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Immune Tolerance to Cardiac Myosin Induced by Anti-CD4 Monoclonal Antibody in Autoimmune Myocarditis Rats

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Autoimmune myocarditis is a T-cell-mediated autoimmune disease. CD4-positive T cells are believed to be the most important for the initiation and mediation of the disease. This study was aimed at evaluating whether anti-CD4 monoclonal antibody could induce immune tolerance to porcine cardiac myosin and whether the immune tolerance could protect rats with autoimmune myocarditis from myocardial injury. Lewis rats were immunized with porcine cardiac myosin to induce experimental autoimmune myocarditis. Immune tolerance was induced by injections of anti-CD4 monoclonal antibody on days −2, −1, 0, and 1. Results showed that cardiac function of antibody-treated rats was significantly increased compared with untreated rats 18 days postimmunization examined by transthoracic echocardiography. Typical cardiac histopathological changes were observed obviously in untreated group but not in antibody-treated group. Lymphocytes obtained from antibody-treated group had no proliferative response to porcine cardiac myosin examined by lymphocyte proliferation assay. Serological examination showed that rats immunized with cardiac myosin could produce high levels of anti-cardiac myosin antibody. The administration of anti-CD4 monoclonal antibody significantly prevented the increase of them. Serum levels of Th1 cytokines were significantly down-regulated by antibody administration, while the production of Th2 cytokines were up-regulated or unaffected evaluated by enzyme-linked immunosorbent assay. It concluded that immune tolerance to porcine cardiac myosin could be induced by anti-CD4 monoclonal antibody in vivo, and cardiac dysfunction and myocardial injury could be prevented by induction of immune tolerance.

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REFERENCES

  1. Fontaine G, Fornes P, Fontaliran F: Myocarditis as a cause of sudden death. Circulation 103:e12; author reply, e12, 2001

    PubMed  CAS  Google Scholar 

  2. Drory Y, Turetz Y, Hiss Y, Lev B, Fisman EZ, Pines A, Kramer MR: Sudden unexpected death in persons less than 40 years of age. Am J Cardiol 68:1388–1392, 1991

    Article  PubMed  CAS  Google Scholar 

  3. Maisch B, Richter A, Sandmoller A, Portig I, Pankuweit S: BMBF—Heart failure network: Inflammatory Dilated Cardiomyopathy (DCMI). Herz 30:535–544, 2005

    Article  PubMed  Google Scholar 

  4. Mason JW: Myocarditis and dilated cardiomyopathy: An inflammatory link. Cardiovasc Res 60:5–10, 2003

    Article  PubMed  CAS  Google Scholar 

  5. Stull LB, DiIulio NA, Yu M, McTiernan CF, Ratliff NB, Tuohy VK, Moravec CS: Alterations in cardiac function and gene expression during autoimmune myocarditis in mice. J Mol Cell Cardiol 32:2035–2049, 2000

    Article  PubMed  CAS  Google Scholar 

  6. Rose NR, Hill SL: Autoimmune myocarditis. Int J Cardiol 54:171–175, 1996

    Article  PubMed  CAS  Google Scholar 

  7. Wakisaka Y, Niwano S, Niwano H, Saito J, Yoshida T, Hirasawa S, Kawada H, Izumi T: Structural and electrical ventricular remodeling in rat acute myocarditis and subsequent heart failure. Cardiovasc Res 63:689–699, 2004

    Article  PubMed  CAS  Google Scholar 

  8. Burch M: Immune suppressive treatment in paediatric myocarditis: Still awaiting the evidence. Heart 90:1103–1104, 2004

    Article  PubMed  CAS  Google Scholar 

  9. Gagliardi MG, Bevilacqua M, Bassano C, Leonardi B, Boldrini R, Camassei FD, Fierabracci A, Ugazio AG, Bottazzo GF: Long term follow up of children with myocarditis treated by immunosuppression and of children with dilated cardiomyopathy. Heart 90:1167–1171, 2004

    Article  PubMed  Google Scholar 

  10. Murakami U, Uchida K, Hiratsuka T: Cardiac myosin from pig heart ventricle. Purification and enzymatic properties. J Biochem 80:611–619, 1976

    PubMed  CAS  Google Scholar 

  11. Mori T, Chen YF, Feng JA, Hayashi T, Oparil S, Perry GJ: Volume overload results in exaggerated cardiac hypertrophy in the atrial natriuretic peptide knockout mouse. Cardiovasc Res 61:771–779, 2004

    Article  PubMed  CAS  Google Scholar 

  12. Matsui S, Zong ZP, Han JF, Katsuda S, Yamaguchi N, Fu ML: Amiodarone minimizes experimental autoimmune myocarditis in rats. Eur J Pharmacol 469:165–173, 2003

    Article  PubMed  CAS  Google Scholar 

  13. 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 82(10):1035–1042, 1998

    PubMed  CAS  Google Scholar 

  14. Rezkalla S, Kloner RA, Khatib G, Smith FE, Khatib R: Effect of metoprolol in acute coxsackievirus B3 murine myocarditis. J Am Coll Cardiol 12:412–414, 1988

    Article  PubMed  CAS  Google Scholar 

  15. 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 Immunopathol 57:250–262, 1990

    Article  PubMed  CAS  Google Scholar 

  16. Inomata T, Watanabe T, Haga M, Hirahara H, Abo T, Okura Y, Hanawa H, Kodama M, Izumi T: Anti-CD2 monoclonal antibodies prevent the induction of experimental autoimmune myocarditis. Jpn Heart J 4:507–517, 2000

