Cellular and molecular mechanisms of human cardiac myocyte injury after transplantation

Abstract

Background: Fetal human cardiac myocytes or a cell line derived from fetal human cardiac myocytes, termed W1, even after experimental induction of "normal" levels of major histocompatibility complex class I and II antigens, fail to induce the activation of primary allogeneic responses. Therefore, our laboratory has investigated the ability of such MHC-expressing cardiac myocytes to induce secondary alloproliferative responses or to serve as target cells for cytotoxic T lymphocytes.

Methods: Cloned CD4+ and CD8+ T-cell lines having specificity for major histocompatibility complex class I and II molecules expressed by the fetal human cardiac myocytes and the W1 cell line were used in standard proliferation and cytotoxicity assays.

Results: Our data show that none of the 19 HLA-DR3 (beta 1 0301)- or HLA-DR15 (beta 1 1501)-specific CD4+ cloned T-cell lines reacted with HLA-DR3- or DR15-expressing W1 or fetal human cardiac myocytes. However, these CD4+ T cells did react, as expected, with similar HLA-DR3/DR15-expressing homozygous typing cells. Of the 16 cloned CD8+ cytotoxic T lymphocytes with specificity for HLA-A2 and the 12 with specificity for HLA-A1, only two of each showed weak cytotoxicity against interferon gamma-pretreated HLA-A2 and A1-expressing W1 and fetal human cardiac myocytes, respectively. Each cloned cytotoxic T lymphocytes line, however, was very effective against HLA-A2 and A1-expressing homozygous typing cells. Although the IFN-gamma-induced W1 and fetal human cardiac myocytes were not susceptible to cytotoxic T lymphocytes-mediated lysis, they were capable of inhibiting specific cytotoxic T lymphocytes function as defined by cold target inhibition studies.

Conclusions: These data suggest that peptide-allo major histocompatibility complex presented by human cardiomyocytes is recognized by T cells and the these lymphocyte/myocyte interactions lead to immunologic ignorance.