Citation: Transplant International. 2013, 26, 47
Author: Archer L.; Regan S.; Khan U.; Najam O.; Yonan N.; Saravanan P.; Fildes J.; Critchley W.
Abstract: Background: CD4+ T cells contribute significantly to allograft rejection and represent a primary target for immunosuppression. The fish oil constituent, eicosapentaenoic acid (EPA) has reported immunomodulatory properties, so we investigated the effect of EPA on T helper cell function and alloresponsiveness. Methods: Gas chromatography was used to determine EPA plasma membrane incorporation. Flow cytometry enumerated CD3+ CD4+ (CD45RA+/ -/RO+/-) T cells. Proteomic analysis of molecules involved in intracellular signalling was performed. The effect of EPA on CD4+ T cell antigen
specificity was determined via rapid CD154 capture and CD45RA/RO phenotyping following donor tissue-recipient CD4+ T cell culture. Results: EPA downregulated CD4+ T cell surface CD45RO expression (p = 0.012) and reduced donor antigen specificity, determined via CD154 analysis (p = 0.008). Cell viability was unaffected (p = 0.495); suggesting EPA acts purely at a functional level. The phosphorylation of intracellular
signalling kinases; STAT2, STAT5, STAT4, STAT1, AMPKalpha2, eNOS, HSP-27, p70- S6Kinase and RSK increased, whilst MEK, ERK, JNK, CREB, STAT3, STAT6 and mTOR decreased. Conclusion: EPA exerts a direct, immunomodulatory effect on CD4+ T cells. Alterations in STAT phosphorylation suggest regulatory T (Treg) cell development, as opposed to TH17. Downregulation of CD45RO, MEK, ERK, JNK and CREB and loss of CD154 following alloantigen exposure indicates EPA impairs T cell
alloresponsiveness. Treg development along with HSP27 and eNOS (assisted by AMPKalpha2) may suppress alloantigen specific T cell activation and induce antiinflammatory mediator release. EPA may represent an important therapeutic strategy to reduce graft rejection and other clinical pathologies.
