PMID- 23908466
OWN - NLM
STAT- MEDLINE
DCOM- 20131118
LR  - 20220330
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 122
IP  - 14
DP  - 2013 Oct 3
TI  - Pharmacologic inhibition of PKCalpha and PKCtheta prevents GVHD while preserving GVL 
      activity in mice.
PG  - 2500-11
LID - 10.1182/blood-2012-12-471938 [doi]
AB  - 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.
FAU - Haarberg, Kelley M K
AU  - Haarberg KM
AD  - Department of Immunology and.
FAU - Li, Jun
AU  - Li J
FAU - Heinrichs, Jessica
AU  - Heinrichs J
FAU - Wang, Dapeng
AU  - Wang D
FAU - Liu, Chen
AU  - Liu C
FAU - Bronk, Crystina C
AU  - Bronk CC
FAU - Kaosaard, Kane
AU  - Kaosaard K
FAU - Owyang, Alexander M
AU  - Owyang AM
FAU - Holland, Sacha
AU  - Holland S
FAU - Masuda, Esteban
AU  - Masuda E
FAU - Tso, Kin
AU  - Tso K
FAU - Blazar, Bruce R
AU  - Blazar BR
FAU - Anasetti, Claudio
AU  - Anasetti C
FAU - Beg, Amer A
AU  - Beg AA
FAU - Yu, Xue-Zhong
AU  - Yu XZ
LA  - eng
GR  - R01 AI082685/AI/NIAID NIH HHS/United States
GR  - R01 CA143812/CA/NCI NIH HHS/United States
GR  - P01 AI056299/AI/NIAID NIH HHS/United States
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - R01 AI 082685/AI/NIAID NIH HHS/United States
GR  - R01 AI034495/AI/NIAID NIH HHS/United States
GR  - R01 CA72669/CA/NCI NIH HHS/United States
GR  - R01 CA072669/CA/NCI NIH HHS/United States
GR  - P01 CA142106/CA/NCI NIH HHS/United States
GR  - R01 CA11816/CA/NCI NIH HHS/United States
GR  - P01 CA065493/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130801
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Isoenzymes)
RN  - EC 2.7.11.13 (Prkcq protein, mouse)
RN  - EC 2.7.11.13 (Protein Kinase C)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.13 (Protein Kinase C-theta)
SB  - IM
CIN - Blood. 2013 Oct 3;122(14):2298-9. PMID: 24092926
MH  - Animals
MH  - Cell Separation
MH  - Disease Models, Animal
MH  - Enzyme Inhibitors/pharmacology
MH  - Flow Cytometry
MH  - Graft vs Host Disease/enzymology/*prevention & control
MH  - Graft vs Leukemia Effect/*drug effects
MH  - Hematopoietic Stem Cell Transplantation/adverse effects
MH  - Isoenzymes/*antagonists & inhibitors
MH  - Leukemia/therapy
MH  - Lymphocyte Activation/drug effects
MH  - Lymphoma/therapy
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Protein Kinase C/*antagonists & inhibitors
MH  - Protein Kinase C-alpha/*antagonists & inhibitors
MH  - Protein Kinase C-theta
MH  - T-Lymphocytes/drug effects/immunology
PMC - PMC3790515
EDAT- 2013/08/03 06:00
MHDA- 2013/11/19 06:00
PMCR- 2014/10/03
CRDT- 2013/08/03 06:00
PHST- 2013/08/03 06:00 [entrez]
PHST- 2013/08/03 06:00 [pubmed]
PHST- 2013/11/19 06:00 [medline]
PHST- 2014/10/03 00:00 [pmc-release]
AID - S0006-4971(20)49966-5 [pii]
AID - 2012/471938 [pii]
AID - 10.1182/blood-2012-12-471938 [doi]
PST - ppublish
SO  - Blood. 2013 Oct 3;122(14):2500-11. doi: 10.1182/blood-2012-12-471938. Epub 2013 
      Aug 1.