Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice

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

doi:10.1182/blood-2012-12-471938

Cited by 36 publications

(40 citation statements)

References 45 publications

(53 reference statements)

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“…This is of enormous benefit for patients receiving allogeneic BMT. Similar results were obtained by Haarberg et al [25]: Consistent with the data obtained from the cardiac allograft experiments [23], the concomitant deficiency of PKCθ and PKCα allowed protection against GvHD in an additive manner. On the other hand, genetic deficiency of PKCθ rendered mice more prone to a Moloney murine leukaemia virus (M-MuLV)-induced leukaemia [26], suggesting a partially compromised anti-tumour host response in PKCθ-deficient mice.…”

Section: Pkcθ In Transplantation Medicinesupporting

confidence: 89%

Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

Wachowicz

Baier

2014

Biochemical Society Transactions

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Activating as well as inhibitory circuits tightly regulate T-cell activation thresholds and effector differentiation processes enabling proper immune response outcomes. Recently, an additional molecular link between T-cell receptor signalling and CD4⁺ Th17 cell skewing has been reported, namely that protein kinase C (PKC) θ critically regulates Th17/Th1 phenotypic differentiation and plasticity in CD4⁺ T-cells by selectively acting as a 'reprogramming element' that suppresses Th1-typical genes during Th17-mediated immune activation in order to stabilize a Th17 cell phenotype.

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Section: Pkcθ In Transplantation Medicinesupporting

confidence: 89%

Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

Wachowicz

Baier

2014

Biochemical Society Transactions

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“…Data are presented for individual GVHD target organs. All slides for GVHD analysis were coded and read in a blinded fashion (48).…”

Section: Methodsmentioning

confidence: 99%

Ceramide synthesis regulates T cell activity and GVHD development

Sofi¹,

Heinrichs²,

Dany³

et al. 2017

JCI Insight

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“…Because GVHD prevention can be achieved by modulation of Tcell migration to organ sites (25)(26)(27), we speculated that ruxolitinib may induce a reduced T-cell recruitment to GVHD targets. Indeed, the immunohistochemical quantification of T-cell (CD3 epsilon þ ) infiltration into GVHD target organs at day 14 post-BMT revealed that treatment with ruxolitinib reduced T-cell numbers in the skin [number of intraepithelial (IEL) cells/skin length: 47 AE 5 vs. 2.5 AE 0.7; P < 0.0001; Fig.…”

Section: Ruxolitinib Treatment Reduced Overall T-cell Infiltrates In mentioning

confidence: 99%

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

Carniti

Gimondi

Vendramin

et al. 2015

Clinical Cancer Research

107

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Purpose: Immune-mediated graft-versus-tumor (GVT) effects can occur after allogeneic hematopoietic stem cell transplantation (HSCT), but GVT is tightly linked to its main complication, graft-versus-host disease (GVHD). Strategies aimed at modulating GVHD, while maintaining the GVT effect, are needed to improve the cure rate of transplant. Given the emerging role of Janus-activated kinase (JAK) signaling in lymphoproliferative and myeloproliferative diseases and its established function at dictating T-cell differentiation, we postulated that JAKs might be potential therapeutic targets through a pharmacologic approach.Experimental Design: We examined the effect of JAK1/JAK2 modulation by ruxolitinib in a mouse model of fully MHC mismatched bone marrow transplant comprising in vivo tumor inoculation.Results: JAK1/JAK2 inhibition by ruxolitinib improved both overall survival (P ¼ 0.03) and acute GVHD pathologic score at target organs (P 0.001) of treated mice. In addition, treatment with ruxolitinib was associated with a preserved GVT effect, as evidenced by reduction of tumor burden (P ¼ 0.001) and increase of survival time (P ¼ 0.01). JAK1/JAK2 inhibition did not impair the in vivo acquisition of donor T-cell alloreactivity; this observation may account, at least in part, to the preserved GVT effect. Rather, JAK1/JAK2 inhibition of GVHDwas associated withthe modulation of chemokine receptor expression, which may have been one factor in the reduced infiltration of donor T cells in GVHD target organs.Conclusions: These data provide further evidence that JAK inhibition represents a new and potentially clinically relevant approach to GVHD prevention.

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Pharmacologic inhibition of PKCα and PKCθ prevents GVHD while preserving GVL activity in mice

Abstract: Key Points PKCα and PKCθ cooperate in T-cell alloresponses, which contribute to GVHD. Pharmacologic inhibition of PKCα and PKCθ prevents GVHD and largely preserves GVL responses.

Cited by 36 publications

References 45 publications

Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

Protein kinase Cθ: the pleiotropic T-cell signalling intermediate

Ceramide synthesis regulates T cell activity and GVHD development

Pharmacologic Inhibition of JAK1/JAK2 Signaling Reduces Experimental Murine Acute GVHD While Preserving GVT Effects

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