Treatment and prevention of experimental autoimmune myocarditis with CD28 superagonists.
OBJECTIVE
Experimental autoimmune myocarditis (EAM), a rodent model of human dilated cardiomyopathy (DCM), is mediated by an autoimmune mechanism. We investigated whether a CD28 superagonistic antibody selectively targeting CD4+CD25+ regulatory T cells (T(regs)) provides effective therapy for EAM.


METHODS
Four groups of 5 rats were used. The normal control group was immunized with PBS. The EAM group was immunized with porcine myosin. The experimental group was immunized with myosin and superagonistic CD28 antibody JJ316. The final group was immunized with myosin and an unrelated rat IgG. Autoantibody and IL-10 production, CD4+CD25+ cell levels, Foxp3 expression and cardiac histology were analyzed.


RESULTS
Anti-myosin autoantibody levels were higher in the EAM and isotype control groups than the normal control group (p < 0.05), and reduced in the CD28-JJ316 group (p < 0.05). The levels of CD25+CD4+ cells, IL-10 and splenocyte Foxp3 expression were significantly lower in the EAM and isotype control groups versus the CD28-JJ316 group (p < 0.05). Infiltration of inflammatory cells was observed in the EAM and isotype control groups, whereas CD28-JJ316 ameliorated myocarditis.


CONCLUSIONS
CD28 superagonists could be effective in EAM treatment by up-regulating Foxp3 expression and contributing to CD4+CD25+ T(reg) activation and expansion. The enhancement in IL-10 by CD28 superagonists also ameliorated the disease.
Wang
Shu
S
Department of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Liu
Jing
J
Wang
Min
M
Zhang
Jinghui
J
Wang
Zhaohui
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D018106:CD28 Antigens / Q000276:immunology*; D024722:Cardiac Myosins; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy; D051858:Forkhead Transcription Factors / Q000032:analysis; D008297:Male; D009205:Myocarditis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D051381:Rats; D011917:Rats, Inbred Lew; D013552:Swine; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D024722:Cardiac Myosins