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Cited by 39Viral Infections and Immunology ResearchT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

Protection against Experimental Autoimmune Myocarditis Is Mediated by Interleukin-10-Producing T Cells that Are Controlled by Dendritic Cells

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Li, Ya, Heuser, Janet S., Kosanke, Stanley D., Hemric, Mark, Cunningham, Madeleine W.·2005·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)62948-3PMC PMC1603447
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Abstract

Experimental autoimmune myocarditis (EAM) can be induced in the Lewis rat by cardiac myosin or its cryptic S2-16 peptide epitope (amino acids 1052 to 1076). To investigate cellular mechanisms and the role of antigen-presenting cells in regulation of myocarditis, we induced protection against EAM in Lewis rats by administration of S2-16 peptide in incomplete Freund's adjuvant (IFA). Protection to EAM was associated with activation of S2-16-reactive splenocytes secreting high levels of interleukin (IL)-10 and reduced levels of interferon-gamma and IL-2. Adoptive transfer of S2-16:IFA-induced splenocytes producing IL-10 suppressed myocarditis induction in syngeneic recipients, suggesting their regulatory cell nature. However, exposure of S2-16:IFA-induced cells to inflammatory cytokine IL-12 converted them to Th1 effectors that transferred EAM. Differentiated function of S2-16-reactive T cells in protected rats resulted from increased IL-10 production by dendritic cells (DCs). Purified DCs from S2-16:IFA-treated rats promoted S2-16-reactive CD4+ T cells to produce increased IL-10 and reduced interferon-gamma. In addition, adoptive transfer of IL-10-producing DCs from S2-16:IFA-treated rats also induced protection to EAM in recipient rats. These studies demonstrated DCs and key cytokines, such as IL-10 and IL-12, regulated the fate of T cells in myocarditis development in the Lewis rat.

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  • Dendritic cells generated in Lewis rats immunized with an emulsion of cardiac myosin peptides and incomplete Freund adjuvant exhibited immunoregulatory characteristics including elevated IL-10 production, also promoting IL-10 production in cocultured T cells.

    “dendritic cells generated in Lewis rats immunized with an emulsion of cardiac myosin peptides and incomplete Freund adjuvant exhibited immunoregulatory characteristics including elevated IL-10 production, also promoting IL-10 production in cocultured T cells”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [132]

  • When transferred to recipient rats, these dendritic cells protected the heart from the development of autoimmune myocarditis.

    “When transferred to recipient rats, these dendritic cells were found to protect the heart from the development of autoimmune myocarditis”

    From Autoimmune Myocarditis, Old Dogs and New Tricks. (2024) · cites this paper as [132]

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Research works printed but not linked: 80

