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.