Effect of seliciclib (CYC202, R-roscovitine) on lymphocyte alloreactivity and acute kidney allograft rejection in rat.
BACKGROUND
T cell stimulation by alloantigens is followed by cell cycle progression, an event that is critically dependent on cyclin-dependent kinases.


METHODS
We conducted a study to evaluate whether the cyclin-dependent kinase inhibitor seliciclib affected rat lymph node cells (LNc) activation and proliferation induced by either concanavalin A or allogeneic splenocytes in vitro and studied the mechanisms underlying the suppressive effect. We also investigated the immunosuppressive properties of seliciclib in vivo.


RESULTS
Seliciclib completely inhibited in vitro proliferation of LNc and CD8 T cells, in response to either concanavalin A or allogeneic splenocytes. The percentage of activated LNc was lower in mixed leukocyte reactions (MLR) added with seliciclib than in MLR added with vehicle. The percentages of viable and apoptotic cells at the end of MLR with seliciclib were comparable to those of MLR with vehicle. LNc pre-exposed in MLR to seliciclib did not respond to further stimulation with alloantigens, and neither IL-2 nor IL-15 restored proliferation. These data indicate that the inhibitory effect of seliciclib on T cell alloreactivity is not because of cytotoxic effect but is associated with induction of profound T cell anergy. LNc harvested at the end of the primary MLR with seliciclib did not suppress the proliferation of syngeneic LNc cells toward allogeneic splenocytes, thus excluding that seliciclib induced the formation of regulatory cells. Finally, seliciclib partially prolonged grafted animal survival in a rat model of fully major histocompatibility complex-mismatched kidney transplantation.


CONCLUSIONS
Altogether these results document that seliciclib regulates lymphocyte reactivity and may exert an immunosuppressive effect in vivo in the setting of transplantation.
Pezzotta
Anna
A
Transplant Research Center Chiara Cucchi de Alessandri e Gilberto Crespi, Mario Negri Institute for Pharmacological Research, Ranica, Bergamo, Italy.
Mister
Marilena
M
Monteferrante
Giuseppe
G
Cassis
Linda
L
Azzollini
Nadia
N
Aiello
Sistiana
S
Satta
Maddalena
M
Benigni
Ariela
A
Remuzzi
Giuseppe
G
Noris
Marina
M
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003208:Concanavalin A / Q000494:pharmacology; D005434:Flow Cytometry; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects; D016030:Kidney Transplantation / Q000276:immunology* / Q000401:mortality; D008198:Lymph Nodes / Q000187:drug effects / Q000473:pathology; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D011920:Rats, Inbred WF; D000077546:Roscovitine; D014184:Transplantation, Homologous / Q000276:immunology*
D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D003208:Concanavalin A