Current advances in humanized mouse models

Ito, Ryoji; Takahashi, Takeshi; Katano, Ikumi; Ito, Mamoru

doi:10.1038/cmi.2012.2

Cited by 311 publications

(294 citation statements)

References 84 publications

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“…Athough both stromal and immune components are replaced over time by murine analogues, the haematopoietic elements show important differences in their spatial distribution 167 or may be missing overall 156,168 . This affects the signal received from molecular profiling, and could require application of specific algorithms for signal correction to avoid or reduce artefacts and biases 156,169 .…”

Section: Main Objectivesmentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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Patient-derived xenografts (PDXs) have emerged as an important platform to elucidate new treatments and biomarkers in oncology. PDX models are used to address clinically relevant questions, including the contribution of tumour heterogeneity to therapeutic responsiveness, the patterns of cancer evolutionary dynamics during tumour progression and under drug pressure, and the mechanisms of resistance to treatment. The ability of PDX models to predict clinical outcomes is being improved through mouse humanization strategies and implementation of co-clinical trials, within which patients and PDXs reciprocally inform therapeutic decisions. This Opinion article discusses aspects of PDX modelling that are relevant to these questions and highlights the merits of shared PDX resources to advance cancer medicine from the 6 perspective of EurOPDX, an international initiative devoted to PDX-based research.Response to anticancer therapies varies owing to the substantial molecular heterogeneity of human tumours and to poorly defined mechanisms of drug efficacy and resistance 1 . Immortalized cancer cell lines, either cultured in vitro or grown as xenografts, cannot interrogate the complexity of human tumours, and only provide determinate insights into human disease, as they are limited in number and diversity, and have been cultured on plastic over decades 2 .This disconnection in scale and biological accuracy contributes considerably to attrition in drug development [3][4][5] .Surgically derived clinical tumour samples that are implanted in mice (known as patient-derived xenografts (PDXs)) are expected to better inform therapeutic development strategies. As intact tissue -in which the tumour architecture and the relative proportion of cancer cells and stromal cells are both maintained -is directly implanted into recipient animals, the alignment with human disease is enhanced. More importantly, PDXs retain the idiosyncratic characteristics of different tumours from different patients; hence, they can effectively recapitulate the intra-tumour and inter-tumour heterogeneity that typifies human cancer 6-9 . 7 Exhaustive information on the key characteristics and the practical applications of PDXs can be found in recent reviews [10][11][12][13] . In this Opinion article, we discuss basic methodological concepts, as well as challenges and opportunities in developing "next-generation" models to improve the reach of PDXs as preclinical tools for in vivo studies (TABLE 1). We also elaborate on the merits of PDXs for exploring the intrinsic heterogeneity and subclonal genetic evolution of individual tumours, and discuss how this may influence therapeutic resistance. Finally, we examine the utility of PDXs in navigating complex variables in clinical decision-making, such as the discovery of predictive and prognostic biomarkers, and the categorization of genotype-drug response correlations in high-throughput formats. Being primarily co-authored by leading members of the EurOPDX Consortium (see Further information), we provide...

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Section: Main Objectivesmentioning

confidence: 99%

Interrogating open issues in cancer precision medicine with patient-derived xenografts

et al. 2017

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“…3a,b), but also as a single low-dose systemic injection into mice transplanted with human peripheral blood mononuclear cells (PBMCs). In such mice, human lymphocytes mainly repopulate the spleen 17 . We observed strong luciferase activity in the spleen of mice injected with IMAC-purified CD4-AAV encoding this transgene, while CD4-AAV that was not affinity-purified-and thus contained both, DARPin-displaying and -deficient particlesresulted only in moderate signals in spleen and the chest region, as observed before for Her2-AAV (Fig.…”

Section: Resultsmentioning

confidence: 99%

Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors

et al. 2015

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We describe receptor-targeted adeno-associated viral (AAV) vectors that allow genetic modification of rare cell types ex vivo and in vivo while showing no detectable off-targeting. Displaying designed ankyrin repeat proteins (DARPins) on the viral capsid and carefully depleting DARPin-deficient particles, AAV vectors were made specific for Her2/neu, EpCAM or CD4. A single intravenous administration of vector targeted to the tumour antigen Her2/neu was sufficient to track 75% of all tumour sites and to extend survival longer than the cytostatic antibody Herceptin. CD4-targeted AAVs hit human CD4-positive cells present in spleen of a humanized mouse model, while CD8-positive cells as well as liver or other off-target organs remained unmodified. Mimicking conditions of circulating tumour cells, EpCAM-AAV detected single tumour cells in human blood opening the avenue for tumour stem cell tracking. Thus, the approach developed here delivers genes to target cell types of choice with antibody-like specificity.

