Stable prodrugs of n-butyric acid: suppression of T cell alloresponses in vitro and prolongation of heart allograft survival in a fully allogeneic rat strain combination

Böhmig, Georg A.; Krieger, Peter-Michael; Säemann, Marcus D.; Ullrich, Robert L.; Karimi, H.; Wekerle, Thomas; Mühlbacher, Ferdinand; Zlabinger, Gerhard J.

doi:10.1016/s0966-3274(99)80006-9

Cited by 20 publications

(11 citation statements)

References 21 publications

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“…However, Böhmig et al did report that n-butyric acid prolonged the MST a little for Brown Norway-to-Lewis rat cardiac transplantations. 18) Mori et al also have reported that the HDAC inhibitor FR235222 exerted marked immunosuppressive effects on Lewis-to-ACI rat heterotopic cardiac transplantation. 19) In this study, the ability of FR276457 to prevent allograft rejection was examined in a ACI-to-Lewis rat heterotopic cardiac transplant model which is a severe transplant model.…”

Section: Discussionmentioning

confidence: 95%

Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model

Kinugasa

Yamada²,

Noto

et al. 2008

Biological & Pharmaceutical Bulletin

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Histone deacetylase (HDAC) is a known modulator of gene transcription, and the immunosuppressive activity of HDAC inhibitors has been demonstrated in recent several reports. In this study, the HDAC inhibitor FR276457, a hydroxamic derivative, was found to have a similar inhibitory effect on all mammalian HDACs tested, but no isozyme selectivity. Both FR276457 and tacrolimus exerted an immunosuppressive effect on in vitro rat splenocyte proliferation stimulated with Concanavalin A. Next, the effect of FR276457 on allograft rejection when administered either as a monotherapy or in combination with tacrolimus was investigated in a rat heterotopic cardiac transplant model. Orally administered FR276457 prolonged the median survival times (MST) of the transplanted grafts in the vehicle group from 6 d to 17 or 21 d at doses of 20 or 40 mg/kg, respectively. Histopathological analysis showed the structures of the myocardium were not affected, but interstitial cellular infiltration could not be suppressed completely. Tacrolimus (0.032 mg/kg) prolonged allograft MST to 16 d. FR276457, when combined with tacrolimus, prevented allograft rejection at a dose lower than that of the monotherapy. The combination dose prolonged the MST in the groups treated with 10 and 20 mg/kg to Ͼ28 d, and cellular infiltration was suppressed completely. In conclusion, this study demonstrated that the oral administration of HDAC inhibitor FR276457 can prevent allograft rejection as a monotherapy, and has additive or synergistic effects when combined with tacrolimus.

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Section: Discussionmentioning

confidence: 95%

Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model

Kinugasa

Yamada²,

Noto

et al. 2008

Biological & Pharmaceutical Bulletin

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“…HDAC inhibitors possess potent antitumor properties at high concentrations (36); however, at lower concentrations they modulate many immune responses (8,9,11,12,(37)(38)(39). Histone acetylation is critical in regulating gene expression for many immune processes (40), but the exact cellular effects and the molecular mechanisms that are critical for immunosuppression caused by these agents are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice

Reddy¹,

Sun²,

Toubai³

et al. 2008

J. Clin. Invest.

189

253

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“…Furthermore, n-butyrate not only suppresses primary T-cell responses, it also induces antigen-specific tolerance (19 -21). Importantly, the recently reported ability of n-butyrate to inhibit antigen-specific immune reactivity in vivo indicates a potential clinical relevance (22,23). A central feature of n-butyrate-mediated inhibition of T-cell expansion is the abrogation of IL-2 production (17,24), which appears to be an important determinant of anergy induction.…”

Section: T-cell Receptor (Tcr)mentioning

confidence: 99%

Novel Mode of Interference with Nuclear Factor of Activated T-cells Regulation in T-cells by the Bacterial Metaboliten-Butyrate

Diakos¹,

Prieschl²,

Säemann³

et al. 2002

Journal of Biological Chemistry

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The transcription factor nuclear factor of activated T-cells (NF-AT) plays an essential role in the activation of many early immune response genes. A dynamic equilibrium between calcineurin and cellular kinases controls its phosphorylation and thus regulates its activity by determining its subcellular localization. Here, we demonstrate that T-cell activation in the presence of the bacterial metabolite n-butyrate, which leads to inhibition of interleukin-2 transcription, is characterized by the maintenance of the activity of counter-regulatory kinases glycogen synthase kinase 3 and protein kinase A as well as persistence of intracellular cAMP levels, whereas calcium response and mitogen-activated protein kinase activation were indistinguishable from cells stimulated in the absence of n-butyrate. Nuclear binding of NF-AT was decreased but other transcription factors implicated in interleukin-2 expression such as AP1 and nuclear factor B were unaffected. The effect on NF-AT binding appeared to be the result of increased nuclear export because the export inhibitor leptomycin B completely restored nuclear binding of NF-AT. We, therefore, provide first evidence for interference with NF-AT regulation alternative to the currently understood inhibition of nuclear import. This mechanism might represent a bacterial strategy to subvert host defense, which could be of particular clinical importance in the gastrointestinal tract where high amounts of nbutyrate are physiologically present.

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Stable prodrugs of n-butyric acid: suppression of T cell alloresponses in vitro and prolongation of heart allograft survival in a fully allogeneic rat strain combination

Cited by 20 publications

References 21 publications

Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model

Effect of a New Immunosuppressant Histon Deacetylase (HDAC) Inhibitor FR276457 in a Rat Cardiac Transplant Model

Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice

Novel Mode of Interference with Nuclear Factor of Activated T-cells Regulation in T-cells by the Bacterial Metaboliten-Butyrate

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