Blockade of T cell costimulatory signals using adenovirus vectors prevents both the induction and the progression of experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis in relation to the autoimmune mechanism and proved to be a T cell-mediated autoimmune disease. Interactions of T cell surface receptors CD28 and CD40L with their ligands B7 and CD40, respectively, on APCs are critical for antigen-specific T cell activation under physiological and pathological conditions. To achieve effective inhibition of these interactions, we have constructed adenovirus vectors containing CTLA4Ig (AdexCTLA4Ig) and CD40Ig (AdexCD40Ig) and examined the effects of these adenovirus vectors in preventing EAM. AdexLacZ as a control, or AdexCTLA4Ig and/or AdexCD40Ig were injected intravenously into rats on day 0 or 14 after immunization to study the preventive effects on EAM in the T cell activation phase or inflammatory phase. Disease severity was estimated by the macroscopic and microscopic findings of the heart, heart weight to body weight ratios, and cellular and humoral immune responses on day 21. The onset of EAM after AdexCTLA4Ig or AdexCD40Ig treatment on day 0 was completely inhibited and antigen-specific lymphocyte proliferation was significantly reduced in those adenovirus-treatment groups, suggesting that those therapies induce antigen-specific T cell anergy. Moreover, significant reduction in disease severity was achieved after the adenovirus vector treatment even on day 14 compared with EAM rats. This study indicates the therapeutic potential of costimulatory pathway blockade by gene-transfer in myocarditis.
Matsui
Yutaka
Y
Division of Molecular Immunology, Institute for Genetic Medicine, Sapporo 060-0815, Japan.
Inobe
Manabu
M
Okamoto
Hiroshi
H
Chiba
Satoru
S
Shimizu
Toshihiro
T
Kitabatake
Akira
A
Uede
Toshimitsu
T
D000069594:Abatacept; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D001835:Body Weight; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D018796:Immunoconjugates; D007150:Immunohistochemistry; D008213:Lymphocyte Activation; D008297:Male; D009205:Myocarditis / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; D018796:Immunoconjugates; D012333:RNA, Messenger; D000069594:Abatacept