Role of P-glycoprotein on CD69(+)CD4(+) cells in the pathogenesis of proliferative lupus nephritis and non-responsiveness to immunosuppressive therapy

INTRODUCTION: P-glycoprotein (P-gp) expression on activated lymphocytes in systemic lupus erythematosus (SLE) plays a role in active efflux of intracellular drugs, resulting in drug resistance. The role of P-gp-expressing lymphocytes in the pathogenesis of SLE remains unclear. The aim of this study was to determine the importance of P-gp(+)CD4(+) cells in organ manifestations in refractory SLE. METHODS: The proportion of P-gp(+)CD4(+) cells was determined by flow cytometry in peripheral blood of patients with SLE (n=116) and healthy adults (n=10). Renal biopsy specimens were examined by immunohistochemistry for P-gp expression. RESULTS: CD69 is a marker of CD4 cell activation. The proportion of both P-gp-expressing CD4(+) cells and CD69-expressing CD4(+) cells in peripheral blood was higher in SLE than control. The proportion of P-gp(+)CD69(+)CD4(+) cells correlated with Systemic Lupus Erythematosus Disease Activity Index and was higher in poor responders to corticosteroids. Furthermore, the proportion of P-gp(+)CD69(+)CD4(+) cells was significantly higher in proliferative lupus nephritis (LN) with poor response to corticosteroids. The efficacy of immunosuppressive therapy depended on the regulation of the proportion of P-gp(+)CD69(+)CD4(+) cells. Marked accumulation of P-gp(+)CD4(+) cells in renal interstitial tissue and high proportion of peripheral P-gp(+)CD69(+)CD4(+) cells were noted in patients with proliferative LN. CONCLUSIONS: The results showed high proportion of P-gp(+)CD69(+)CD4(+) cells in peripheral blood and their accumulation in renal tissue in patients with proliferative LN refractory to CS therapy, suggesting that P-gp expression on activated CD4(+) T cells is a potentially useful marker for refractoriness to treatment and a novel target for treatment.