AUTOIMMUNE-RESPONSE IN CHRONIC ONGOING MYOCARDITIS DEMONSTRATED BY HETEROTOPIC CARDIAC TRANSPLANTATION IN MICE

Background Autoimmune mechanisms have been implicated in the pathogene sis of chronic ongoing myocarditis. To investigate this relation, we u sed an A/J mouse model inoculated with coxsackievirus B3 and determine d 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; 3 X 10(4) plaque-forming units) and housed for >60 days. The presence of the viral genome in the myocardium was determined by the p olymerase chain reaction with primers specific for the 5' end of the c oxsackievirus B3 genome performed at 40, 50, or 60 days after inoculat ion. 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 wee ks after transplantation. Conventional histological examination of inf iltrated T cells and macrophages was performed, and the expression of intercellular adhesion molecule-1, major histocompatibility complex (M HC) class I antigen, and MHC class II antigen was evaluated by immunoe nzymatic staining. The concentrations of interleukin-1 alpha (IL-1 alp ha) and tumor necrosis factor (TNF-alpha) in the grafts were measured with an ELISA. The viral RNA genomes were not detected in the mice wit h chronic ongoing myocarditis, but their transplanted hearts did show myocarditis. In the hearts with induced myocarditis, infiltrated monon uclear 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 Mere expressed in the vascular endothelial cells and myocardial cells in and around the inf iltrated lesions. The concentrations of IL-1 alpha and TNF-alpha in gr oup B were significantly higher than those in group A (group A versus group B: IL-1 alpha. 125+/-35 versus 180+/-34 pg/mL: TNF-alpha 45+/-15 versus 96+/-40 pg/mL, P<.05). Conclusions Results suggest that an aut oimmune response may play a key role in the progression of chronic ong oing myocarditis.