Cyclosporine inhibits class II major histocompatibility antigen presentation by xenogeneic endothelial cells to human T lymphocytes by altering expression of the class II transcriptional activator gene

Background. Cyclosporine (CsA) is currently given to recipients of vascular ized xenografts as part of the immunosuppressive regimen required to preven t the hyperacute rejection phase. The effects of CsA on nonlymphoid immune cells, such as endothelial cells (ECs), have not been well characterized an d sometimes seem contradictory, because both protective and adverse effects have been reported. In the present study, we investigated in vitro whether CsA could alter the antigenicity of activated porcine aortic endothelial c ells (PAECs) by reducing class I and class ZI MHC antigen expression, Methods. The effect of CsA on MRC antigen expression during tumor necrosis factor (TNF)-alpha- or lymphocyte-mediated PAEC activation was evaluated in vitro by flow cytometry and correlated to the ability of porcine ECs to pr omote human T lymphocyte proliferation. The effect of CsA on class II MHC a ntigen mRNA expression was also analyzed and related to class II transcript ional activator (CIITA) mRNA expression. Results, Flow cytometry analysis showed that TNF-alpha-mediated induction o f class II MHC antigen expression on PAECs was completely inhibited by CsA, whereas expression of class I MHC was reduced by 50%. The inhibition was d ose dependent (at drug concentrations ranging from 2.5 mu g/ml to 20.0 mu g /ml) and was consistently observed at all time points (24-72 hr) during the activation period. Decreased MHC antigen expression dramatically reduced t he ability of PAECs to further promote human T-cell proliferation, Similar levels of inhibition were achieved using an anti-porcine class II MHC block ing monoclonal antibody, Pretreatment of PAECs with CsA for 4 hr before coc ulture with human peripheral blood leukocytes efficiently blocked the induc tion on PAECs of E-selectin and class TT MHC antigens and inhibited overexp ression of class I antigens, Semiquantitative reverse transcriptase-polymer ase chain reaction experiments showed that Cs,4 markedly reduced the steady -state level of porcine class H (SLA-DRA and SLA-DQA) mRNA at 16 hr, compar ed with PAECs stimulated with TNF-alpha alone. The reduced level of class I I MHC mRNA was associated with a lack of CIITA expression at this time poin t, suggesting that CsA could alter transcription or promote the rapid decay of CIITA mRNA, Conclusion. Our study indicates that CsA could play a role in preventing po rcine MHC antigens being directly presented to human T lymphocytes by xenog eneic ECs.