Hepatic expression of IL-15 mRNA is associated with liver graft acceptance

Abstract

Background: Acute allograft rejection continues to be a major cause of morbidity following organ transplantation. The aim of this study was to investigate the local expression of a range of immunomodulatory molecules which may be mediating rejection of, or tolerance to, liver allografts. Methods: RNA was extracted from 31 protocol liver biopsies taken 7–10 days post-transplantation, reverse transcribed and screened by a sensitive RT-PCR for a wide range of cytokines and other immunomodulatory molecules. The mRNA profile of each biopsy was subsequently related to the histological and clinical status of the graft. Samples of RNA isolated from activated leukocytes and T cell clones, and from normal liver, were used as controls to compare to the ‘immunological snapshot’ obtained from the biopsies. Results: Presence of tumour necrosis factor-α, fas ligand, granzyme B and perforin mRNA in most of the liver biopsies reflected the occurrence of cell-mediated immune reactions. However, the expression of only one cytokine, interleukin-15 (IL-15), was significantly more frequent in allografts that showed no histological or biochemical signs of rejection during the early post-transplant period. Using an in vitro model it was demonstrated that recombinant IL-15 expands tenfold the number of CD3 +CD56 + (natural T; NT) cells from peripheral blood mononuclear cells cultures. Conditioning with IL-15 also increased cytotoxic activity of lymphocytes against leukaemic target cells. Conclusions: Although considerable evidence for cell-mediated immunity was shown for all liver allografts, the only clinical association was for IL-15 mRNA expression and graft acceptance. An in vitro model suggested that IL-15 may be enhancing the numbers and the activity of local regulatory cells, in particular resident NT cells in the liver, which may have a role in killing activated lymphocytes such as graft-reactive host T cells.