Direct Gene Transfer with IP-10 Mutant Ameliorates Mouse CVB3-Induced Myocarditis by Blunting Th1 Immune ResponsesReportar como inadecuado




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Background

Myocarditis is an inflammation of the myocardium that often follows the enterovirus infections, with coxsackievirus B3 CVB3 being the most dominant etiologic agent. We and other groups previously reported that chemokine IP-10 was significantly induced in the heart tissue of CVB3-infected mice and contributed to the migration of massive inflammatory cells into the myocardium, which represents one of the most important mechanisms of viral myocarditis. To evaluate the direct effect of IP-10 on the inflammatory responses in CVB3 myocarditis, herein an IP-10 mutant deprived of chemo-attractant function was introduced into mice to antagonize the endogenous IP-10 activity, and its therapeutic effect on CVB3-induced myocarditis was evaluated.

Methodology-Principal Findings

The depletion mutant pIP-10-AT, with an additional methionine after removal of the 5 N-terminal amino acids, was genetically constructed and intramuscularly injected into BALB-c mice after CVB3 infection. Compared with vector or no treatment, pIP-10-AT treatment had significantly reduced heart-body weight ratio and serum CK-MB level, increased survival rate and improved heart histopathology, suggesting an ameliorated myocarditis. This therapeutic effect was not attributable to an enhanced viral clearance, but to a blunted Th1 immune response, as evidenced by significantly decreased splenic CD4+-CD8+IFN-γ+ T cell percentages and reduced myocardial Th1 cytokine levels.

Conclusion-Significance

Our findings constitute the first preclinical data indicating that interfering in vivo IP-10 activity could ameliorate CVB3 induced myocarditis. This strategy may represent as a new therapeutic approach in treating viral myocarditis.



Autor: Yan Yue, Jun Gui, Wenqing Ai, Wei Xu , Sidong Xiong

Fuente: http://plos.srce.hr/



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