Pharmacologic inhibition of PKC? and PKC? prevents GVHD while preserving GVL activity in mice.

ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is the most effective therapy for hematopoietic malignancies through T-cell-mediated graft-vs-leukemia (GVL) effects but often leads to severe graft-vs-host disease (GVHD). Given that protein kinase C? (PKC?), in cooperation with PKC?, is essential for T-cell signaling and function, we have evaluated PKC? and PKC? as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKC?(-/-)/?(-/-) donor T cells to induce GVHD was further reduced compared with PKC?(-/-) T cells in relation with the relevance of both isoforms to allogeneic donor T-cell proliferation, cytokine production, and migration to GVHD target organs. Treatment with a specific inhibitor for both PKC? and PKC? impaired donor T-cell proliferation, migration, and chemokine/cytokine production and significantly decreased GVHD in myeloablative preclinical murine models of allogeneic HCT. Moreover, pharmacologic inhibition of PKC? and PKC? spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKC? and ? contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKC? and PKC? signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT.

SUBMITTER: Haarberg KM 

PROVIDER: S-EPMC3790515 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature