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CD4 T-cell immunoregulation in cardiac transplant recipients by ezetimibe and atorvastatin in vitro
  1. O Najam,
  2. UA Khan,
  3. SG Williams,
  4. N Yonan,
  5. SM Shaw,
  6. JE Fildes
  1. University Hospital of South Manchester NHS Foundation Trust, Manchester, UK

Abstract

Background 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are potent cholesterol-lowering agents that reduce coronary allograft vasculopathy (CAV) and mortality after cardiac transplantation. Furthermore, “pleiotropic effects” such as immunomodulation have been demonstrated in both clinical and experimental studies. Ezetimibe is an alternative cholesterol-lowering agent. It is currently unclear whether similar pleiotropic effects are seen with this agent. We investigated the in-vitro effect of atorvastatin, ezetimibe or placebo on T lymphocytes. These cells are implicated in the pathogenesis of atherosclerosis, allograft rejection and CAV.

Methods Lymphocytes were isolated from the whole blood of 30 cardiac transplant recipients and co-cultured in increasing doses of atorvastatin or ezetimibe (or placebo) over 48 h. For both drugs, concentrations were calculated to simulate 10 mg or 100 mg daily in a 70 kg adult. Flow cytometry was performed to compare the T-lymphocyte count and functional characteristics.

Results Ezetimibe reduced the CD3+CD4+ T-cell count and CD3+CD4+CD45ro T memory count by a dose linear effect (p<0.001). Atorvastatin also reduced the CD3+CD4+ T-cell count and CD3+CD4+CD45ro T memory count by a dose linear effect (p = 0.004). CD3+CD8+ cytotoxic T cells showed no significant change with either drug (see figs 1 and 2).

Abstract 112 Figure 1.

The effect of atorvastatin co-culture on CD3+CD4+ T-lymphocyte counts.

Abstract 112 Figure 2.

The effect of ezetimibe co-culture on CD3+CD4+ T-lymphocyte counts.

Discussion For the first time, we have demonstrated that ezetimibe has the capacity to immunomodulate T lymphocytes in vitro. Statins are hypothesised to cause pleiotropic effects via the mevalonate pathway. However, our results might indicate that immunomodulation may occur via alternative mechanisms, given that ezetimibe appears to exert similar effects to statins on CD4 T cells in vitro, yet lowers cholesterol via alternative mechanisms. Although speculative, both of these agents could offer benefit in the transplant setting by modulating the immune system. The reduction in T lymphocytes may have significant implications, given their fundamental involvement in CAV and rejection processes.

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