Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice

Kelley M.K. Haarberg, Jun Li, Jessica Heinrichs, Dapeng Wang, Chen Liu, Crystina C. Bronk, Kane Kaosaard, Alexander M. Owyang, Sacha Holland, Esteban Masuda, Kin Tso, Bruce R. Blazar, Claudio Anasetti, Amer A. Beg, Xue Zhong Yu

Research output: Contribution to journalArticle

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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 Cu (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-/--/- 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, andmigration 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 u 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. (Blood. 2013;122(14):2500-2511).

Original languageEnglish (US)
Pages (from-to)2500-2511
Number of pages12
JournalBlood
Volume122
Issue number14
DOIs
StatePublished - Jan 1 2013

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Graft vs Host Disease
Grafts
Protein Kinases
Leukemia
T-cells
Transplants
Graft vs Leukemia Effect
T-Lymphocytes
Cell Transplantation
Transplantation (surgical)
Cell proliferation
Tissue Donors
Cell Proliferation
Cytokines
Cell signaling
Hematologic Neoplasms
Therapeutics
Protein Kinase Inhibitors
Chemokines
Cell Movement

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Haarberg, K. M. K., Li, J., Heinrichs, J., Wang, D., Liu, C., Bronk, C. C., ... Yu, X. Z. (2013). Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice. Blood, 122(14), 2500-2511. https://doi.org/10.1182/blood-2012-12-471938
Haarberg, Kelley M.K. ; Li, Jun ; Heinrichs, Jessica ; Wang, Dapeng ; Liu, Chen ; Bronk, Crystina C. ; Kaosaard, Kane ; Owyang, Alexander M. ; Holland, Sacha ; Masuda, Esteban ; Tso, Kin ; Blazar, Bruce R. ; Anasetti, Claudio ; Beg, Amer A. ; Yu, Xue Zhong. / Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice. In: Blood. 2013 ; Vol. 122, No. 14. pp. 2500-2511.
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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 Cu (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, andmigration 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 u 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. (Blood. 2013;122(14):2500-2511).",
author = "Haarberg, {Kelley M.K.} and Jun Li and Jessica Heinrichs and Dapeng Wang and Chen Liu and Bronk, {Crystina C.} and Kane Kaosaard and Owyang, {Alexander M.} and Sacha Holland and Esteban Masuda and Kin Tso and Blazar, {Bruce R.} and Claudio Anasetti and Beg, {Amer A.} and Yu, {Xue Zhong}",
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Haarberg, KMK, 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 2013, 'Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice', Blood, vol. 122, no. 14, pp. 2500-2511. https://doi.org/10.1182/blood-2012-12-471938

Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice. / Haarberg, Kelley M.K.; Li, Jun; Heinrichs, Jessica; Wang, Dapeng; Liu, Chen; Bronk, Crystina C.; Kaosaard, Kane; Owyang, Alexander M.; Holland, Sacha; Masuda, Esteban; Tso, Kin; Blazar, Bruce R.; Anasetti, Claudio; Beg, Amer A.; Yu, Xue Zhong.

In: Blood, Vol. 122, No. 14, 01.01.2013, p. 2500-2511.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacologic inhibition of PKCa & PKCu prevents GVHD while preserving GVL activity in mice

AU - Haarberg, Kelley M.K.

AU - Li, Jun

AU - Heinrichs, Jessica

AU - Wang, Dapeng

AU - Liu, Chen

AU - Bronk, Crystina C.

AU - Kaosaard, Kane

AU - Owyang, Alexander M.

AU - Holland, Sacha

AU - Masuda, Esteban

AU - Tso, Kin

AU - Blazar, Bruce R.

AU - Anasetti, Claudio

AU - Beg, Amer A.

AU - Yu, Xue Zhong

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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 Cu (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, andmigration 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 u 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. (Blood. 2013;122(14):2500-2511).

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 Cu (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, andmigration 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 u 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. (Blood. 2013;122(14):2500-2511).

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