Adenovirus-Mediated Gene Transfer of ICOSIg Fusion Protein Ameliorates Ongoing Experimental Autoimmune Myocarditis

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Abstract
Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis. We previously demonstrated that blockade of B7/CD28 or CD40/CD40 ligand (CD40L) had a potential preventive effect on EAM, but less therapeutic effect on ongoing EAM. Thus, we searched for the involvement of other costimulatory molecules in EAM. We demonstrated the expression of inducible costimulator (ICOS)/ICOSL molecules in the lymph nodes, spleen, and heart in the EAM rat. We constructed adenovirus vectors containing ICOSIg (Adex1CAICOSIg) to achieve effective inhibition of ICOS/ICOSL interaction, and examined the effects of Adex1CAICOSIg on EAM. Adex1CAICOSIg treatment shortly after the immunization did not inhibit the onset and severity of EAM compared to control rats. On the other hand, delayed treatment with Adex1CAICOSIg significantly inhibited ongoing EAM. The survival rate in rats treated with Adex1CAICOSIg was significantly higher than that of the control group. Furthermore, the affected area ratio of the Adex1CAICOSIg treatment group was significantly lower than that of the control group. This study indicates that ICOS/ICOSL costimulation makes an important contribution to the progression of EAM and that the blockade of this pathway by gene transfer has therapeutic potential for ongoing autoimmune myocarditis.