Effects of the new immunosuppressive agent AEB071 on human immune cells.
BACKGROUND. The novel immunosuppressive agent AEB071 is currently being evaluated for its capability to prevent rejection after kidney transplantation as a potential adjunct to calcineurin inhibitor-based regimen. AEB071 is a selective protein kinase C inhibitor and has been shown to be well tolerated in humans. We here present extensive in vitro studies that contribute to the understanding of AEB071 effects on human lymphocyte, natural killer (NK) cell and dendritic cell (DC) action.


METHODS
The impact of AEB071 on several T-cell activation and costimulatory markers was assessed. Furthermore, assays were performed to study the effect on T-cell proliferation and intracellular cytokine production. Additionally, the effect of AEB071 on DC maturation and their capacity to stimulate allogeneic T-cells was examined. Also, an evaluation of AEB071 effects on the lytic activity of human NK cells was performed.


RESULTS
We were able to show that T-cell proliferation and cytokine production rates are significantly reduced after AEB071 administration. Also, mitogen-induced T-cell activation characterized by expression levels of surface markers could be significantly inhibited. In contrast, the T-cell stimulatory capacity of AEB071-treated mature monocyte-derived DC (Mo-DC) is not reduced, and AEB071 administration does not prevent lipopolysaccharide (LPS)-induced Mo-DC maturation. It could be demonstrated that AEB071 significantly inhibited the cytotoxic activity of NK cells.


CONCLUSIONS
The promising immunosuppressive agent AEB071 has a strong impact on T-cell activation, proliferation and cytokine production as well as NK cell activity, but not DC maturation in vitro, and therefore, seems to function T-cell and NK cell specific via protein kinase C (PKC) inhibition.
Matz
Mareen
M
Department of Nephrology, Universitätsmedizin Charité Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany. mareen.matz@charite.de
Weber
Ulrike
U
Mashreghi
Mir-Farzin
MF
Lorkowski
Christine
C
Ladhoff
Juliane
J
Kramer
Stefan
S
Neumayer
Hans-H
HH
Budde
Klemens
K
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015759:Ionomycin / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism
D016207:Cytokines; D007166:Immunosuppressive Agents; D011758:Pyrroles; D011799:Quinazolines; D015759:Ionomycin; C543528:sotrastaurin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate