Studies of T-lymphocytes in acute and chronic cardiac allograft rejection in humans.

摘要

Cardiac allograft rejection is a common cause of death in heart transplant patients. Understanding the nature of T-cell responses associated with cardiac allograft rejection may lead to development of novel treatment modalities which prevent development of graft rejection.; The objectives of this study are: (1) to determine whether graft infiltrating lymphocytes (GIL) from patients with acute and/or chronic cardiac allograft rejection contain oligoclonal populations of T-cells, (2) to develop, in low concentrations of rIL-2, T-cell lines from patients with chronic cardiac allograft rejection and phenotypically characterize these T-cell lines for presence of various cell-surface markers and T-cell activation markers, and (3) to determine whether there is a Th1 and/or Th2 cytokine response in both acute and chronic cardiac allograft rejection.; We have demonstrated that coronary arteries from patients with chronic cardiac allograft rejection contain oligoclonal populations of T-cells. Sequence analysis of beta-chain TCR transcripts revealed substantial proportions of identical beta-chain TCR transcripts, the presence of which may suggest that T-cells have undergone specific antigen-driven proliferation and clonal expansion at the site of the graft. Additionally, within particular patients, we have observed a persistence of T-cell clones from the early post-transplantation period through to end-stage graft failure.; Analysis of T-cell lines indicated that in both acute and chronic rejection there is a preponderance of alpha/betaTCR+CD3+ T-cell populations. T-cell lines generated from chronically rejected hearts contained predominantly CD8+ T-cells in comparison to a T-cell line derived from an acute rejection specimen which was 96% CD4+ T-cells. T-cell lines from chronically rejected allografts were also predominantly CD38+ and CD25+. The presence of intermediate (CD25 and CD38) activation antigens in high proportions on cells from these lines suggests that they have been derived from sites with active on-going inflammation.; In both acute and chronic cardiac allograft rejection, there was an association between presence of Th1 cytokines IL-2 and IFN-gamma and rejection. In endomyocardial biopsies from patients experiencing an acute rejection episode, levels of both IL-2 and IFN-gamma associated with increasing rejection grade. Similar observations were made when analyzing the levels of cytokine transcripts in the coronary arteries of patients with chronic rejection. These results suggest that Th1 cytokines may play a role in pathogenesis of both acute and chronic allograft rejection.; Together, these results suggest that: (1) antigen-specific T-cells may be present in GIL populations from patients with cardiac allograft rejection, (2) T-cells isolated from coronary arteries of patients with chronic rejection are activated and may be cytotoxic in nature, and (3) Th I cytokines IL-2 and IFN-gamma are clearly associated with both acute and chronic cardiac allograft rejection.