN1412: right target, wrong cell. Br J Pharmacol. 2010;161:509-511. doi: 10.1111/j.1476-5381.2010.00925.x.
105. Tabares P, Berr S, Römer PS, Chuvpilo S, Matskevich AA, Tyrsin D, Fedotov Y, Einsele H, Tony HP, Hünig T. Human regulatory T cells are selectively activated by low-dose application of the CD28 superagonist TGN1412/TAB08. Eur J Immunol. 2014;44:1225-1236. doi: 10.1002/eji.201343967.
106. Daifotis AG, Koenig S, Chatenoud L, Herold KC. Anti-CD3 clinical trials in type 1 diabetes mellitus. Clin Immunol. 2013;149:268-278. doi: 10.1016/j.clim.2013.05.001.
107. Penaranda C, Tang Q, Bluestone JA. Anti-CD3 therapy promotes tolerance by selectively depleting pathogenic cells while preserving regulatory T cells. J Immunol. 2011;187:2015-2022. doi: 10.4049/jimmunol.1100713.
108. Saadoun D, Cacoub P. [Interleukin-2 immunotherapy in autoimmune disorders]. Rev Med Interne. 2013;34:133-135. doi: 10.1016/j. revmed.2012.10.003.
109. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, Sene D, Cacoub P, Klatzmann D. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365:2067-2077. doi: 10.1056/NEJMoa1105143.
110. Krieg C, Létourneau S, Pantaleo G, Boyman O. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. Proc Natl Acad Sci USA. 2010;107:11906-11911. doi: 10.1073/pnas.1002569107.
111. Dinh TN, Kyaw TS, Kanellakis P, To K, Tipping P, Toh BH, Bobik A, Agrotis A. Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation. 2012;126:1256-1266. doi: 10.1161/CIRCULATIONAHA.112.099044.
112. Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev. 2011;241:241-259. doi: 10.1111/j.1600-065X.2011.01017.x.
113. Faria AM, Weiner HL. Oral tolerance. Immunol Rev. 2005;206:232-259. doi: 10.1111/j.0105-2896.2005.00280.x.
114. Ramos GC, Dalbó S, Leite DP, Goldfeder E, Carvalho CR, Vaz NM, Assreuy J. The autoimmune nature of post-infarct myocardial healing: oral tolerance to cardiac antigens as a novel strategy to improve cardiac healing. Autoimmunity. 2012;45:233-244. doi: 10.3109/08916934.2011.647134.
115. Frenkel D, Pachori AS, Zhang L, Dembinsky-Vaknin A, Farfara D, Petrovic-Stojkovic S, Dzau VJ, Weiner HL. Nasal vaccination with troponin reduces troponin specific T-cell responses and improves heart function in myocardial ischemia-reperfusion injury. Int Immunol. 2009;21:817-829. doi: 10.1093/intimm/dxp051.
116. Li J, Göser S, Leuschner F, Volz HC, Buss S, Andrassy M, Öttl R, Pfitzer G, Katus HA, Kaya Z. Mucosal tolerance induction in autoimmune myocarditis and myocardial infarction. Int J Cardiol. 2013;162:245-252. doi: 10.1016/j.ijcard.2011.05.057.