Adenovirus-mediated gene transfer of ICOSIg fusion protein ameliorates ongoing experimental autoimmune myocarditis.
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.
Matsui
Yutaka
Y
Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Okamoto
Hiroshi
H
Inobe
Manabu
M
Jia
Nan
N
Shimizu
Toshihiro
T
Akino
Masatoshi
M
Sugawara
Takeshi
T
Tezuka
Katsunari
K
Nakayama
Yousuke
Y
Morimoto
Junko
J
Kimura
Chiemi
C
Kon
Shigeyuki
S
Miyazaki
Tadaaki
T
Kitabatake
Akira
A
Uede
Toshimitsu
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000097:blood; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009218:Myosins / Q000276:immunology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000097:blood; D013154:Spleen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C498514:ICOSLG protein, human; C556695:Icos protein, rat; D007136:Immunoglobulins; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D011993:Recombinant Fusion Proteins; D009218:Myosins