Normal human fetal and adult cardiac myocytes do not express detectable levels of either MHC Class I or Class II histocompatibility antigens. Yet, these cardiac myocytes appear to be susceptible to cytotoxic immune responses of infiltrating host mononuclear cells post primary cardiac allotransplantation. While the presence of mononuclear cell infiltrate have been documented in human cardiac biopsy specimens at various times post transplantation, relatively little is known about MHC antigen expression on cardiac myocytes. Considerable controversy exists on the phenotype of mononuclear cells that induce cardiac graft rejection. Thus, helper T cells (CD4+), cytotoxic T cells (CD8+) and natural killer cells have all been implicated. The CD4+ cells presumably mediate their response primarily through recognition of MHC-Class II molecules and the CD8+ cells by primarily recognition of MHC Class I molecules resulting in deleterious DTH type and direct cytotoxicity responses respectively. Three lines of approach have been planned in this research proposal. First, studies will concern the examination of serial cardiac biopsy specimen post transplantation for MHC Class I, II antigen expression on cardiac myocytes and correlate these with quantitative phenotypic and functional characterization of mononuclear cell infiltrates. Functional studies such as specific and non-specific donor MLR, CTL and MLR suppressor cell activity will be performed on mononuclear cells cultured and cloned from portions of the cardiac biopsies in vitro using IL-2. Secondly, primary cell cultures of human cardiac myocytes will be used to investigate the phenotype, cellular genetic and subcellular requirements for induction of MHC antigens. Thirdly, use of a unique established cloned cardiac myocyte cell line (EU-MY086- 003-05) will provide a homogenous cell population which will allow the precise determination of the cellular, genetic, subcellular and molecular requirements for induction of MHC gene products in vitro. The influence of immunosuppressive drugs on the induction and regulation of MHC antigen expression in the presence and absence of purified CD4+ and CD8+ specifically allosensitized cells will also be studied. The results will provide a systematic evaluation of the role of phenotypically distinct mononuclear allogeneic cells on MHC antigen expression by cardiac myocytes and more importantly, provide unique insight in the mechanisms of organ allograft rejection.
| Yoshida, T; Bonkovsky, H; Ansari, A et al. (1990) Antibodies against mitochondrial dehydrogenase complexes in primary biliary cirrhosis. Gastroenterology 99:187-94 |
| Ahmed-Ansari, A; Tadros, T S; Knopf, W D et al. (1988) Major histocompatibility complex class I and class II expression by myocytes in cardiac biopsies posttransplantation. Transplantation 45:972-8 |
| Sell, K W; Tadros, T; Wang, Y C et al. (1988) Studies of major histocompatibility complex class I/II expression on sequential human heart biopsy specimens after transplantation. J Heart Transplant 7:407-18 |
