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1.
Ikumi Katano Ryoji Ito Tsutomu Kamisako Tomoo Eto Tomoyuki Ogura Kenji Kawai Hiroshi Suemizu Takeshi Takahashi Yutaka Kawakami Mamoru Ito 《Experimental Animals》2014,63(3):321-330
We have developed NOD-Rag2null IL-2Rγnull (NR2G)
mice similar to NOD-scidIL-2Rγnull (NOG) mice
that are known as an excellent host to generate humanized mice. To evaluate the usefulness
of NR2G mice as a host for humanized mice, the engraftment rates and differentiation of
human cells after human hematopoietic stem cell (HSC) transplantation were compared among
NR2G, NOG, and NOD-scid mice. For this purpose, the appropriate
irradiation doses to expand the niche for human stem cells in the bone marrow were first
determined. As a result, 8 and 2.5 Gy in adult, and 4 and 1 Gy in newborn NR2G and NOG
mice, respectively, were found to be appropriate. Next, 5 × 104 human umbilical
cord blood CD34+ cells were intravenously inoculated into irradiated adult or
newborn of the immunodeficient mice. These HSC transplantation experiments demonstrated
that both NR2G and NOG mice showed high engraftment rates compared with
NOD-scid mice, although NOG mice showed a slightly higher engraftment
rate than that for NR2G mice. However, no difference was found in the human cell
populations differentiated from HSCs between NR2G and NOG mice. The HSC transplantation
experiments to adults and newborns of two immunodeficient mice also revealed that the HSC
transplantation into newborn mice resulted in higher engraftment rate than those into
adults. These results showed that NR2G mice could be used as an alternative host to NOG
mice to generate humanized mice. 相似文献
2.
Yoichi Haji Makiko Suzuki Kunihiko Moriya Takanori So Katsuto Hozumi Masamichi Mizuma Michiaki Unno Naoto Ishii 《Biochemical and biophysical research communications》2014
Notch1 mutations are found in more than 50% of human T cell acute lymphoblastic leukemia (T-ALL) cells. However, the functions of Notch1 for human T cell development and leukemogenesis are not well understood. To examine the role of Notch1, human hematopoietic stem cells (HSCs), which had been transduced with a constitutively active form of Notch1 (ICN1), were transplanted into severely immunodeficient NOD/Shi-scid-IL2rγnull (NOG) mice. We found that the great majority of the ICN1-expressing hematopoietic cells in the bone marrow expressed surface markers for T cells, such as CD3, CD4, and CD8, and that this T cell development was independent of the thymus. Accordingly, phenotypically mature CD8+ single positive (SP) T cells were observed in the spleen. Furthermore, T-ALL developed in one NOG recipient mouse out of 26 that had been secondary transferred with the T cells developed in the first NOG mice. These results indicate that Notch1 signaling in HSCs promotes CD8+ SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation. 相似文献
3.
A robust animal model for “hypothesis-testing/mechanistic” research in human immunology and immuno-pathology should meet the
following criteria. First, it has well-studied hemato-lymphoid organs and target cells similar to those of humans. Second,
the human pathogens establish infection and lead to relevant diseases. Third, it is genetically inbred and can be manipulated
via genetic, immunological and pharmacological means. Many human-tropic pathogens such as HIV-1 fail to infect murine cells
due to the blocks at multiple steps of their life cycle. The mouse with a reconstituted human immune system and other human
target organs is a good candidate. A number of human-mouse chimeric models with human immune cells have been developed in
the past 20 years, but most with only limited success due to the selective engraftment of xeno-reactive human T cells in hu-PBL-SCID
mice or the lack of significant human immune responses in the SCID-hu Thy/Liv mouse. This review summarizes the current understanding
of HIV-1 immuno-pathogenesis in human patients and in SIV-infected primate models. It also reviews the recent progress in
the development of humanized mouse models with a functional human immune system, especially the recent progress in the immunodeficient
mice that carry a defective gammaC gene. NOD/SCID/gammaC−/− (NOG or NSG) or the Rag2−/−gammaC−/− double knockout (DKO) mice, which lack NK as well as T and B cells (NTB-null mice), have been used to reconstitute a functional
human immune system in central and peripheral lymphoid organs with human CD34+ HSC. These NTB-hu HSC humanized models have been used to investigate HIV-1 infection, immuno-pathogenesis and therapeutic
interventions. Such models, with further improvements, will contribute to study human immunology, human-tropic pathogens as
well as human stem cell biology in the tissue development and function in vivo. 相似文献
4.
