Experimental Autoimmune Myocarditis Produced by Adoptive Transfer of Splenocytes After Myocardial Infarction

From the Department of Medicine, Division of Cardiology, and Department of Pathology, Veterans Affairs Medical Center and University of California, San Diego.

Correspondence to Alan Maisel, MD, VAMC Cardiology 111-A, 3350 La Jolla Village Dr, San Diego, CA 921161. E-mail amaisel{at}ucsd.edu

Abstract—One possible mechanism for neurohumoral activation after myocardial infarction may be the generation of an immune response against cardiac self-antigens. We hypothesize that if there is a T cell–mediated reaction to self-antigens, the transfer of splenic lymphocytes from postinfarct rats into syngeneic rats with normal hearts should result in a T cell–mediated autoimmune myocarditis in the healthy syngeneic rats. Rats were killed 6 weeks after coronary ligation. Splenocytes from animals with large and small infarcts were purified from spleens, activated with concanavalin A, and injected in varying doses into normal syngeneic rats. These recipient rats were killed 6 weeks later, and histopathological studies were performed. Our results demonstrate in vivo evidence of lymphocyte-mediated myocardial injury by adoptive transfer of sensitized lymphocytes from rats who developed congestive heart failure after acute myocardial infarction. The amount of infiltrate and necrosis in the recipient rats appeared directly related to the size of the infarct from the donor rats. This suggests that larger infarcts lead to a greater inflammatory response as well as a greater propensity for alteration of cardiac surface antigens or the emergence of previously sequestered antigens. None of the other organs (kidney, liver, lung, or brain) had evidence of infiltrates. Two-dimensional echocardiography did not reveal systolic dysfunction. This study provides direct evidence of autoimmune myocardial injury produced by adoptive transfer of concanavalin A–activated splenocytes after myocardial infarction. We propose that neurohumoral activation early in the postinfarction period triggers a series of specific inflammatory and immunological events that lead to formation of specific clones of T cells. When these are activated and transferred into normal rats, cardiac-specific cellular infiltration occurs, occasionally accompanied by myocardial necrosis. This model should help to further explore the link between neurohumoral activation after myocardial infarction and the subsequent immune alterations that might be associated with the development and/or progression of congestive heart failure. Additionally, this might be a useful model in which to study other immune-mediated cardiomyopathies.

Key Words: myocardial infarction • myocarditis • concanavalin A

This article has been cited by other articles:

				Y. Maekawa, N. Mizue, A. Chan, Y. Shi, Y. Liu, S. Dawood, M. Chen, F. Dawood, G. de Couto, G. H. Li, et al. Survival and Cardiac Remodeling After Myocardial Infarction Are Critically Dependent on the Host Innate Immune Interleukin-1 Receptor-Associated Kinase-4 Signaling: A Regulator of Bone Marrow-Derived Dendritic Cells Circulation, October 6, 2009; 120(14): 1401 - 1414. [Abstract] [Full Text] [PDF]

				K. Naito, T. Anzai, Y. Sugano, Y. Maekawa, T. Kohno, T. Yoshikawa, K. Matsuno, and S. Ogawa Differential Effects of GM-CSF and G-CSF on Infiltration of Dendritic Cells during Early Left Ventricular Remodeling after Myocardial Infarction J. Immunol., October 15, 2008; 181(8): 5691 - 5701. [Abstract] [Full Text] [PDF]

				F. Leuschner, J. Li, S. Goser, L. Reinhardt, R. Ottl, P. Bride, J. Zehelein, G. Pfitzer, A. Remppis, E. Giannitsis, et al. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction Eur. Heart J., August 2, 2008; 29(16): 1949 - 1955. [Abstract] [Full Text] [PDF]

				J. S. Burchfield, M. Iwasaki, M. Koyanagi, C. Urbich, N. Rosenthal, A. M. Zeiher, and S. Dimmeler Interleukin-10 From Transplanted Bone Marrow Mononuclear Cells Contributes to Cardiac Protection After Myocardial Infarction Circ. Res., July 18, 2008; 103(2): 203 - 211. [Abstract] [Full Text] [PDF]

				A Abbate, R Bussani, G Liuzzo, G G L Biondi-Zoccai, E Barresi, P Mellone, G Sinagra, A Dobrina, F De Giorgio, R Sharma, et al. Sudden coronary death, fatal acute myocardial infarction and widespread coronary and myocardial inflammation Heart, June 1, 2008; 94(6): 737 - 742. [Abstract] [Full Text] [PDF]

				C. Izgi, C. Cevik, N. Ozdemir, C. Kaymaz, and M. Ozkan Serum anti-p53 antibodies do not occur in patients with heart failure due to idiopathic dilated and ischemic cardiomyopathies Eur J Heart Fail, December 1, 2005; 7(7): 1095 - 1098. [Abstract] [Full Text] [PDF]

				X. Cheng, Y.-H. Liao, J. Zhang, B. Li, H. Ge, J. Yuan, M. Wang, B. Lu, Y. Liu, and Y. Cheng Effects of Atorvastatin on Th polarization in patients with acute myocardial infarction Eur J Heart Fail, December 1, 2005; 7(7): 1099 - 1104. [Abstract] [Full Text] [PDF]

				S. L. Karackattu, M. H. Picard, and M. Krieger Lymphocytes Are Not Required for the Rapid Onset of Coronary Heart Disease in Scavenger Receptor Class B Type I/Apolipoprotein E Double Knockout Mice Arterioscler Thromb Vasc Biol, April 1, 2005; 25(4): 803 - 808. [Abstract] [Full Text] [PDF]

				M. Satoh, J. Iwasaka, M. Nakamura, T. Akatsu, Y. Shimoda, and K. Hiramori Increased expression of tumor necrosis factor-{alpha} converting enzyme and tumor necrosis factor-{alpha} in peripheral blood mononuclear cells in patients with advanced congestive heart failure Eur J Heart Fail, December 1, 2004; 6(7): 869 - 875. [Abstract] [Full Text] [PDF]

				Y. Matsumoto, Y. Tsukada, A. Miyakoshi, H. Sakuma, and K. Kohyama C Protein-Induced Myocarditis and Subsequent Dilated Cardiomyopathy: Rescue from Death and Prevention of Dilated Cardiomyopathy by Chemokine Receptor DNA Therapy J. Immunol., September 1, 2004; 173(5): 3535 - 3541. [Abstract] [Full Text] [PDF]

				F. Calabrese and G. Thiene Myocarditis and inflammatory cardiomyopathy: microbiological and molecular biological aspects Cardiovasc Res, October 15, 2003; 60(1): 11 - 25. [Abstract] [Full Text] [PDF]

				K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]

				A. Davidson and B. Diamond Autoimmune Diseases N. Engl. J. Med., August 2, 2001; 345(5): 340 - 350. [Full Text] [PDF]

				Y. SETA, T. KANDA, T. TANAKA, M. ARAI, K. SEKIGUCHI, T. YOKOYAMA, M. KURIMOTO, J.'I. TAMURA, and M. KURABAYASHI Interleukin 18 in acute myocardial infarction Heart, December 1, 2000; 84(6): 668 - 669. [Full Text]

				A. M. Feldman and D. McNamara Myocarditis N. Engl. J. Med., November 9, 2000; 343(19): 1388 - 1398. [Full Text] [PDF]