Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease

Corbett, Jennifer M.; Hawthorne, Ian J.; Coulter, Ivan S.; English, Karen

doi:10.1016/j.trim.2021.101373

Cited by 3 publications

(5 citation statements)

References 28 publications

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“…The humanized mouse model of aGvHD was set up as previously described. 5 , 30 , 31 NOD‐SCID IL‐2rγ null mice (NSG) (Jackson Laboratories, Bar Harbour, Maine) (6‐18 weeks old) were exposed to a conditioning dose of 2.4 Gray (Gy) whole‐body gamma irradiation. Both male and female mice were used and sex‐matched mice were used in the experiments.…”

Section: Methodsmentioning

confidence: 99%

IFN-γ and PPARδ Influence the Efficacy and Retention of Multipotent Adult Progenitor Cells in Graft vs Host Disease

Carty

Dunbar

Hawthorne

et al. 2021

Stem Cells Translational Medicine

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Cell-based therapy for the treatment of inflammatory disorders has focused on the application of mesenchymal stromal cells (MSCs) and multipotent adult progenitor cells (MAPCs). Despite the recent positive findings in industry-sponsored clinical trials of MSCs and MAPCs for graft vs host disease (GvHD), cell therapy is efficacious in some but not all patients, highlighting the need to identify strategies to enhance cell-based therapeutic efficacy. Here, we demonstrate the capacity for interferon (IFN)-γ licensing to enhance human MAPC efficacy and retention following early administration in a humanized mouse model of acute GvHD (aGvHD). Activation of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ) negatively influenced the retention and efficacy of human MAPCs as well as IFNγ-licensed MAPCs in the aGvHD model. PPARδ antagonism significantly enhanced the efficacy of human MAPCs when administered early in the humanized aGvHD model. COX-2 expression in human MAPC was significantly decreased in IFN-γ licensed MAPCs exposed to a PPARδ agonist. Importantly, MAPC exposure to the PPARδ antagonist in the presence of a COX-2 inhibitor indomethacin before administration significantly reduced the efficacy of PPARδ antagonized MAPCs in the aGvHD humanized mouse model. This is the first study to demonstrate the importance of PPARδ in human MAPC efficacy in vivo and highlights the importance of understanding the disease microenvironment in which cell-based therapies are to be administered. In particular, the presence of PPARδ ligands may negatively influence MAPC or MSC therapeutic efficacy.

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Section: Methodsmentioning

confidence: 99%

IFN-γ and PPARδ Influence the Efficacy and Retention of Multipotent Adult Progenitor Cells in Graft vs Host Disease

Carty

Dunbar

Hawthorne

et al. 2021

Stem Cells Translational Medicine

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“…When GVHD occurs (~4-5 weeks after reconstitution 21 ), test mice represent evident signs of weight loss, arch back, diarrhea, hair removal, and peeling. 32 35 This model is well adapted for studies on adaptive immune responses such as HIV infection, 36 inflammation in visceral organs, 37 and delayed type hypersensitivity. 38,39 Because of the better HIS simulation effect of the Hu-BLT model overcoming the disadvantages of the first two models, its application in CAR-T relevant research has also increased in recent years.…”

Section: The Inhibition Of Hiv Infection By Multi-specific Car-t Cell...mentioning

confidence: 99%

“…Human T cells respond rapidly in mice to achieve rapid proliferation while creating a strong antihost response to mouse heterologous cells called GVHD. When GVHD occurs (~4–5 weeks after reconstitution 21 ), test mice represent evident signs of weight loss, arch back, diarrhea, hair removal, and peeling 32 . Therefore, the observational window period of Hu‐PBMC should be specially considered based on different strains in the experimental design to avoid GVHD fatality in the process of data acquisition and to prevent fatality from covering up due to disease symptoms and signs.…”

Section: Hu‐pbmc Modelmentioning

confidence: 99%

“…When GVHD occurs (~4–5 weeks after reconstitution 21 ), test mice represent evident signs of weight loss, arch back, diarrhea, hair removal, and peeling. 32 Therefore, the observational window period of Hu‐PBMC should be specially considered based on different strains in the experimental design to avoid GVHD fatality in the process of data acquisition and to prevent fatality from covering up due to disease symptoms and signs. Regarding CD19 CAR‐T cells that have been used in clinical practice to play a good role in leukemia treatment, combining the advantages of multiple models, Hu‐HSC, Hu‐PBMC, and PDX models, can provide efficient data support for CD8‐LV 33 and CD4‐LV 34 targeted delivery vectors, the key technologies for first selective generation of CD19 CAR‐T in vivo, breaking the previous restrictions on the production cycle and quantity of CAR‐T generated by activating and transmitting isolated cells before.…”