Haruko Shima Keiyo Takubo Hiroki Yoshihara Yumiko Gomei Fumio Arai Toshio Suda 《Biochemical and biophysical research communications》2009,378(3):467-3420
Hematopoietic stem cells (HSCs) reside in hypoxic areas of the bone marrow. However, the role of hypoxia in the maintenance of HSCs has not been fully characterized. We performed xenotransplantation of human cord blood cells cultured in hypoxic or normoxic conditions into adult NOD/SCID/IL-2Rγnull (NOG) mice. Hypoxic culture (1% O2) for 6 days efficiently supported the maintenance of HSCs, although cell proliferation was suppressed compared to the normoxic culture. In contrast, hypoxia did not affect in vitro colony-forming ability. Upregulation of a cell cycle inhibitor, p21, was observed in hypoxic culture. Immunohistochemical analysis of recipient bone marrow revealed that engrafted CD34+CD38− cord blood HSCs were hypoxic. Taken together, these results demonstrate the significance of hypoxia in the maintenance of quiescent human cord blood HSCs. 相似文献
5.
Marina E. Fomin Yanchen Zhou Ashley I. Beyer Jean Publicover Jody L. Baron Marcus O. Muench 《PloS one》2013,8(10)
Liver sinusoidal endothelial cells (LSECs) form a semi-permeable barrier between parenchymal hepatocytes and the blood. LSECs participate in liver metabolism, clearance of pathological agents, immunological responses, architectural maintenance of the liver and synthesis of growth factors and cytokines. LSECs also play an important role in coagulation through the synthesis of Factor VIII (FVIII). Herein, we phenotypically define human LSECs isolated from fetal liver using flow cytometry and immunofluorescence microscopy. Isolated LSECs were cultured and shown to express endothelial markers and markers specific for the LSEC lineage. LSECs were also shown to engraft the liver when human fetal liver cells were transplanted into immunodeficient mice with liver specific expression of the urokinase-type plasminogen activator (uPA) transgene (uPA-NOG mice). Engrafted cells expressed human Factor VIII at levels approaching those found in human plasma. We also demonstrate engraftment of adult LSECs, as well as hepatocytes, transplanted into uPA-NOG mice. We propose that overexpression of uPA provides beneficial conditions for LSEC engraftment due to elevated expression of the angiogenic cytokine, vascular endothelial growth factor. This work provides a detailed characterization of human midgestation LSECs, thereby providing the means for their purification and culture based on their expression of CD14 and CD32 as well as a lack of CD45 expression. The uPA-NOG mouse is shown to be a permissive host for human LSECs and adult hepatocytes, but not fetal hepatoblasts. Thus, these mice provide a useful model system to study these cell types in vivo. Demonstration of human FVIII production by transplanted LSECs encourages further pursuit of LSEC transplantation as a cellular therapy for the treatment of hemophilia A. 相似文献
6.
Sacci JB Alam U Douglas D Lewis J Tyrrell DL Azad AF Kneteman NM 《International journal for parasitology》2006,36(3):353-360
The exoerythrocytic stage of Plasmodium falciparum has remained a difficult phase of the parasite life-cycle to study. The host and tissue specificity of the parasite requires the experimental infection of humans or non-human primates and subsequent surgical recovery of parasite-infected liver tissue to analyze this stage of the parasites development. This type of study is impossible in humans due to obvious ethical considerations and the cost and complexity in working with primate models has precluded their use for extensive studies of the exoerythrocytic stage. In this study we assessed, for the first time, the use of transgenic, chimeric mice containing functioning human hepatocytes as an alternative for modeling the in vivo interaction of P. falciparum parasites and human hepatocytes. Infection of these mice with P. falciparum sporozoites produced morphologically and antigenically mature liver stage schizonts containing merozoites capable of invading human red blood cells. Additionally, using microdissection, highly enriched P. falciparum liver stage parasites essentially free of hepatocyte contamination, were recovered for molecular studies. Our results establish a stable murine model for P. falciparum that will have a wide utility for assessing the biology of the parasite, potential anti-malarial chemotherapeutic agents and vaccine design. 相似文献
7.
