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Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice. Blood 2013 Oct 03;122(14):2500-11

Date

08/03/2013

Pubmed ID

23908466

Pubmed Central ID

PMC3790515

DOI

10.1182/blood-2012-12-471938

Scopus ID

2-s2.0-84887761550 (requires institutional sign-in at Scopus site)   35 Citations

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 Cθ (PKCθ), in cooperation with PKCα, is essential for T-cell signaling and function, we have evaluated PKCθ and PKCα as potential therapeutic targets in allogeneic HCT using genetic and pharmacologic approaches. We found that the ability of PKCα(-/-)/θ(-/-) donor T cells to induce GVHD was further reduced compared with PKCθ(-/-) 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 PKCθ and PKCα 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 PKCθ and PKCα spared T-cell cytotoxic function and GVL effects. Our findings indicate that PKCα and θ contribute to T-cell activation with overlapping functions essential for GVHD induction while less critical to the GVL effect. Thus, targeting PKCα and PKCθ signaling with pharmacologic inhibitors presents a therapeutic option for GVHD prevention while largely preserving the GVL activity in patients receiving HCT.

Author List

Haarberg KM, Li J, Heinrichs J, Wang D, Liu C, Bronk CC, Kaosaard K, Owyang AM, Holland S, Masuda E, Tso K, Blazar BR, Anasetti C, Beg AA, Yu XZ

Author

Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Separation
Disease Models, Animal
Enzyme Inhibitors
Flow Cytometry
Graft vs Host Disease
Graft vs Leukemia Effect
Hematopoietic Stem Cell Transplantation
Isoenzymes
Leukemia
Lymphocyte Activation
Lymphoma
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Protein Kinase C
Protein Kinase C-alpha
Protein Kinase C-theta
T-Lymphocytes