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(Circulation. 1996;94:3348-3354.)
© 1996 American Heart Association, Inc.

Articles

Autoimmune Response in Chronic Ongoing Myocarditis Demonstrated by Heterotopic Cardiac Transplantation in Mice

Hiroshi Nakamura, MD, PhD; Taisei Yamamura, MD; Seiji Umemoto, MD, PhD; Shinji Fukuta, MD, PhD; Tetsuo Shioi, MD, PhD; Akira Matsumori, MD, PhD; Shigetake Sasayama, MD, PhD; Masunori Matsuzaki, MD, PhD

the Second Department of Internal Medicine (H.N., T.Y., S.U., S.F., M.M.), Yamaguchi University School of Medicine, Yamaguchi; and Department of Cardiovascular Medicine (T.S., A.M., S.S.), Kyoto University Graduate School of Medicine, Kyoto, Japan.

Correspondence to Masunori Matsuzaki, MD, The Second Department of Internal Medicine, Yamaguchi University School of Medicine, 1144 Kogushi, Ube, Yamaguchi, 755 Japan. E-mail ninai@po.cc.yamaguchi-u.ac.jp.

Background Autoimmune mechanisms have been implicated in the pathogenesis of chronic ongoing myocarditis. To investigate this relation, we used an A/J mouse model inoculated with coxsackievirus B3 and determined whether myocarditis would be transferred to normal hearts that were heterotopically transplanted.

Methods and Results Inbred 3-week-old A/J mice were inoculated intraperitoneally with coxsackievirus B3 (Nancy strain; 2x10⁴ plaque-forming units) and housed for >60 days. The presence of the viral genome in the myocardium was determined by the polymerase chain reaction with primers specific for the 5' end of the coxsackievirus B3 genome performed at 40, 50, or 60 days after inoculation. Normal A/J mouse hearts were transplanted into the same strain of mice without myocarditis (group A) and into mice with chronic ongoing myocarditis (group B). The hearts were evaluated histologically 2 weeks after transplantation. Conventional histological examination of infiltrated T cells and macrophages was performed, and the expression of intercellular adhesion molecule-1, major histocompatibility complex (MHC) class I antigen, and MHC class II antigen was evaluated by immunoenzymatic staining. The concentrations of interleukin-1 (IL-1) and tumor necrosis factor (TNF-) in the grafts were measured with an ELISA. The viral RNA genomes were not detected in the mice with chronic ongoing myocarditis, but their transplanted hearts did show myocarditis. In the hearts with induced myocarditis, infiltrated mononuclear cells consisted of CD4+ T cells, CD8+ T cells (CD4+ cell number >CD8+ cell number), and macrophages. Intercellular adhesion molecule-1, MHC class I antigen, and MHC class II antigen were expressed in the vascular endothelial cells and myocardial cells in and around the infiltrated lesions. The concentrations of IL-1 and TNF- in group B were significantly higher than those in group A (group A versus group B: IL-1, 125±35 versus 180±34 pg/mL; TNF-, 45±15 versus 96±40 pg/mL; P<.05).

Conclusions Results suggest that an autoimmune response may play a key role in the progression of chronic ongoing myocarditis.

Key Words: myocarditis • transplantation • immune system • cytokines

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