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Hepatic expression of IL-15 mRNA is associated with liver graft acceptance
Sharon Cookson1, Derek G Doherty, Stephen Todryk
1Institute of Liver Studies, King's College Hospital, Denmark Hill, London, UK. sharon.cookson@ucd.ie
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-alpha, 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.
Insights
Interleukin-15 (IL-15) mRNA expression in liver allografts correlates with early graft acceptance. This suggests IL-15 may promote regulatory T cells, aiding in the prevention of acute allograft rejection.
Area of Science:
- Immunology
- Transplantation Medicine
- Molecular Biology
Background:
- Acute allograft rejection is a significant complication in organ transplantation.
- Investigating immunomodulatory molecules is crucial for understanding rejection and tolerance.
- Liver allografts are susceptible to rejection, necessitating research into underlying mechanisms.
Purpose of the Study:
- To investigate the local expression of immunomodulatory molecules in liver allografts.
- To determine the role of these molecules in mediating rejection or tolerance.
- To identify specific markers associated with early graft acceptance or rejection.
Main Methods:
- RNA extraction from 31 liver biopsies (7-10 days post-transplantation).
- RT-PCR screening for cytokines and immunomodulatory molecules.
- Correlation of mRNA profiles with histological and clinical graft status.
Main Results:
- Tumor necrosis factor-alpha, fas ligand, granzyme B, and perforin mRNA indicated cell-mediated immunity.
- Interleukin-15 (IL-15) mRNA expression was significantly higher in non-rejected allografts.
- In vitro studies showed IL-15 expands natural T (NT) cells and enhances lymphocyte cytotoxicity.
Conclusions:
- IL-15 mRNA expression is associated with early liver allograft acceptance.
- IL-15 may promote regulatory NT cells in the liver.
- These IL-15-mediated effects could help eliminate graft-reactive host T cells, preventing rejection.