Les souris ne sont pas des hommes et pourtant…

Cachat, Anne; Villaudy, Julien; Rigal, Dominique; Gazzolo, Louis; Dodon, Madeleine Duc

doi:10.1051/medsci/2012281018

Cited by 8 publications

(3 citation statements)

References 40 publications

(38 reference statements)

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“…Ten weeks after HSC inoculation, the analysis of human cells in mice indicated that immune reconstitution was achieved (10–40% of human CD45 + cells) with known frequencies of B (CD19 + ) and T (CD3 + ) cells and macrophages (CD163 + ) (Fig 1B). At the time of the sacrifice, human CD45 + cells as well as major subsets of human immune cells were also detected in the thymus, mesenteric lymph nodes, and bone marrow of these hu-mice (data not shown), as previously described in studies using this hu-mice model [21,22]. This reconstitution of immune cell populations demonstrated that a human-like immune system was achieved, which validated hu-mouse as a model to assess biocompatibility of human allogeneic cartilage constructs.…”

Section: Resultssupporting

confidence: 71%

Evaluation of the biocompatibility and stability of allogeneic tissue-engineered cartilage in humanized mice

et al. 2019

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Articular cartilage (AC) has poor capacities of regeneration and lesions often lead to osteoarthritis. Current AC reconstruction implies autologous chondrocyte implantation which requires tissue sampling and grafting. An alternative approach would be to use scaffolds containing off-the-shelf allogeneic human articular chondrocytes (HACs). To investigate tolerance of allogeneic HACs by the human immune system, we developed a humanized mouse model implanted with allogeneic cartilage constructs generated in vitro . A prerequisite of the study was to identify a scaffold that would not provoke inflammatory reaction in host. Therefore, we first compared the response of hu-mice to two biomaterials used in regenerative medicine, collagen sponge and agarose hydrogel. Four weeks after implantation in hu-mice, acellular collagen sponges, but not acellular agarose hydrogels, showed positive staining for CD3 (T lymphocytes) and CD68 (macrophages), suggesting that collagen scaffold elicits weak inflammatory reaction. These data led us to deepen our evaluation of the biocompatibility of allogeneic tissue-engineered cartilage by using agarose as scaffold. Agarose hydrogels were combined with allogeneic HACs to reconstruct cartilage in vitro . Particular attention was paid to HLA-A2 compatibility between HACs to be grafted and immune human cells of hu-mice: HLA-A2 + or HLA-A2 - HACs agarose hydrogels were cultured in the presence of a chondrogenic cocktail and implanted in HLA-A2 + hu-mice. After four weeks implantation and regardless of the HLA-A2 phenotype, chondrocytes were well-differentiated and produced cartilage matrix in agarose. In addition, no sign of T-cell or macrophage infiltration was seen in the cartilaginous constructs and no significant increase in subpopulations of T lymphocytes and monocytes was detected in peripheral blood and spleen. We show for the first time that humanized mouse represents a useful model to investigate human immune responsiveness to tissue-engineered cartilage and our data together indicate that allogeneic cartilage constructs can be suitable for cartilage engineering.

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Section: Resultssupporting

confidence: 71%

Evaluation of the biocompatibility and stability of allogeneic tissue-engineered cartilage in humanized mice

et al. 2019

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“…Efficacy studies in mice are a critical hurdle to advance translational research of therapeutic compounds for many diseases, including tuberculosis,[1–4] malaria,[5,6] cancer,[7–11] Alzheimer’s disease,[12] and many other therapeutic areas[13–15] before clinical trials in humans are considered. A compound of interest for mouse in vivo studies should ideally be soluble, have good absorption (if orally dosed), and must also exhibit metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

Predicting Mouse Liver Microsomal Stability with “Pruned” Machine Learning Models and Public Data

et al. 2015

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Purpose Mouse efficacy studies are a critical hurdle to advance translational research of potential therapeutic compounds for many diseases. Although mouse liver microsomal (MLM) stability studies are not a perfect surrogate for in vivo studies of metabolic clearance, they are the initial model system used to assess metabolic stability. Consequently, we explored the development of machine learning models that can enhance the probability of identifying compounds possessing MLM stability. Methods Published assays on MLM half-life values were identified in PubChem, reformatted, and curated to create a training set with 894 unique small molecules. These data were used to construct machine learning models assessed with internal cross-validation, external tests with a published set of antitubercular compounds, and independent validation with an additional diverse set of 571 compounds (PubChem data on percent metabolism). Results “Pruning” out the moderately unstable/moderately stable compounds from the training set produced models with superior predictive power. Bayesian models displayed the best predictive power for identifying compounds with a half-life ≥1 hour. Conclusions Our results suggest the pruning strategy may be of general benefit to improve test set enrichment and provide machine learning models with enhanced predictive value for the MLM stability of small organic molecules. This study represents the most exhaustive study to date of using machine learning approaches with MLM data from public sources.

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“…Actually, humanized mouse technology has made rapid progress, and it is now possible to achieve high levels of human chimerism in various organs and tissues, particularly the immune system and the liver (Legrand et al, 2006a, 2009; Shultz et al, 2007; Koyanagi et al, 2008; Manz and Di Santo, 2009; Brehm et al, 2010; Cachat et al, 2012). …”

Section: The Use Of Humanized Mice To Recapitulate Htlv-1 Infectionmentioning

confidence: 99%

What we are learning on HTLV-1 pathogenesis from animal models

et al. 2012

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Isolated and identified more than 30 years ago, human T cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T cell leukemia/lymphoma, an aggressive lymphoproliferative disease of activated CD4+ T cells, and other inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis. A variety of animal models have contributed to the fundamental knowledge of HTLV-1 transmission, pathogenesis, and to the design of novel therapies to treat HTLV-1-associated diseases. Small animal models (rabbits, rats, and mice) as well as large animal models (monkeys) have been utilized to significantly advance characterization of the viral proteins and of virus-infected cells in the early steps of infection, as well as in the development of leukemogenic and immunopathogenic processes. Over the past two decades, the creation of new immunocompromised mouse strains that are robustly reconstituted with a functional human immune system (HIS) after being transplanted with human tissues or progenitor cells has revolutionized the in vivo investigation of viral infection and pathogenesis. Recent observations obtained in HTLV-1-infected humanized HIS mice that develop lymphomas provide the opportunity to study the evolution of the proviral clonality in human T cells present in different lymphoid organs. Current progress in the improvement of those humanized models will favor the testing of drugs and the development of targeted therapies against HTLV-1-associated diseases.

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Les souris ne sont pas des hommes et pourtant…

Cited by 8 publications

References 40 publications

Evaluation of the biocompatibility and stability of allogeneic tissue-engineered cartilage in humanized mice

Evaluation of the biocompatibility and stability of allogeneic tissue-engineered cartilage in humanized mice

Predicting Mouse Liver Microsomal Stability with “Pruned” Machine Learning Models and Public Data

What we are learning on HTLV-1 pathogenesis from animal models

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