Ziping Qi Lu Li Xuefu Wang Xiang Gao Xin Wang Haiming Wei Jian Zhang Rui Sun Zhigang Tian 《PloS one》2014,9(9)
Liver immunopathologic mechanisms during hepatotropic infection, malignant transformation, and autoimmunity are still unclear. Establishing a chimeric mouse with a reconstituted liver and immune system derived from a single donor across species is critical to study regional donor immune responses in recipient liver. Using a strain of mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase (fah
-/-) and bone marrow transplantation (BMT), we reconstituted the donor''s hepatocytes and immune cells across host species barrier. Syngeneic, allogeneic or even xenogeneic rat BMT rescued most recipient fah-/- mice against liver failure by donor BM-derived FAH+ hepatocytes. Importantly, immune system developed normally in chimeras, and the immune cells together with organ architecture were intact and functional. Thus, donor BM can across host species barrier and concurrently reconstitutes MHC-identical response between immune cells and hepatocytes, giving rise to a new simple and convenient small animal model to study donor''s liver immune response in mice. 相似文献
8.
Generation of hybrid hepatocytes by cell fusion from monkey embryoid body cells in the injured mouse liver 总被引:5,自引:2,他引:3
Okamura K Asahina K Fujimori H Ozeki R Shimizu-Saito K Tanaka Y Teramoto K Arii S Takase K Kataoka M Soeno Y Tateno C Yoshizato K Teraoka H 《Histochemistry and cell biology》2006,125(3):247-257
Monkey embryonic stem (ES) cells have characteristics that are similar to human ES cells, and might be useful as a substitute
model for preclinical research. When embryoid bodies (EBs) formed from monkey ES cells were cultured, expression of many hepatocyte-related
genes including cytochrome P450 (Cyp) 3a and Cyp7a1 was observed. Hepatocytes were immunocytochemically observed using antibodies
against albumin (ALB), cytokeratin-8/18, and α1-antitrypsin in the developing EBs. The in vitro differentiation potential
of monkey ES cells into the hepatic lineage prompted us to examine the transplantability of monkey EB cells. As an initial
approach to assess the repopulation potential, we transplanted EB cells into immunodeficient urokinase-type plasminogen activator
transgenic mice that undergo liver failure. After transplantation, the hepatocyte colonies expressing monkey ALB were observed
in the mouse liver. Fluorescence in-situ hybridization revealed that the repopulating hepatocytes arise from cell fusion between
transplanted monkey EB cells and recipient mouse hepatocytes. In contrast, neither cell fusion nor repopulation of hepatocytes
was observed in the recipient liver after undifferentiated ES cell transplantation. These results indicate that the differentiated
cells in developing monkey EBs, but not contaminating ES cells, generate functional hepatocytes by cell fusion with recipient
mouse hepatocytes, and repopulate injured mouse liver. 相似文献
9.
