Inhibition of the IL-15 pathway in anti-CD25 mAb treated renal allograft recipients.

Anti-CD25 mAb's are used for prophylaxis of rejection in allograft transplantation. These agents target the alpha-chain, part of the IL-2Ralphabetagamma complex. The beta- and gamma-chain are signaling components that are not specific for IL-2. The T-cell growth factors IL2, IL-7 and IL-15 utilize the gamma-chain and IL-2 and IL-15 share the beta-chain. We have studied the consequences of targeting the IL-2R alpha-chain with the anti-CD25 mAb basiliximab by measuring the IL-2R alphabetagamma expression levels and the IL-2, IL-7 and IL-15 driven proliferation. By flowcytometry and limiting dilution analysis, the IL-2R complex was analyzed in peripheral blood samples from renal allograft recipients (n = 29) who received basiliximab (20 mg IV bolus on day 0 and 4), cyclosporin and mycophenolate mofetil. In peripheral blood, after induction therapy with basiliximab, no CD25 positive T-cells were detectable for 61 days (median, range 25-93 days). When CD25 cells were covered with basiliximab, the percentage and the mean fluorescence intensity (MFI) of IL-2Rbeta positive T-cells significantly decreased, P = 0.02 and P = 0.013, respectively, whereas the expression level of the IL-2Rgamma was not affected. The inhibition of the expression of the IL-2R alpha- and beta-chain had significant consequences for the function of these cells. Both the IL-2- and the IL-15-dependent proliferation were inhibited, P = 0.007 and P = 0.01, respectively. The control, the IL-7 driven proliferation, was not influenced by basiliximab. In conclusion, therapy with anti-CD25 mAb's affect T-cell-dependent allogeneic immune responses, not only by blocking IL-2 signaling but also by impairing IL-15 signaling through downregulating the IL-2/IL-15 receptor beta-chain.