The cyclin dependent kinase inhibitor (R)-roscovitine prevents alloreactive T cell clonal expansion and protects against acute GvHD.
Cell cycle re-entry of quiescent T lymphocytes regulated by cdk2 is required for antigen-specific clonal expansion and generation of productive T cell responses. Recently, we determined that induction of antigen-specific T cell tolerance results in impaired cdk2 activity leading to enhanced Smad3 transactivation, upregulation of p15 and blockade of cell cycle progression. Here we report that pharmacologic inhibition of cdk2 with (R)-roscovitine blocked expansion of alloreactive T cells in vitro and in vivo and protected from lethal acute GvHD. In addition to inhibiting alloreactive T cell responses, (R)-roscovitine prevented TNF-alpha-mediated activation of NF-kappa B pathway, which is involved in the inflammatory process leading to the development of GvHD. The combined anti-proliferative and anti-inflammatory properties of (R)-roscovitine make it an attractive treatment modality toward control of GvHD.
Li
Lequn
L
Harvard Medical School; Boston, MA
Wang
Hui
H
Kim
Jin sub
Js
Pihan
German
G
Boussiotis
Vassiliki
V
D000208:Acute Disease; D000818:Animals; D002453:Cell Cycle; D002460:Cell Line; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000737:chemistry / Q000494:pharmacology*; D000077546:Roscovitine; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011687:Purines; D051900:Smad3 Protein; D014409:Tumor Necrosis Factor-alpha; D000077546:Roscovitine; D051357:Cyclin-Dependent Kinase 2