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Immune-deficient Mice (immune-deficient + mouse)
Selected AbstractsMaladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cellsDEVELOPMENTAL NEUROBIOLOGY, Issue 6 2006Hagit Cohen Abstract Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006 [source] Regulatory T cells and intestinal homeostasisIMMUNOLOGICAL REVIEWS, Issue 1 2005Janine L. Coombes Summary:, Murine models of inflammatory bowel disease (IBD) are useful tools for the study of the pathogenesis and regulation of intestinal inflammation. Colitis can be induced in immune-deficient mice following transfer of populations of T cells or following infection with Helicobacter hepaticus and other intestinal pathogens. In these situations, colitis occurs as a result of the absence of a specialized population of regulatory cells, as transfer of CD4+CD25+ T cells prevents disease. Importantly, from a clinical perspective, CD4+CD25+ T cells can also reverse an established colitis. CD4+CD25+ T cells proliferate both in the secondary lymphoid organs and at the site of inflammation, suggesting that regulation occurs both locally and systemically. CD4+CD25+ T cells are not only capable of regulating other T cells but are also capable of suppressing components of the innate immune system. Control of colitis is dependent on the presence of the immunosuppressive cytokines interleukin-10 and transforming growth factor-,, although their roles are divergent and complex. Regulatory T cells represent one of the host's mechanisms to prevent immune pathology during chronic immune stimulation. Enhancement of regulatory T-cell activity may be useful to control autoreactive T-cell responses and inhibit harmful inflammatory diseases such as asthma and IBD. [source] Human embryonic stem cell-derived neural precursors develop into neurons and integrate into the host brainJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2006Daniel J. Guillaume Abstract Whether and how in-vitro-produced human neural precursors mature and integrate into the brain are crucial to the utility of human embryonic stem (hES) cells in treating neurological disorders. After transplantation into the ventricles of neonatal immune-deficient mice, hES-cell-derived neural precursors stopped expressing the cell division marker Ki67, except in neurogenic areas, and differentiated into neurons and then glia in a temporal course intrinsic to that of human cells regardless of location. The human cells located in the gray matter became neurons in the olfactory bulb and striatum, whereas those in the white matter produced exclusively glia. Importantly, the grafted human cells formed synapses. Thus, the in-vitro-produced human neural precursors follow their intrinsic temporal program to produce neurons and glia and, in response to environmental signals, generate cells appropriate to their target regions and integrate into the brain. © 2006 Wiley-Liss, Inc. [source] In vivo bioluminescence imaging study to monitor ectopic bone formation by luciferase gene marked mesenchymal stem cellsJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 7 2008Cristina Olivo Abstract Mesenchymal stem cells (MSCs) represent a powerful tool for applications in regenerative medicine. In this study, we used in vivo bioluminescence imaging to noninvasively investigate the fate and the contribution to bone formation of adult MSCs in tissue engineered constructs. Goat MSCs expressing GFP-luciferase were seeded on ceramic scaffolds and implanted subcutaneously in immune-deficient mice. The constructs were monitored weekly with bioluminescence imaging and were retrieved after 7 weeks to quantify bone formation by histomorphometry. With increasing amounts of seeded MSCs (from 0 to 1,×,106 MSC/scaffold), a cell-dose related increase in bioluminescence was observed at all time points, correlating with increased bone formation at 7 weeks. To investigate the relevance of MSC proliferation to bone deposition, cell-seeded scaffolds were irradiated. The irradiated cells were functional with respect to oxygen consumption but no increase in bioluminescence was observed in vivo, and only minimal bone was produced. Proliferating MSCs are likely required for initiation of bone formation in tissue engineered constructs in vivo. Bioluminescence is a useful tool to monitor cellular responses and predict bone formation in vivo. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:901,909, 2008 [source] MMP-7 (matrilysin) expression in human brain tumorsMOLECULAR CARCINOGENESIS, Issue 6 2007Claire Rome Abstract Matrix metalloproteinases (MMP) which degrades protein components of the extra-cellular matrix and basement membrane seems to be largely involved in cancer invasiveness. MMP proteolitic activity essentially comes from stromal cells but matrilysin (MMP-7) is produced by the tumor itself. Thus, MMP-7 is investigated to address the particular invasive behavior of human glioma. Both MMP-7 mRNA and protein were clearly identified in human glioma. MMP-7 mRNA expression was highly variable within our glioma population. When analyzing MMP-7 mRNA expression in different primary brain tumors, we found highly variable levels of expression not related to their invasive behavior. In successive biopsies obtained in the same patients with glioblastoma, MMP-7 mRNA was quantified and appeared variable, but intra-individual variations were lower than inter-individual differences. With a xenograft model of U87 human tumors in RAG2/,c immune-deficient mice, the strict tumor origin of MMP-7 was shown. Additionally, MMP-7 expression by U87 cells which is low in culture was stimulated by these cells while forming tumors and the level of expression was higher when the tumor cells were implanted within the