The effect of early and late treatment with the tyrphostin AG-556 on the progression of experimental autoimmune myocarditis.
Experimental autoimmune myocarditis (EAM) in rats is a T-cell-mediated disorder; the involvement of TNF-alpha in this disorder has been demonstrated. EAM represents a model for human autoimmune myocarditis, a condition for which no optimal treatment is currently available. Tyrphostins AG-126 and AG-556 were previously shown to reduce TNF-alpha production and its end-organ cytotoxicity, thus proving beneficial in animal models of septic shock and experimental autoimmune encephalomyelitis. To study the effects of AG-126 and AG-556 on EAM, we induced the disorder in male Lewis rats through immunization against myosin and subsequently treated the rats with both agents or the control DMSO both before and after the appearance of myocardial inflammation. AG-556 administered daily for 21 days from the day of EAM induction, significantly reduced the severity of myocarditis. Similarly, AG-556 administered for an additional 10 days after myosin immunization (when signs of inflammation are already present) attenuated the progression of myocarditis, though AG-126 did not. TNF-alpha and IFN-gamma production by in vitro sensitized splenocytes from AG-556-treated rats was significantly diminished as compared with control cells from EAM animals. Thus, AG-556 may represent a novel strategy of ameliorating the progression of myocarditis without non-selectively compromising the immune system.
George
Jacob
J
Department of Cardiology and the Cardiovascular Research Laboratory, Tel-Aviv Medical Center, Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel. jacobg@post.tau.ac.il
Barshack
Iris
I
Goldberg
Iris
I
Keren
Pnina
P
Gazit
Aviv
A
Levitzki
Alexander
A
Keren
Gad
G
Roth
Arie
A
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D024722:Cardiac Myosins / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D007114:Immunization; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D009205:Myocarditis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013552:Swine; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020032:Tyrphostins / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C069028:AG 127; C098981:AG 556; D007371:Interferon-gamma; D009195:Peroxidase; D011505:Protein-Tyrosine Kinases; D024722:Cardiac Myosins