  1. Leslie K, Blay R, Haisch C, Lodge A, Weller A, Huber S: Clinical and experimental aspects of viral myocarditis. Clin Microbiol Rev 1989, 2:191-203
  2. Olinde KD, O'Connell JB: Inflammatory heart disease: pathogenesis, clinical manifestations, and treatment of myocarditis. Annu Rev Med 1994, 45:481-490
  3. Feldman AM, McNamara D: Medical progress: myocarditis. N Engl J Med 2000, 343:1388 -1398
  4. Fuster V, Gersh BJ, Giuliani ER, Tajik AJ, Brandenburg RO, Frye RL: The natural history of idiopathic dilated cardiomyopathy. Am J Cardiol 1981, 47:525-531
  5. Brown CA, O'Connell JB: Myocarditis and idiopathic dilated cardio- myopathy. Am J Med 1995, 99:309 -314
  6. Towbin JA, Bowles KR, Bowles NE: Etiologies of cardiomyopathy and heart failure. Nat Med 1999, 78:270 -283
  7. Lange LG, Schreiner GF: Immune mechanisms of cardiac disease. N Engl J Med 1994, 330:1129 -1135
  8. Caforio AL, Goldman JH, Haven AJ, Baig KM, McKenna WJ: Evi- dence for autoimmunity to myosin and other heart-specific autoanti- gens in patients with dilated cardiomyopathy and their relatives. Int J Cardiol 1996, 54:157-163
  9. Kawai C: From myocarditis to cardiomyopathy: mechanisms of in- flammation and cell death: learning from the past for the future. Circulation 1999, 99:1091-1100
  10. Neu N, Rose NR, Beisel KW, Herskowitz A, Gurri-Glass G, Craig SW: Cardiac myosin induces myocarditis in genetically predisposed mice. J Immunol 1987, 139:3630 -3636
  11. Kodama M, Matsumoto Y, Fujiwara M, Masani F, Izumi T, Shibata A: A novel experimental model of giant cell myocarditis induced in rats by immunization with cardiac myosin fraction. Clin Immunol Immuno- pathol 1990, 57:250 -262
  12. Liao L, Sindhwani R, Leinwand L, Diamond B, Factor S: Cardiac alpha-myosin heavy chains differ in their induction of myocarditis. Identification of pathogenic epitopes. J Clin Invest 1993, 92:2877-2882
  13. Wegmann KW, Zhao W, Griffin AC, Hickey WF: Identification of myo- carditogenic peptides derived from cardiac myosin capable of induc- ing experimental allergic myocarditis in the Lewis rat. The utility of a class II binding motif in selecting self-reactive peptides. J Immunol 1994, 153:892-900
  14. Inomata T, Hanawa H, Miyanishi T, Yajima E, Nakayama S, Maita T, Kodama M, Izumi T, Shibata A, Abo T: Localization of porcine cardiac myosin epitopes that induce experimental autoimmune myocarditis. Circ Res 1995, 76:726 -733
  15. Donermeyer DL, Beisel KW, Allen PM, Smith SC: Myocarditis-induc- ing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart. J Exp Med 1995, 182:1291-1300
  16. Pummerer CL, Luze K, Grassl G, Bachmaier K, Offner F, Burrell SK, Lenz DM, Zamborelli TJ, Penninger JM, Neu N: Identification of cardiac myosin peptides capable of inducing autoimmune myocar- ditis in BALB/c mice. J Clin Invest 1996, 97:2057-2062
  17. Kohno K, Takagaki Y, Aoyama N, Yokoyama H, Takehana H, Izumi T: A peptide fragment of beta cardiac myosin heavy chain (beta-CMHC) can provoke autoimmune myocarditis as well as the corresponding alpha cardiac myosin heavy chain (alpha-CMHC) fragment. Autoim- munity 2001, 34:177-185
  18. Cunningham MW: Cardiac myosin and the TH1/TH2 paradigm in autoimmune myocarditis. Am J Pathol 2001, 159:5-12
  19. Galvin JE, Hemric ME, Kosanke SD, Factor SM, Quinn A, Cunning- ham MW: Induction of myocarditis and valvulitis in Lewis rats by different epitopes of cardiac myosin and its implications in rheumatic carditis. Am J Pathol 2002, 160:297-306
  20. Smith SC, Allen PM: Myosin-induced acute myocarditis is a T cell- mediated disease. J Immunol 1991, 147:2141-2147
  21. Pummerer C, Berger P, Fruhwirth M, Ofner C, Neu N: Cellular infiltrate, major histocompatibility antigen expression and immunopathogenic mechanisms in cardiac myosin-induced myocarditis. Lab Invest 1991, 65:538 -547
  22. Kodama M, Matsumoto Y, Fujiwara M: In vivo lymphocyte-mediated myocardial injuries demonstrated by adoptive transfer of experimen- tal autoimmune myocarditis. Circulation 1992, 85:1918 -1926
  23. Penninger JM, Neu N, Timms E, Wallace VA, Koh DR, Kishihara K, Pummerer C, Mak TW: The induction of experimental autoimmune myocarditis in mice lacking CD4 or CD8 molecules. [Corrected erra- tum appears in J Exp Med 1994 Jan 1;179(1):371]. J Exp Med 1993, 178:1837-1842
  24. Janeway Jr CA: The immune system evolved to discriminate infec- tious nonself from noninfectious self. Immunol Today 1992, 13:11-16
  25. Medzhitov R, Janeway Jr CA: Innate immunity: impact on the adap- tive immune response. Curr Opin Immunol 1997, 9:4 -9
  26. Ohashi PS, DeFranco AL: Making and breaking tolerance. Curr Opin Immunol 2002, 14:744 -759
