通过小鼠异位心脏移植证明的慢性持续性心肌炎中的自身免疫反应。

Autoimmune response in chronic ongoing myocarditis demonstrated by heterotopic cardiac transplantation in mice.

作者信息

Nakamura H, Yamamura T, Umemoto S, Fukuta S, Shioi T, Matsumori A, Sasayama S, Matsuzaki M

机构信息

Second Department of Internal Medicine, Yamaguchi University School of Medicine, Japan.

出版信息

Circulation. 1996 Dec 15;94(12):3348-54. doi: 10.1161/01.cir.94.12.3348.

DOI:10.1161/01.cir.94.12.3348

PMID:8989150

Abstract

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; 2 x 10(4) 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 alpha (IL-1 alpha) and tumor necrosis factor (TNF-alpha) 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 alpha and TNF-alpha in group 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 autoimmune response may play a key role in the progression of chronic ongoing myocarditis.

摘要

背景

自身免疫机制被认为与慢性进行性心肌炎的发病机制有关。为了研究这种关系，我们使用接种柯萨奇病毒B3的A/J小鼠模型，并确定心肌炎是否会转移到异位移植的正常心脏。

方法与结果

将3周龄的近交系A/J小鼠腹腔内接种柯萨奇病毒B3（南希株；2×10⁴ 空斑形成单位），饲养超过60天。在接种后40、50或60天，通过聚合酶链反应，使用针对柯萨奇病毒B3基因组5'端的特异性引物来确定心肌中病毒基因组的存在情况。将正常A/J小鼠心脏移植到没有心肌炎的同品系小鼠（A组）和患有慢性进行性心肌炎的小鼠（B组）体内。移植后2周对心脏进行组织学评估。进行浸润T细胞和巨噬细胞的常规组织学检查，并通过免疫酶染色评估细胞间黏附分子-1、主要组织相容性复合体（MHC）I类抗原和MHC II类抗原的表达。用酶联免疫吸附测定法测量移植物中白细胞介素-1α（IL-1α）和肿瘤坏死因子（TNF-α）的浓度。在患有慢性进行性心肌炎的小鼠中未检测到病毒RNA基因组，但它们移植的心脏确实显示出心肌炎。在诱导性心肌炎的心脏中，浸润的单核细胞由CD4⁺ T细胞、CD8⁺ T细胞（CD4⁺ 细胞数量＞CD8⁺ 细胞数量）和巨噬细胞组成。在浸润病变及其周围的血管内皮细胞和心肌细胞中表达细胞间黏附分子-1、MHC I类抗原和MHC II类抗原。B组中IL-1α和TNF-α的浓度显著高于A组（A组与B组比较：IL-1α，125±35对180±34 pg/mL；TNF-α，45±15对96±40 pg/mL；P＜0.05）。