title: Pharmacologic inhibition of PKCα and PKCθ 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 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.
authors.affiliation: Department of Immunology and.
authors.forename: Kelley M K
authors.initials: KM
authors.lastname: Haarberg
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Crystina C
authors.initials: CC
authors.lastname: Bronk
authors.forename: Kane
authors.initials: K
authors.lastname: Kaosaard
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Owyang
authors.forename: Sacha
authors.initials: S
authors.lastname: Holland
authors.forename: Esteban
authors.initials: E
authors.lastname: Masuda
authors.forename: Kin
authors.initials: K
authors.lastname: Tso
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000818:Animals; D002469:Cell Separation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000201:enzymology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007938:Leukemia / Q000628:therapy; D008213:Lymphocyte Activation / Q000187:drug effects; D008223:Lymphoma / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D000074121:Protein Kinase C-theta
references.citation: Blood. 2011 Mar 24;117(12):3268-76
references.pmid: 21245483
references.citation: Blood. 2005 Aug 1;106(3):1113-22
references.pmid: 15855275
references.citation: Transfus Med Rev. 1998 Jan;12(1):1-17
references.pmid: 9460186
references.citation: Immunol Rev. 1997 Jun;157:79-109
references.pmid: 9255624
references.citation: Blood. 1998 Oct 1;92(7):2303-14
references.pmid: 9746768
references.citation: Science. 1999 Jul 16;285(5426):412-5
references.pmid: 10411505
references.citation: Blood. 1992 Dec 15;80(12):2964-8
references.pmid: 1467511
references.citation: Blood. 2005 Feb 1;105(3):1355-61
references.pmid: 15459004
references.citation: Mol Immunol. 2009 Jun;46(10):2071-9
references.pmid: 19356803
references.citation: Curr Opin Cell Biol. 2009 Apr;21(2):262-7
references.pmid: 19195860
references.citation: Blood. 2008 Jan 15;111(2):954-62
references.pmid: 17928532
references.citation: Annu Rev Immunol. 1994;12:141-79
references.pmid: 8011280
references.citation: J Clin Invest. 2008 Sep;118(9):3151-9
references.pmid: 18688284
references.citation: J Clin Invest. 2009 Dec;119(12):3774-86
references.pmid: 19907075
references.citation: Eur J Immunol. 2010 Feb;40(2):505-15
references.pmid: 19950169
references.citation: J Biol Chem. 2004 Aug 13;279(33):34472-80
references.pmid: 15192100
references.citation: Blood. 2004 Feb 15;103(4):1542-7
references.pmid: 14563643
references.citation: Blood Rev. 2003 Dec;17(4):187-94
references.pmid: 14556773
references.citation: Trends Immunol. 2011 Aug;32(8):358-63
references.pmid: 21733754
references.citation: Rev Clin Esp. 2006 Apr;206(4):197-8
references.pmid: 16750093
references.citation: Cancer Res. 2004 Jun 1;64(11):3914-21
references.pmid: 15173002
references.citation: FEBS Lett. 2003 Apr 24;541(1-3):155-62
references.pmid: 12706837
references.citation: Mol Immunol. 2008 Dec;46(2):213-24
references.pmid: 18842300
references.citation: Am J Transplant. 2010 Mar;10(3):571-81
references.pmid: 20121745
references.citation: J Biol Chem. 2005 Sep 9;280(36):31530-6
references.pmid: 16009713
references.citation: J Immunol. 1990 Mar 15;144(6):2117-22
references.pmid: 2107252
references.citation: Nat Immunol. 2007 Jan;8(1):25-30
references.pmid: 17179969
references.citation: Nat Immunol. 2011 Oct 19;12(11):1031-2
references.pmid: 22012436
references.citation: Science. 2010 Apr 16;328(5976):372-6
references.pmid: 20339032
references.citation: J Immunol. 2006 Jun 15;176(12):7502-10
references.pmid: 16751397
references.citation: J Immunol. 2006 Mar 15;176(6):3383-90
references.pmid: 16517706
references.citation: Blood. 2006 Jun 15;107(12):4841-8
references.pmid: 16514061
references.citation: Blood. 2008 Dec 1;112(12):4617-27
references.pmid: 18796635
references.citation: Eur J Immunol. 1981 Aug;11(8):657-61
references.pmid: 6456149
references.citation: Blood. 2005 Nov 1;106(9):3322-30
references.pmid: 16037386
references.citation: Exp Hematol. 2003 Oct;31(10):897-902
references.pmid: 14550805
references.citation: Bone Marrow Transplant. 1998 Dec;22(11):1097-102
references.pmid: 9877273
references.citation: Blood. 2006 Feb 15;107(4):1703-11
references.pmid: 16291587
references.citation: Cell Signal. 2000 Dec;12(11-12):759-68
references.pmid: 11152962
references.citation: Immunol Rev. 2003 Apr;192:64-79
references.pmid: 12670396
references.citation: Blood. 2007 Nov 1;110(9):3447-55
references.pmid: 17641205
references.citation: Hum Immunol. 2006 Jun;67(6):433-8
references.pmid: 16728266
references.citation: Blood. 2005 Jul 1;106(1):18-26
references.pmid: 15774622
references.citation: Blood. 2011 Nov 3;118(18):5011-20
references.pmid: 21856864