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“…The humanized mice used in these studies, while having excellent reconstitution of T cells, monocytes, and macrophages, all of which are targets of S. aureus toxins [4,14,15,19,21], does not yet fully replicate a functioning human immune system. It has been recognized that neutrophil numbers are not optimal in the peripheral blood of humanized mice, and hence there may be a more limited number of cells to recruit; thus, this is an area to improve in subsequent models [38,39].…”

Section: Discussionmentioning

confidence: 99%

Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

Prince

Wang

Kitur³

et al. 2016

J Infect Dis.

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Staphylococcus aureus is a highly successful human pathogen that has evolved in response to human immune pressure. The common USA300 methicillin-resistant S. aureus (MRSA) strains express a number of toxins, such as Panton-Valentine leukocidin and LukAB, that have specificity for human receptors. Using nonobese diabetic (NOD)-scid IL2Rγ null (NSG) mice reconstituted with a human hematopoietic system, we were able to discriminate the roles of these toxins in the pathogenesis of pneumonia. We demonstrate that expression of human immune cells confers increased severity of USA300 infection. The expression of PVL but not LukAB resulted in more-severe pulmonary infection by the wild-type strain (with a 30-fold increase in the number of colony-forming units/mL; P < .01) as compared to infection with the lukS/F-PV (Δpvl) mutant. Treatment of mice with anti-PVL antibody also enhanced bacterial clearance. We found significantly greater numbers (by 95%; P < .05) of macrophages in the airways of mice infected with the Δpvl mutant compared with those infected with the wild-type strain, as well as significantly greater expression of human tumor necrosis factor and interleukin 6 (84% and 51% respectively; P < .01). These results suggest that the development of humanized mice may provide a framework to assess the contribution of human-specific toxins and better explore the roles of specific components of the human immune system in protection from S. aureus infection.Keywords. Staphylococcus aureus; pneumonia; lung; respiratory; host-pathogen; humanized; mouse model; PVL; Panton-Valentine leukocidin.Staphylococcus aureus is a well-recognized human pathogen associated with infection in diverse hosts; it is an important cause of healthcare-associated infection but also a major cause of morbidity and mortality in healthy patients with no factors predisposing them to infection. Nasal colonization with S. aureus is associated with subsequent infection and occurs in up to 30% of unselected individuals [1,2]. Yet, despite the prevalence of S. aureus in the general population, the specific correlates of protective immunity against staphylococcal infection are not well defined.A number of S. aureus virulence factors, including several bicomponent toxins, are specific for human receptors [3,4]. One of the first of these human-specific toxins to be fully characterized was Panton-Valentine leukocidin (PVL), which targets neutrophils, macrophages, and monocytes [5,6]. Although epidemiologically linked to severe infection in humans [7,8], the PVL null mutant (lukS/lukF) did not consistently demonstrate the expected phenotype in murine models [5,[8][9][10][11][12][13], although it was significantly attenuated in rabbit models of pneumonia [5]. The molecular basis for this discrepancy was ascribed to the high human (and rabbit) specificity for the PVL receptors, C5aR and C5L2 [14]. Additional toxins, LukAB and HlgCB, have also been shown to have high specificity to the human forms of the receptors, CD11b and C5aR, respectively [4,14,15]. These ...

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Current advances in humanized mouse models

Cited by 311 publications

References 84 publications

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Interrogating open issues in cancer precision medicine with patient-derived xenografts

Off-target-free gene delivery by affinity-purified receptor-targeted viral vectors

Humanized Mice Exhibit Increased Susceptibility toStaphylococcus aureusPneumonia

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