  27. Lane JR, Neumann DA, Lafond-Walker A, Herskowitz A, Rose NR: Interleukin 1 or tumor necrosis factor can promote Coxsackie B3- induced myocarditis in resistant B10.A mice. J Exp Med 1992, 175:1123-1129
  28. Okura Y, Takeda K, Honda S, Hanawa H, Watanabe H, Kodama M, Izumi T, Aizawa Y, Seki S, Abo T: Recombinant murine interleukin-12 facilitates induction of cardiac myosin-specific type 1 helper T cells in rats. Circ Res 1998, 82:1035-1042
  29. Grabie N, Delfs MW, Westrich JR, Love VA, Stavrakis G, Ahmad F, Seidman CE, Seidman JG, Lichtman AH: IL-12 is required for differ- entiation of pathogenic CD8ϩ T cell effectors that cause myocarditis. J Clin Invest 2003, 111:671-680
  30. Bachmaier K, Pummerer C, Kozieradzki I, Pfeffer K, Mak TW, Neu N, Penninger JM: Low-molecular-weight tumor necrosis factor receptor p55 controls induction of autoimmune heart disease. Circulation 1996, 95:655-661
  31. Afanasyeva M, Wang Y, Kaya Z, Stafford EA, Dohmen KM, Sadighi Akha AA, Rose NR: Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-gamma-independent pathway. Circulation 2001, 104:3145-3151
  32. Seko Y, Takahashi N, Azuma M, Yagita H, Okumura K, Yazaki Y: Effects of in vivo administration of anti-B7-1/B7-2 monoclonal antibod- ies on murine acute myocarditis caused by coxsackievirus B3. Circ Res 1998, 82:613-618
  33. Seko Y, Takahashi N, Azuma M, Yagita H, Okumura K, Yazaki Y: Expression of costimulatory molecule CD40 in murine heart with acute myocarditis and reduction of inflammation by treatment with anti-CD40L/B7-1 monoclonal antibodies. Circ Res 1998, 83:463-469
  34. Estrin M, Smith C, Huber S: Antigen-specific suppressor T cells prevent cardiac injury in Balb/c mice infected with a nonmyocarditic variant of coxsackievirus group B, type 3. Am J Pathol 1986, 125:578 -584
  35. Job LP, Lyden DC, Huber SA: Demonstration of suppressor cells in coxsackievirus group B, type 3 infected female Balb/c mice which prevent myocarditis. Cell Immunol 1986, 98:104 -113
  36. Huber SA, Cunningham MW: Streptococcal M protein peptide with similarity to myosin induces CD4ϩ T cell-dependent myocarditis in MRL/ϩϩ mice and induces partial tolerance against coxsackieviral myocarditis. J Immunol 1996, 156:3528 -3534
  37. Wang Y, Afanasyeva M, Hill SL, Kaya Z, Rose NR: Nasal administra- tion of cardiac myosin suppresses autoimmune myocarditis in mice. J Am Coll Cardiol 2000, 36:1992-1999
  38. Godsel LM, Wang K, Schodin BA, Leon JS, Miller SD, Engman DM: Prevention of autoimmune myocarditis through the induction of anti- gen-specific peripheral immune tolerance. Circulation 2001, 103:1709 -1714
  39. Kaya Z, Dohmen KM, Wang Y, Schlichting J, Afanasyeva M, Leus- chner F, Rose NR: Cutting edge: a critical role for IL-10 in induction of nasal tolerance in experimental autoimmune myocarditis. J Immunol 2002, 168:1552-1556
  40. Harrison LC, Hafler DA: Antigen-specific therapy for autoimmune disease. Curr Opin Immunol 2000, 12:704 -711
  41. Link H, Xiao BG: Rat models as tool to develop new immunotherapies. Immunol Rev 2001, 184:117-128
  42. Steinman RM, Hawiger D, Nussenzweig MC: Tolerogenic dendritic cells. Annu Rev Immunol 2003, 21:685-711
  43. Shevach EM: Regulatory T cells in autoimmmunity. Annu Rev Immu- nol 2000, 18:423-449
  44. Read S, Powrie F: CD4(ϩ) regulatory T cells. Curr Opin Immunol 2001, 13:644 -649
  45. Maloy KJ, Powrie F: Regulatory T cells in the control of immune pathology. Nat Immunol 2001, 2:816 -822
  46. Francois Bach J: Regulatory T cells under scrutiny. Nat Rev Immunol 2003, 3:189 -198
  47. Jonuleit H: Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol 2001, 22:394 -400
  48. Nussenzweig MC, Steinman RM: Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance. Proc Natl Acad Sci USA 2002, 99:351-358
  49. Rauch HC, Einstein ER, Csejtey J, Davis WJ: Protective action of the encephalitogen and other basic proteins in experimental allergic encephalomyelitis. Immunochemistry 1968, 5:567-575
  50. Swierkosz JE, Swanborg RH: Suppressor cell control of unrespon- siveness to experimental allergic encephalomyelitis. J Immunol 1975, 115:631-633
  51. Gaur A, Wiers B, Liu A, Rothbard J, Fathman CG: Amelioration of autoimmune encephalomyelitis by myelin basic protein synthetic peptide-induced anergy. Science 1992, 258:1491-1494
  52. Marusic S, Tonegawa S: Tolerance induction and autoimmune en- cephalomyelitis amelioration after administration of myelin basic pro- tein-derived peptide. J Exp Med 1997, 186:507-515
  53. Segal BM, Chang JT, Shevach EM: CpG oligonucleotides are potent adjuvants for the activation of autoreactive encephalitogenic T cells in vivo. J Immunol 2000, 164:5683-5688