    Article  Google Scholar 

  17. Liao YH, Yuan J, Wang ZH, Cheng X, Zhang JH, Tian Y, Dong JH, Guo HP, Wang M: Infectious tolerance to ADP/ATP carrier peptides induced by anti-L3T4 monoclonal antibody in dilated cardiomyopathy mice. J Clin Immunol 25:376–384, 2005

    Article  PubMed  CAS  Google Scholar 

  18. Steinman L: The use of monoclonal antibodies for treatment of autoimmune disease. J Clin Immunol 10(6 Suppl):30S–38S, 1990

    Article  PubMed  CAS  Google Scholar 

  19. Yuan J, Liao YH, Wang ZH, Zhang JH, Tian Y, Dong JH, Wang JP: Cardiac impairments induced by adoptive transfer of lymphocytes from the experimental cardiomyopathy in mice. Zhonghua Yi Xue Za Zhi 85:892–896, 2005

    PubMed  CAS  Google Scholar 

  20. Smith SC, Allen PM: Myosin-induced acute myocarditis is a T cell-mediated disease. J Immunol 147:2141–2147, 1991

    PubMed  CAS  Google Scholar 

  21. Afanasyeva M, Georgakopoulos D, Rose NR: Autoimmune myocarditis: Cellular mediators and cardiac dysfunction. Autoimmun Rev 3:476–486, 2004

    Article  PubMed  CAS  Google Scholar 

  22. Nissler K, Pohlers D, Huckel M, Simon J, Brauer R, Kinne RW: Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen induced arthritis: Influence on macrophage activation. Ann Rheum Dis 63:1470–1477, 2004

    Article  PubMed  CAS  Google Scholar 

  23. Darby CR, Morris PJ, Wood KJ: Evidence that long-term cardiac allograft survival induced by anti-CD4 monoclonal antibody does not require depletion of CD4+ T cells. Transplantation 54:483–490, 1992

    Article  PubMed  CAS  Google Scholar 

  24. Thompson C, Jacobsen H, Pomeranz Krummel D, Nagai K, Cooke A: Non-depleting anti-CD4 antibody not only prevents onset but resolves sialadenitis in NOD mice. Autoimmunity 37:549–554, 2004

    Article  PubMed  CAS  Google Scholar 

  25. Arima T, Lehmann M, Flye MW: Induction of donor specific transplantation tolerance to cardiac allografts following treatment with nondepleting (RIB 5/2) or depleting (OX-38) anti-CD4 mAb plus intrathymic or intravenous donor alloantigen. Transplantation 63:284–292, 1997

    Article  PubMed  CAS  Google Scholar 

  26. Lu X, Schulz M, Zihlmann HR, Borel JF: Long-term survival of hamster islet xenografts in mice under short-course treatment with nondepleting versus depleting anti-CD4 monoclonal antibodies. Xenotransplantation 5:154–163, 1998

    Article  PubMed  CAS  Google Scholar 

  27. Plain KM, Fava L, Spinelli A, He XY, Chen J, Boyd R, Davidson CL, Hall BM: Induction of tolerance with nondepleting anti-CD4 monoclonal antibodies is associated with down-regulation of TH2 cytokines. Transplantation 64:1559–1567, 1997

    Article  PubMed  CAS  Google Scholar 

  28. Li L, Crowley M, Nguyen A, Lo D: Ability of a nondepleting anti-CD4 antibody to inhibit Th2 responses and allergic lung inflammation is independent of coreceptor function. J Immunol 163:6557–6566, 1999

    PubMed  CAS  Google Scholar 

  29. Nel AE: T-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J Allergy Clin Immunol 109:758–770, 2002

    Article  CAS  Google Scholar 

  30. Pullar CE, Morris PJ, Wood KJ: Altered proximal T-cell receptor signaling events in mouse CD4+ T cells in the presence of anti-CD4 monoclonal antibodies: Evidence for reduced phosphorylation of Zap-70 and LAT. Scand J Immunol 57:333–341, 2003

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

This research is supported by the grant of Science and Technology Department of Shandong Province 02BS081. It is the Doctoral Research Fund. The authors thank Professor Ma Peiran and Doctor Liang Hao and Zhang Lei for technical assistance.

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Authors and Affiliations

  1. Department of Pediatrics, Shandong Provincial Hospital, Shandong University, Jinan, China

    Wang Qing-Qing, Wang Yu-Lin, Liu Feng-Qin, Jin You-Peng & Han Bo

  2. Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, China

    Yuan Hai-Tao

  3. Department of Cardiology, Shandong Provincial Hospital, Shandong University, 324 Jing Wu Wei Qi Road, Jinan, 250021, China

    Yuan Hai-Tao

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  1. Wang Qing-Qing
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  2. Wang Yu-Lin
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Correspondence to Yuan Hai-Tao.

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Qing-Qing, W., Yu-Lin, W., Hai-Tao, Y. et al. Immune Tolerance to Cardiac Myosin Induced by Anti-CD4 Monoclonal Antibody in Autoimmune Myocarditis Rats. J Clin Immunol 26, 213–221 (2006). https://doi.org/10.1007/s10875-006-9018-2

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  • DOI: https://doi.org/10.1007/s10875-006-9018-2

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