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 alpha-(CD25) and beta-(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.
Forrest
Kathy
K
Department of Pediatrics, University of Kentucky, Lexington, KY 40536, USA.
Logan
Barbara
B
Strange
Jennifer
J
Roszman
Thomas L
TL
Goebel
Jens
J
D000293:Adolescent; D000367:Age Factors; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000077561:Daclizumab; D015536:Down-Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology* / Q000627:therapeutic use; D016030:Kidney Transplantation; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D015375:Receptors, Interleukin-2; D000077561:Daclizumab