  54. Conant SB, Swanborg RH: Autoreactive T cells persist in rats pro- tected against experimental autoimmune encephalomyelitis and can be activated through stimulation of innate immunity. J Immunol 2004, 172:5322-5328
  55. Warren HS, Vogel FR, Chedid LA: Current status of immunological adjuvants. Annu Rev Immunol 1986, 4:369 -388
  56. Mueller DL, Jenkins MK, Schwartz RH: Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway de- termines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol 1989, 7:445-480
  57. Fearon DT, Locksley RM: The instructive role of innate immunity in the acquired immune response. Science 1996, 272:50 -53
  58. Clayton JP, Gammon GM, Ando DG, Kono DH, Hood L, Sercarz EE: Peptide-specific prevention of experimental allergic encephalomyeli- tis. Neonatal tolerance induced to the dominant T cell determinant of myelin basic protein. J Exp Med 1989, 169:1681-1691
  59. Vidard L, Colarusso LJ, Benacerraf B: Specific T-cell tolerance may reflect selective activation of lymphokine synthesis. Proc Natl Acad Sci USA 1995, 92:2259 -2262
  60. Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL: Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of trans- forming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci USA 1992, 89:421-425
  61. Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL: Regulatory T cell clones induced by oral tolerance: suppression of autoimmune en- cephalomyelitis. Science 1994, 265:1237-1240
  62. Chen Y, Inobe J, Weiner HL: Induction of oral tolerance to myelin basic protein in CD8-depleted mice: both CD4ϩ and CD8ϩ cells mediate active suppression. J Immunol 1995, 155:910 -916
  63. Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683-765
  64. Ichikawa HT, Williams LP, Segal BM: Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease. J Immunol 2002, 169:2781-2787
  65. Hofstetter HH, Shive CL, Forsthuber TG: Pertussis toxin modulates the immune response to neuroantigens injected in incomplete Freund's adjuvant: induction of Th1 cells and experimental autoim- mune encephalomyelitis in the presence of high frequencies of Th2 cells. J Immunol 2002, 169:117-125
  66. Schmidt CS, Mescher MF: Adjuvant effect of IL-12: conversion of peptide antigen administration from tolerizing to immunizing for CD8ϩ T cells in vivo. J Immunol 1999, 163:2561-2567
  67. Pasare C, Medzhitov R: Toll pathway-dependent blockade of CD4ϩCD25ϩ T cell-mediated suppression by dendritic cells. Sci- ence 2003, 299:1033-1036
  68. Cella M, Sallusto F, Lanzavecchia A: Origin, maturation and antigen presenting function of dendritic cells. Curr Opin Immunol 1997, 9:10 -16
  69. Banchereau J, Steinman RM: Dendritic cells and the control of im- munity. Nature 1998, 392:245-252
  70. Lutz MB, Schuler G: Immature, semi-mature and fully mature den- dritic cells: which signals induce tolerance or immunity? Trends Im- munol 2002, 23:445-449
  71. Akbari O, DeKruyff RH, Umetsu DT: Pulmonary dendritic cells pro- ducing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2001, 2:725-731
  72. Penna G, Adorini L: 1 Alpha,25-dihydroxyvitamin D3 inhibits differen- tiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 2000, 164:2405-2411
  73. Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L: Regulatory T cells induced by 1 alpha,25-dihydroxyvitamin D3 and mycophenolate mofetil treatment mediate transplantation tol- erance. J Immunol 2001, 167:1945-1953
  74. Rissoan MC, Soumelis V, Kadowaki N, Grouard G, Briere R, Malefyt W, Liu YJ: Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999, 283:1183
  75. Maldonado-Lopez R, De Smedt T, Michel P, Godfroid J, Pajak B, Heirman C, Thielemans K, Leo O, Urbain J, Moser M: CD8alphaϩ and CD8alphaϪ subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med 1999, 189:587-592
  76. Pulendran B, Smith JL, Caspary G, Brasel K, Pettit D, Maraskovsky E, Maliszewski CR: Distinct dendritic cell subsets differentially regulate the class of immune response in vivo. Proc Natl Acad Sci USA 1999, 96:1036 -1041
  77. Legge KL, Gregg RK, Maldonado-Lopez R, Li L, Caprio JC, Moser M, Zaghouani H: On the role of dendritic cells in peripheral T cell toler- ance and modulation of autoimmunity. J Exp Med 2002, 196:217-227
  78. Mellman I, Steinman RM: Dendritic cells: specialized and regulated antigen processing machines. Cell 2001, 106:255-258
  79. Heath WR: Immunity or tolerance? That is the question for dendritic cells. Nat Immunol 2001, 2:988 -989
  80. Martin E, O'Sullivan B, Low P, Thomas R: Antigen-specific suppres- sion of a primed immune response by dendritic cells mediated by regulatory T cells secreting interleukin-10. Immunity 2003, 18:155-167

