Development of transplant immunosuppressive agents – considerations in the use of animal models

Costello, Russell; Kissenpfennig, Adrien; Martins, Paulo N.; McDaid, James

doi:10.1080/17460441.2018.1535589

“…Recent advances have made the heart transplantation model an excellent tool for quantifying immune rejection by monitoring palpations of the grafted heart (Costello et al , 2018). Heart graft mice were further treated with 2.0 mg/kg FK506 and 2.0 mg/kg CX5461, which was the most effective concentration in the skin graft experiments.…”

Section: Resultsmentioning

confidence: 99%

NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development

Tsai

¹

,

Zeng

²

,

Liu

³

et al. 2021

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Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2‐like sequences in rDNA promoter upon T‐cell activation in vitro. The elevated pre‐rRNA level of T cells is also observed in both mouse heart or skin transplantation models and in kidney transplanted patients. Importantly, T‐cell activation can be significantly suppressed by inhibiting NF45/NF90‐dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription‐specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off‐target activity (i.e., toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90‐mediated rDNA transcription as a novel signaling pathway essential for T‐cell activation and as a new target for the development of safe and effective immunosuppressants.

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“…Recent advances have made the heart transplantation model an excellent tool for quantifying immune rejection by monitoring palpations of the grafted heart (Costello et al , 2018). Heart graft mice were further treated with 2.0 mg•kg −1 FK506 and 2.0 mg•kg −1 CX5461, which was the most effective concentration in the skin graft experiments.…”

Section: Resultsmentioning

confidence: 99%

NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development

Tsai¹,

Zeng

²

,

Liu

³

et al. 2020

Preprint

0

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Herein, we demonstrate that NFAT, a key regulator of the immune response, translocates from cytoplasm to nucleolus and interacts with NF45/NF90 complex to collaboratively promote rDNA transcription via triggering the directly binding of NF45/NF90 to the ARRE2 consensus sequences in rDNA promoter upon T cell activation in vitro. The elevated pre-rRNA level of T cells are also observed in both mouse heart or skin transplantation models, and in kidney transplanted patients.Importantly, T cell activation can be significantly suppressed by inhibiting NF45/NF90-dependent rDNA transcription. Amazingly, CX5461, a rDNA transcription specific inhibitor, outperformed FK506, the most commonly used immunosuppressant, both in terms of potency and off-target activity (i.e. toxicity), as demonstrated by a series of skin and heart allograft models. Collectively, this reveals NF45/NF90-mediated rDNA transcription as a novel signaling pathway essential for T cell activation, and as a new target for the development of safe and effective immunosuppressants.Keyword: NF45/NF90; immunosuppressive agents; organ transplant rejection; calcineurin-NFAT pathway; nucleolus RNA Pol I to rDNA promoter regions. We found that the NF45/NF90-regulation of rRNA transcription positively regulates T cell activation. Suppressing rDNA transcription using the Pol I inhibitor CX5461 significantly inhibited IL-2 secretion, reduced the proliferation of T lymphocytes, and enhanced the survival of mouse skin and heart allografts. This mechanism constitutes a novel therapeutic strategy for immunosuppression.

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“…The CYP subfamily member CYP2J is coded by a single gene in humans but by four in rats and by eight genes in mice. This pharmacodynamic and pharmacokinetic differences are important to consider in the use of immunosuppressants [20,21]. In addition, it can be very challenging to obtain pure and reliable samples from small animals.…”

Section: Small Animal Modelsmentioning

confidence: 99%

Animal Models in Allogenic Solid Organ Transplantation

Wenzel¹,

Blasczyk²,

Figueiredo³

2021

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Animal models provide the link between in vitro research and the first in-man application during clinical trials. They provide substantial information in preclinical studies for the assessment of new therapeutic interventions in advance of human clinical trials. However, each model has its advantages and limitations in the ability to imitate specific pathomechanisms. Therefore, the selection of an animal model for the evaluation of a specific research question or evaluation of a novel therapeutic strategy requires a precise analysis. Transplantation research is a discipline that largely benefits from the use of animal models with mouse and pig models being the most frequently used models in organ transplantation research. A suitable animal model should reflect best the situation in humans, and the researcher should be aware of the similarities as well as the limitations of the chosen model. Small animal models with rats and mice are contributing to the majority of animal experiments with the obvious advantages of these models being easy handling, low costs, and high reproductive rates. However, unfortunately, they often do not translate to clinical use. Large animal models, especially in transplantation medicine, are an important element for establishing preclinical models that do often translate to the clinic. Nevertheless, they can be costly, present increased regulatory requirements, and often are of high ethical concern. Therefore, it is crucial to select the right animal model from which extrapolations and valid conclusions can be obtained and translated into the human situation. This review provides an overview in the models frequently used in organ transplantation research.

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Development of transplant immunosuppressive agents – considerations in the use of animal models

Cited by 11 publications

References 96 publications

NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development

NF45/NF90‐mediated rDNA transcription provides a novel target for immunosuppressant development

NF45/NF90-mediated rDNA transcription provides a novel target for immunosuppressant development

Animal Models in Allogenic Solid Organ Transplantation

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