Racial differences in the inhibition of calcineurin in stimulated T cells

The introduction of calcineurin inhibitors (CIs) greatly improved short‐term graft survival but long‐term outcomes have not significantly improved. While multiple factors can effect organ survival, as a group, African American (AA) transplant recipients suffer higher rates of rejection than other racial groups. Despite intense effort, no explanation for this difference has been identified. The aim of this study was to determine if differences in sensitivity to CIs contributes to racial disparities. T cells were isolated from control volunteers and renal transplant recipients and calcineurin stimulation and response to CIs was determined. T cell CaN activity was significantly increased in response to CD3/CD28 co‐stimulation in control but not transplant subjects. Despite comparable blood levels of FK506, T cell activation was markedly higher in AA patients compared to Caucasians (CC). Similarly, both FK506 and cyclosporin A failed to inhibit calcineurin activity in T cells of AA control subjects. Finally, increased stimulation of CaN activity was associated with elevated production of cytokines including IL‐3, IL‐4, and TGFâ. Consistent with this, AA transplant patients had significantly higher serum levels of TGFâ compared to CC. These data suggest that reduced efficacy of CIs at blocking T cell calcineurin activity may contribute to worse long‐term outcomes of AA patients.