Cited by

Sorted by citations

Authors
Li, Y., Heuser, J. S., Kosanke, S. D., Hemric, M., & Cunningham, M. W.
Affiliations
University of Oklahoma Health Sciences Center (US)
Corresponding author
Cunningham, Madeleine W.
ORCID
Cunningham, Madeleine W.
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2005-07
Volume
167
Issue
1
Pages
5-15
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)62948-3
PMC
PMC1603447
OpenAlex
W1964025326
Cited by
39
References
3
Citations by year
2026: 1 · 2024: 2 · 2023: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 1 · 2013: 6 · 2012: 1
FWCI
1.53
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons (Liberty University) (submittedVersion)
Funders
  • American Heart Association (AHA-0215176Z)
  • National Heart, Lung, and Blood Institute (HL 56267)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Viral Infections and Immunology Research
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
experimental autoimmune myocarditis, IL-10, dendritic cells, regulatory T cells, adoptive transfer, IL-12, Th1 cells, interferon-gamma, CD4+ T cells, antigen-presenting cells, Lewis rats, immunomodulation
MeSH terms
Animals, Antigen-Presenting Cells, Autoimmune Diseases, Dendritic Cells, Female, Flow Cytometry, Interferon-gamma, Myocarditis, Rats, Inbred Lew, T-Lymphocytes, Interleukin-10, Immunomagnetic Separation, Interleukin-12, Adoptive Transfer, Reverse Transcriptase Polymerase Chain Reaction, Cardiac Myosins, Cell Proliferation, Rats

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