Effects of cellular elements of the immune response on myocyte function and survival

Abstract

The immune response is known to be associated with abnormalities of systolic and diastolic cardiac function during cardiac transplant rejection [1-3] and myocarditis [4]. In addition, autoimmunity may be an important contributor to depressed function in idiopathic dilated cardiomyopathy [5,6]. This immune response may impair cardiac performance by altering the function of individual myocytes, by causing myocyte necrosis and thus reducing the mass of functioning myocardium, or by a combination of these effects. The immune response consists of both cellular and humoral components. The cellular component can result in direct interaction of an inflammatory cell with the myocyte, or an indirect effect produced on the myocyte by virtue of secretion of soluble products such as cytokines by the inflammatory cell. The effects of cytokines on myocardial cells are considered at length in other articles in this issue. In this discussion we consider primarily the effects of direct interaction of various inflammatory cells participating in the immune response on myocyte function and survival. Components of the Cellular Inflammatory InfiltrateIt is first appropriate to consider the nature of the cellular infiltrate that occurs in an immune-mediated cardiac inflammation. Tilney and associates [7,8] showed that acutely rejecting cardiac rat allografts contain macrophages (15-25%), lymphocytes (75%), and neutrophils (5%). Of the lymphocytes, approximately 35% were B cells and the remainder were T lymphocytes. The initial infiltrate consists primarily of lymphocytes, with infiltration by a larger number of macrophages and neutrophils occurring with more complete rejection. Acute murine viral myocarditis is also associated with an infiltrate of macrophages and lymphocytes, including natural killer (NK) cells [9]. Recent work from our laboratory with the murine heterotopic mouse heart transplant model [10] demonstrated that the heart-infiltrating cell population consists of 44% lymphocytes, 30% macrophages, and 20% neutrophils 5-7 days after transplantation. Further studies in our laboratory have documented that the function of the transplanted heart is significantly depressed at this point [11]. We will therefore consider which components of this immune infiltrate could be responsible for cardiac depression during immune-mediated injury and the mechanisms involved. The work to be described will be focused primarily on the transplant rejection model, although, as mentioned earlier, it is very likely that similar mechanisms are involved in the myocardial functional depression noted during myocarditis, and possibly during autoimmune injury associated with idiopathic dilated cardiomyopathy. Effects of Lymphocytes on Cardiac MyocytesWe will first consider the effects oflymphocytes on myocyte function and survival. There are several types of lymphocytes that are involved in immune reactions. Cellular responses are mediated by T lymphocytes. Helper T lymphocytes (HTL; CD4 ÷) recognize endocytosed peptides that are bound to class II MHC mol...