Section: Hu‐pbmc Modelmentioning

confidence: 99%

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Progress, implications, and challenges in using humanized immune system mice in CAR‐T therapy—Application evaluation and improvement

Yue,

Bai

2023

Anim Models and Exp Med

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In recent years, humanized immune system (HIS) mice have been gradually used as models for preclinical research in pharmacotherapies and cell therapies with major breakthroughs in tumor and other fields, better mimicking the human immune system and the tumor immune microenvironment, compared to traditional immunodeficient mice. To better promote the application of HIS mice in preclinical research, we selectively summarize the current prevalent and breakthrough research and evaluation of chimeric antigen receptor (CAR) ‐T cells in various antiviral and antitumor treatments. By exploring its application in preclinical research, we find that it can better reflect the actual clinical patient condition, with the advantages of providing high‐efficiency detection indicators, even for progressive research and development. We believe that it has better clinical patient simulation and promotion for the updated design of CAR‐T cell therapy than directly transplanted immunodeficient mice. The characteristics of the main models are proposed to improve the use defects of the existing models by reducing the limitation of antihost reaction, combining multiple models, and unifying sources and organoid substitution. Strategy study of relapse and toxicity after CAR‐T treatment also provides more possibilities for application and development.

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“…In mice, CsA has been delivered by oral gavage, subcutaneous or intraperitoneal injection at doses ranging from as low as 10 mg/kg up to 200 mg/kg. [3][4][5][6][7][8] The oral LD 50 for CsA in mice is 2329 mg/kg, and the intravenous LD 50 is 148 mg/kg. 9 In animal studies, the drug is normally diluted in saline or phosphate buffered saline but has also been diluted in olive oil for oral gavage.…”

Section: Introductionmentioning

confidence: 99%

Case report: An adverse response to cyclosporin A treatment in BALB/cJ mice

Ticar,

Tschirley,

Wilson

et al. 2023

Lab Anim

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Cyclosporin A (CsA) is an immunosuppressive drug that has been widely used in mice at a range of doses from 10 to 200 mg/kg. Our group carried out an experiment in 2016 where we delivered 75 mg/kg CsA (NeoralTM) to BALB/cJ mice by oral gavage to enable wart formation in mice, which was moderately well-tolerated. We recently commenced another study using the same dose and route of delivery of CsA in BALB/cJ mice in order to immune suppress mice to make them susceptible for mouse papillomavirus infection. We highlight in this case report that in contrast to our earlier study, we observed almost immediate unexpected toxicity and had to terminate the recent experiment after only five days of treatment. Seven to eight-week-old female BALB/cJ mice were treated with 75 mg/kg of CsA by oral gavage daily for five days before treatment was stopped due to body weight loss and mice becoming moribund. The probability of survival of the mice following CsA treatment was 80% in this study, compared with 98% in our 2016 study. Mice showed signs of probable acute kidney injury, which was reversible following withdrawal of CsA. Although it is unclear why the clinical response to CsA in BALB/cJ mice differed markedly between the two experiments, this case report highlights the risk of CsA to mouse welfare. CD3 depletion has been used rather than CsA treatment in other studies and should be considered as an alternative to CsA treatment as it is immune-selective, and may be more effective at enabling wart formation in mice.

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Drug delivery formulation impacts cyclosporine efficacy in a humanised mouse model of acute graft versus host disease

Cited by 3 publications

References 28 publications

IFN-γ and PPARδ Influence the Efficacy and Retention of Multipotent Adult Progenitor Cells in Graft vs Host Disease

IFN-γ and PPARδ Influence the Efficacy and Retention of Multipotent Adult Progenitor Cells in Graft vs Host Disease

Progress, implications, and challenges in using humanized immune system mice in CAR‐T therapy—Application evaluation and improvement

Case report: An adverse response to cyclosporin A treatment in BALB/cJ mice

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