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Generation and characterization of a humanized PPAR? mouse model.

ABSTRACT: BACKGROUND AND PURPOSE: Humanized mice for the nuclear receptor peroxisome proliferator-activated receptor ? (PPAR?), termed PPAR? knock-in (PPAR? KI) mice, were generated for the investigation of functional differences between mouse and human PPAR? and as tools for early drug efficacy assessment. EXPERIMENTAL APPROACH: Human PPAR? function in lipid metabolism was assessed at baseline, after fasting or when challenged with the GW0742 compound in mice fed a chow diet or high-fat diet (HFD). KEY RESULTS: Analysis of PPAR? mRNA levels revealed a hypomorph expression of human PPAR? in liver, macrophages, small intestine and heart, but not in soleus and quadriceps muscles, white adipose tissue and skin. PPAR? KI mice displayed a small decrease of high-density lipoprotein-cholesterol whereas other lipid parameters were unaltered. Plasma metabolic parameters were similar in wild-type and PPAR? KI mice when fed chow or HFD, and following physiological (fasting) and pharmacological (GW0742 compound) activation of PPAR?. Gene expression profiling in liver, soleus muscle and macrophages showed similar gene patterns regulated by mouse and human PPAR?. The anti-inflammatory potential of human PPAR? was also similar to mouse PPAR? in liver and isolated macrophages. CONCLUSIONS AND IMPLICATIONS: These data indicate that human PPAR? can compensate for mouse PPAR? in the regulation of lipid metabolism and inflammation. Overall, this novel PPAR? KI mouse model shows full responsiveness to pharmacological challenge and represents a useful tool for the preclinical assessment of PPAR? activators with species-specific activity.

SUBMITTER: Gross B

PROVIDER: S-EPMC3171871 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Generation and characterization of a humanized PPARδ mouse model.

Gross B B Hennuyer N N Bouchaert E E Rommens C C Grillot D D Mezdour H H Staels B B

British journal of pharmacology 20110901 1

<h4>Background and purpose</h4>Humanized mice for the nuclear receptor peroxisome proliferator-activated receptor δ (PPARδ), termed PPARδ knock-in (PPARδ KI) mice, were generated for the investigation of functional differences between mouse and human PPARδ and as tools for early drug efficacy assessment.<h4>Experimental approach</h4>Human PPARδ function in lipid metabolism was assessed at baseline, after fasting or when challenged with the GW0742 compound in mice fed a chow diet or high-fat diet ...[more]

PMID: 21426320

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Project description:Immune checkpoint blockade (ICB) monotherapy shows early promise for the treatment of nasopharyngeal carcinoma (NPC) in patients. Nevertheless, limited representative NPC models hamper preclinical studies to evaluate the efficacy of novel ICB and combination regimens. In the present study, we engrafted NPC biopsies in non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain-null (NSG) mice and established humanized mouse NPC-patient-derived xenograft (NPC-PDX) model successfully. Epstein-Barr virus was detected in the NPC in both NSG and humanized mice as revealed by Epstein-Barr virus-encoded small RNA (EBER) in situ hybridization (ISH) and immunohistochemical (IHC) staining. In the NPC-bearing humanized mice, the percentage of tumor-infiltrating CD8+ cytotoxic T cells was lowered, and the T cells expressed higher levels of various inhibitory receptors, such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) than those in blood. The mice were then treated with nivolumab and ipilimumab, and the anti-tumor efficacy of combination immunotherapy was examined. In line with paired clinical data, the NPC-PDX did not respond to the treatment in terms of tumor burden, whilst an immunomodulatory response was elicited in the humanized mice. From our results, human proinflammatory cytokines, such as interferon-gamma (IFN-?) and interleukin-6 (IL-6) were significantly upregulated in plasma. After treatment, there was a decrease in CD4/CD8 ratio in the NPC-PDX, which also simulated the modulation of intratumoral CD4/CD8 profile from the corresponding donor. In addition, tumor-infiltrating T cells were re-activated and secreted more IFN-? towards ex vivo stimulation, suggesting that other factors, including soluble mediators and metabolic milieu in tumor microenvironment may counteract the effect of ICB treatment and contribute to the tumor progression in the mice. Taken together, we have established and characterized a novel humanized mouse NPC-PDX model, which plausibly serves as a robust platform to test for the efficacy of immunotherapy and may predict clinical outcomes in NPC patients.

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Generation and characterization of a humanized PPAR? mouse model.

Publications

Generation and characterization of a humanized PPARδ mouse model.

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