The cyclin dependent kinase inhibitor (R)-roscovitine prevents alloreactive T cell clonal expansion and protects against acute GvHD

Abstract

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 TNFα-mediated activation of NFκB 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.

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…68 Furthermore, defective activation of Cdk2 (along with Cdk4 and 6) has been associated with tolerance induced by IL-10 and transforming growth factor b 69 and with a reduction in experimental GVHD. 32 These data notwithstanding, the administration of roscovitine at the dose and schedule delivered did effectivity abrogate Cdk5 activity and, consistent with a previous report, 32 was associated with a reduction in clinical GVHD and preservation of GVL effects (Figure 7). Finally, any strategy to modulate GVHD severity that focuses on T-cell activation or migration (to SLOs or peripheral organs) may influence (negatively) responses to opportunistic infection.…”

“…29,30 Cdk inhibitors have shown activity in experimental models of inflammation 31 and in improving outcomes in preclinical models of allo-HCT. 32 However, the specific role of Cdk5 as a mediator of these events remains an important area of investigation.…”

From Roscovitine to CYC202 to Seliciclib – from bench to bedside: discovery and development

“…These results were in agreement with the findings that roscovitine induced apoptosis of mature neutrophils [141], eosinophils [142]. and proliferating T-cells [143] in a concentration and exposure-time dependent manner.…”

Foxp3 Protein Stability Is Regulated by Cyclin-dependent Kinase 2*

“…Modulating CDK2 activity could therefore be used to affect the balance between immunity and tolerance. Roscovitine (seliciclib), a pharmacologic inhibitor that targets CDK2, CDK7, and CDK9 (44), is in clinical trials to treat cancer (45) and was shown to ameliorate graft-versus-host disease in mice (46). CDK2 may therefore be a relevant target in the treatment of autoimmunity or during transplantation.…”