| Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory heart disease that is (i) mediated initially by CD 4+ T cells and (ii) biphasic, with a proinflammatory phase followed by a phase of repair and fibrosis. The specificities and functions of the T helper (Th) immune responses underlying the induction, progression, and resolution of EAM in A/J mice was unclear, because published data suggested involvement of both Th1 and Th2 responses in disease pathogenesis. This was confounded both by an inability to assess antigen-specific in vivo and in vitro T cell responses in cardiac myosin immunized animals and by ignorance of a powerful and at the time undiscovered T helper response mediated by interleukin 17 (Th17). I developed an alternative model of EAM based on a recombinant fragment of cardiac myosin that enables measurement of functional T cell responses that is not possible with purified native protein. A/J mice immunized with a recombinant fragment of cardiac myosin spanning amino acids 1074-1646, termed Myo4, develop severe myocarditis characterized by cardiac hypertrophy, massive mononuclear cell infiltration and fibrosis, three weeks post-immunization. Myo4-immunized mice develop an IgG1 dominant humoral immune response specific for both Myo4 and purified cardiac myosin. The in vitro stimulation of splenocytes and lymphocytes harvested from Myo4-immunized animals with Myo4 results in cellular proliferation with preferential production of the Th1- and Th17-associated cytokines, IFN-gamma, IL-17 and IL-6, as well as IL-4. Thus, my thesis research led to the development of a new and powerful model of EAM, inducible by immunization with a specific fragment of cardiac myosin, from which antigen-specific analyses reveal an importance for peripheral cellular and humoral immunity. |
