Daclizumab therapy in kidney transplantation-different mechanisms of action in- versus ex-vivo?

Stimulated human T cells from healthy volunteers demonstrate attenuated early interleukin (IL)-2 receptor (R) signaling in the presence of daclizumab (Dac). Aiming to confirm that this ex-vivo effect of Dac is also observed in-vivo, we studied T cells from 3 kidney transplant recipients before and 2-3 weeks and 4-6 months after transplantation. We found by flow cytometry that T cells obtained pre-transplant and stimulated ex-vivo with phytohemeagglutinine upregulated the IL-2R α-(CD25) and β-(CD122) chains as expected. Moreover, exogenous IL-2 induced characteristic tyrosine phosphorylation events detectable by immunoblotting in these cells. However, T cells studied post-transplant neither exhibited CD25 or -122 upregulation nor IL-2-induced tyrosine phosphorylation events, indicating broad, persistent suppression of the IL-2R signaling machinery which thus appears largely inaccessible for Dac in actual transplant recipients. We therefore conclude that the clinical efficacy of this agent may depend on additional mechanisms in-vivo other than those identified ex-vivo.