Etsuko Fujii Atsuhiko Kato Yu Jau Chen Koichi Matsubara Yasuyuki Ohnishi Masami Suzuki 《Experimental Animals》2014,63(3):289-296
Human tumor tissue line models established in the severely immunodeficient
NOD.Cg-Prkdcscid Il2rgtm1Sug/Jic
(NOD/Shi-scid, IL-2Rγnull or NOG) mouse are important tools
for oncology research. During the establishment process, a lymphoproliferative lesion
(LPL) that replaces the original tumor cells in the site of transplantation occurs. In the
present study, we studied the impact of the LPL on the establishment process and the
characteristics of the lesion, investigated the systemic distribution of the lesion in the
mouse, and evaluated the potential of a simple identification method. The incidence of the
lesion varied among tumor types, and the lesion was found to be the leading cause of
unsuccessful establishment with gastric and colorectal cancer. The lesion consisted of a
varying population of proliferating lymphoid cells that expressed CD20. The cells were
positive for Epstein-Barr virus (EBV)-related antigens, and EBV DNA was detected. There
was systemic distribution of the lesion within the NOG mouse, and the most consistent
gross finding was splenomegaly. Additionally, identification of LPL-affected cases was
possible by detecting splenomegaly in the 1st and 2nd generation mice at necropsy. From
our findings the lesion was judged to arise from EBV-infected B cells originating from the
donor, and monitoring splenomegaly at necropsy was thought effective as a simple method
for identifying the lesion at an early stage of the establishment process. 相似文献
10.
Hanako Morita Masahiko Yasuda Masafumi Yamamoto Yurina Tomiyama Ritsuki Uchida Yuyo Ka Tomoyuki Ogura Kenji Kawai Hiroshi Suemizu Nobuhito Hayashimoto 《Experimental Animals》2021,70(3):355
Astroviruses are often associated with gastrointestinal diseases in mammals and birds. Murine astrovirus (MuAstV) is frequently detected in laboratory mice. Previous studies on MuAstV in mice did not report any symptoms or lesions. However, little information is available regarding its pathogenicity in immunodeficient mice. Therefore, in this study, we experimentally infected germ-free NOD.Cg-PrkdcscidIl2rgtm1Sug/ShiJic (NOG) mice, which are severely immunodeficient, with MuAstV. Germ-free mice were used for experimental infection to eliminate the effects of intestinal bacteria. Mice in each group were then necropsied and subjected to PCR for MuAstV detection, MuAstV RNA quantification in each organ, and histopathological examination at 4 and 28 days post inoculation (DPI). Tissue samples from the small intestine were examined by transmission electron microscopy. No symptoms or abnormalities were detected in any mice during necropsy. The MuAstV concentration was highest in the lower small intestine, where it increased approximately 8-fold from 4 to 28 DPI. Transmission electron microscopy revealed circular virus particles of approximately 25 nm in diameter in the cytoplasm of the villous epithelial cells of the lower small intestine. Histopathological examination did not reveal any abnormalities, such as atrophy, in the intestinal villi. Our results suggest that MuAstV proliferates in the villous epithelial cells of the lower small intestine and has weak pathogenicity. 相似文献
11.
Masayuki Takahashi Noriyuki Tsujimura Tomoko Yoshino Masahito Hosokawa Kensuke Otsuka Tadashi Matsunaga Satoshi Nakasono 《PloS one》2012,7(12)
Despite recent advancements, it is still difficult to evaluate in vivo responses to toxicants in humans. Development of a system that can mimic the in vivo responses of human cells will enable more accurate health risk assessments. A surrogate human hematopoietic lineage can be established in NOD/Shi-scid/IL-2Rγnull (NOG) mice by transplanting human hematopoietic stem/progenitor cells (Hu-NOG mice). Here, we first evaluated the toxic response of human-like hematopoietic lineage in NOG mice to a representative toxic agent, benzene. Flow cytometric analysis showed that benzene caused a significant decrease in the number of human hematopoietic stem/progenitor cells in the bone marrow and the number of human leukocytes in the peripheral blood and hematopoietic organs. Next, we established chimeric mice by transplanting C57BL/6 mouse-derived bone marrow cells into NOG mice (Mo-NOG mice). A comparison of the degree of benzene-induced hematotoxicity in donor-derived hematopoietic lineage cells within Mo-NOG mice indicated that the toxic response of Hu-NOG mice reflected interspecies differences in susceptibilities to benzene. Responses to the toxic effects of benzene were greater in lymphoid cells than in myeloid cells in Mo-NOG and Hu-NOG mice. These findings suggested that Hu-NOG mice may be a powerful in vivo tool for assessing hematotoxicity in humans, while accounting for interspecies differences. 相似文献
12.
