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

SUBMITTER: Haarberg KM

PROVIDER: S-EPMC3790515 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Haarberg Kelley M K KM Li Jun J Heinrichs Jessica J Wang Dapeng D Liu Chen C Bronk Crystina C CC Kaosaard Kane K Owyang Alexander M AM Holland Sacha S Masuda Esteban E Tso Kin K Blazar Bruce R BR Anasetti Claudio C Beg Amer A AA Yu Xue-Zhong XZ

Blood 20130801 14

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(-/- ...[more]

PMID: 23908466

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Project description:ObjectiveRecent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), and related comorbidities. Whether this metabolic dysfunction is driven by the excess dietary calories contained in fructose or whether fructose catabolism itself is uniquely pathogenic remains controversial. We sought to test whether a small molecule inhibitor of the primary fructose metabolizing enzyme ketohexokinase (KHK) can ameliorate the metabolic effects of fructose.MethodsThe KHK inhibitor PF-06835919 was used to block fructose metabolism in primary hepatocytes and Sprague Dawley rats fed either a high-fructose diet (30% fructose kcal/g) or a diet reflecting the average macronutrient dietary content of an American diet (AD) (7.5% fructose kcal/g). The effects of fructose consumption and KHK inhibition on hepatic steatosis, insulin resistance, and hyperlipidemia were evaluated, along with the activation of DNL and the enzymes that regulate lipid synthesis. A metabolomic analysis was performed to confirm KHK inhibition and understand metabolite changes in response to fructose metabolism in vitro and in vivo. Additionally, the effects of administering a single ascending dose of PF-06835919 on fructose metabolism markers in healthy human study participants were assessed in a randomized placebo-controlled phase 1 study.ResultsInhibition of KHK in rats prevented hyperinsulinemia and hypertriglyceridemia from fructose feeding. Supraphysiologic levels of dietary fructose were not necessary to cause metabolic dysfunction as rats fed the American diet developed hyperinsulinemia, hypertriglyceridemia, and hepatic steatosis, which were all reversed by KHK inhibition. Reversal of the metabolic effects of fructose coincided with reductions in DNL and inactivation of the lipogenic transcription factor carbohydrate response element-binding protein (ChREBP). We report that administering single oral doses of PF-06835919 was safe and well tolerated in healthy study participants and dose-dependently increased plasma fructose indicative of KHK inhibition.ConclusionsFructose consumption in rats promoted features of metabolic dysfunction seen in metabolic diseases such as T2D and NASH, including insulin resistance, hypertriglyceridemia, and hepatic steatosis, which were reversed by KHK inhibition.

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Pharmacologic inhibition of PKC? and PKC? prevents GVHD while preserving GVL activity in mice.

Publications

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

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