brain. These data provide some consistent information about cross-talk occurring between the tumor and the surrounding stroma to regulate MMP-7 expression. © 2007 Wiley-Liss, Inc. [source] Initial testing of cisplatin by the pediatric preclinical testing program,PEDIATRIC BLOOD & CANCER, Issue 5 2008Mimi Tajbakhsh BS Abstract Background Cisplatin is one of the most widely used drugs for the treatment of solid tumors in adults and children. Here, we report the activity of cisplatin against the PPTP panels of childhood cancer xenografts. Procedures Cisplatin was evaluated against 23 cell lines, and 40 xenografts representing brain tumors, neuroblastoma, rhabdoid tumors, sarcoma, Wilms tumor, and acute lymphoblastic leukemia (ALL). The IC50 concentration in vitro was determined for 96 hr exposure. Solid tumors were grown subcutaneously in immune-deficient mice, and tumor dimensions measured weekly. ALL xenografts were inoculated intravenously and the percent human CD45+ cells in the peripheral blood determined weekly. The antitumor activity of cisplatin (7 mg/kg administered intraperitoneally on Days 0 and 21) was evaluated using time to event (EFS T/C), tumor growth delay (tumor volume T/C), and objective response measures. Results The median IC50 concentration in vitro was 0.87 µM (0.24,4.29 µM), and cisplatin exhibited broad range activity. Cisplatin induced significant differences in EFS distributions compared to controls in 20/28 solid tumors and 4/8 ALL models. Objective responses were observed in 7/28 solid tumor models (25%): partial responses in three rhabdomyosarcomas and one Ewing's sarcoma; complete responses in one rhabdoid tumor and the medulloblastoma; and a maintained complete response in one Wilms tumor. No objective responses were observed in the ALL panel. Conclusions Cisplatin exhibits significant antitumor activity against a broad range of solid tumor xenograft models and limited activity against ALL xenografts. This preclinical pattern of activity is generally consistent with cisplatin's clinical activity. Pediatr Blood Cancer 2008;50:992,1000. © 2007 Wiley-Liss, Inc. [source] The pediatric preclinical testing program: Description of models and early testing results,PEDIATRIC BLOOD & CANCER, Issue 7 2007Peter J. Houghton PhD Abstract Background The Pediatric Preclinical Testing Program (PPTP) is an initiative supported by the National Cancer Institute (NCI) to identify novel therapeutic agents that may have significant activity against childhood cancers. The PPTP has established panels of childhood cancer xenografts and cell lines to be used for in vivo and in vitro testing. These include panels for Wilms tumor, sarcomas (rhabdomyosarcoma, Ewing sarcoma, and osteosarcoma), neuroblastoma, brain tumors (glioblastoma, ependymoma, and medulloblastoma), rhabdoid tumors (CNS and renal), and acute lymphoblastic leukemia (ALL). Here, we describe the characteristics of the in vivo tumor panels and report results for the in vivo evaluation of two standard agents, vincristine and cyclophosphamide. Procedures Solid tumors were grown subcutaneously in immune-deficient mice and tumor dimensions were measured weekly. ALL xenografts were inoculated intravenously and human CD45-positive cells were enumerated weekly. Results Vincristine-induced objective responses in 6 of 24 (25%) and cyclophosphamide-induced objective responses in 18 of 28 (64%) solid tumor models. Comparable assessments of high levels of activity for these two agents were obtained using a tumor growth delay (TGD) measure. Both agents induced regressions in each of the ALL models evaluated. Conclusions We have established 51 solid tumor and 10 ALL in vivo models. The models identify vincristine and cyclophosphamide as having broad-spectrum activity. The PPTP tumor panels appear to generally recapitulate the activity of these agents against specific childhood cancers and to have the potential for identifying novel agents having significant clinical activity. Pediatr Blood Cancer 2007;49:928,940. Published 2006 Wiley-Liss, Inc. [source] Modeling of congenital erythropoietic porphyria by RNA interference: a new tool for preclinical gene therapy evaluationTHE JOURNAL OF GENE MEDICINE, Issue 8 2010Elodie Robert-Richard Abstract Background Congenital erythropoietic porphyria (CEP) is a severe autosomal recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. We recently demonstrated the definitive cure of a murine model of CEP by lentiviral vector-mediated hematopoietic stem cell (HSC) gene therapy. In the perspective of a gene therapy clinical trial, human cellular models are required to evaluate the therapeutic potential of lentiviral vectors in UROS-deficient cells. However, the rare incidence of the disease makes difficult the availability of HSCs derived from patients. Methods RNA interference (RNAi) has been used to develop a new human model of the disease from normal cord blood HSCs. Lentivectors were developed for this purpose. Results We were able to down-regulate the level of human UROS in human cell lines and primary hematopoietic cells. A 97% reduction of UROS activity led to spontaneous uroporphyrin accumulation in human erythroid bone marrow cells of transplanted immune-deficient mice, recapitulating the phenotype of cells derived from patients. A strong RNAi-induced UROS inhibition allowed us to test the efficiency of different lentiviral vectors with the aim of selecting a safer vector. Restoration of UROS activity in these small hairpin RNA-transduced CD34+ cord blood cells by therapeutic lentivectors led to a partial correction of the phenotype in vivo. Conclusions The RNAi strategy is an interesting new tool for preclinical gene therapy evaluation. Copyright © 2010 John Wiley & Sons, Ltd. [source] | |||||||||||||