First Author | Haarberg KM | Year | 2013 |
Journal | Blood | Volume | 122 |
Issue | 14 | Pages | 2500-11 |
PubMed ID | 23908466 | Mgi Jnum | J:203281 |
Mgi Id | MGI:5525946 | Doi | 10.1182/blood-2012-12-471938 |
Citation | Haarberg KM, et al. (2013) Pharmacologic inhibition of PKCalpha and PKCtheta prevents GVHD while preserving GVL activity in mice. Blood 122(14):2500-11 |
abstractText | 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 Ctheta (PKCtheta), in cooperation with PKCalpha, is essential for T-cell signaling and function, we have evaluated PKCtheta and PKCalpha as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKCalpha(-/-)/theta(-/-) donor T cells to induce GVHD was further reduced compared with PKCtheta(-/-) 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 PKCtheta and PKCalpha 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 PKCtheta and PKCalpha spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKCalpha and theta contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKCalpha and PKCtheta signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT. |