Asahi Ito Takashi Ishida Hiroki Yano Atsushi Inagaki Susumu Suzuki Fumihiko Sato Hisashi Takino Fumiko Mori Masaki Ri Shigeru Kusumoto Hirokazu Komatsu Shinsuke Iida Hiroshi Inagaki Ryuzo Ueda 《Cancer immunology, immunotherapy : CII》2009,58(8):1195-1206
Purpose There are no suitable small animal models to evaluate human antibody-dependent cellular cytotoxicity (ADCC) in vivo, due to
species incompatibilities. Thus, the first aim of this study was to establish a human tumor-bearing mouse model in which human
immune cells can engraft and mediate ADCC, but where the endogenous mouse immune cells cannot mediate ADCC. The second aim
was to evaluate ADCC mediated in these humanized mice by the defucosylated anti-CC chemokine receptor 4 (CCR4) monoclonal
antibody (mAb) which we have developed and which is now in phase I clinical trials.
Experimental design NOD/Shi-scid, IL-2Rγnull (NOG) mice were the recipients of human immune cells, and CCR4-expressing Hodgkin lymphoma (HL) and cutaneous T-cell lymphoma
(CTCL) cell lines were used as target tumors.
Results Humanized mice have been established using NOG mice. The chimeric defucosylated anti-CCR4 mAb KM2760 showed potent antitumor
activity mediated by robust ADCC in these humanized mice bearing the HL or CTCL cell lines. KM2760 significantly increased
the number of tumor-infiltrating CD56-positive NK cells which mediate ADCC, and reduced the number of tumor-infiltrating FOXP3-positive
regulatory T (Treg) cells in HL-bearing humanized mice.
Conclusions Anti-CCR4 mAb could be an ideal treatment modality for many different cancers, not only to directly kill CCR4-expressing tumor
cells, but also to overcome the suppressive effect of Treg cells on the host immune response to tumor cells. In addition,
using our humanized mice, we can perform the appropriate preclinical evaluation of many types of antibody based immunotherapy. 相似文献
13.
D Xiang C-C Liu M-J Wang J-X Li F Chen H Yao B Yu L Lu U Borjigin Y-X Chen L Zhong K J Wangensteen Z-Y He X Wang Y-P Hu 《Cell death & disease》2014,5(5):e1252
Hepatocyte transplantation as a substitute strategy of orthotopic liver transplantation is being studied for treating end-stage liver diseases. Several technical hurdles must be overcome in order to achieve the therapeutic liver repopulation, such as the problem of insufficient expansion of the transplanted hepatocytes in recipient livers. In this study, we analyzed the application of FoxM1, a cell-cycle regulator, to enhance the proliferation capacity of hepatocytes. The non-viral sleeping beauty (SB) transposon vector carrying FoxM1 gene was constructed for delivering FoxM1 into the hepatocytes. The proliferation capacities of hepatocytes with FoxM1 expression were examined both in vivo and in vitro. Results indicated that the hepatocytes with FoxM1 expression had a higher proliferation rate than wild-type (WT) hepatocytes in vitro. In comparison with WT hepatocytes, the hepatocytes with FoxM1 expression had an enhanced level of liver repopulation in the recipient livers at both sub-acute injury (fumaryl acetoacetate hydrolase (Fah)–/– mice model) and acute injury (2/3 partial hepatectomy mice model). Importantly, there was no increased risk of tumorigenicity with FoxM1 expression in recipients even after serial transplantation. In conclusion, expression of FoxM1 in hepatocytes enhanced the capacity of liver repopulation without inducing tumorigenesis. FoxM1 gene delivered by non-viral SB vector into hepatocytes may be a viable approach to promote therapeutic repopulation after hepatocyte transplantation. 相似文献
14.
Etsuko FUJII Atsuhiko KATO Yu Jau CHEN Koichi MATSUBARA Yasuyuki OHNISHI Masami SUZUKI 《Experimental Animals》2015,64(2):181-190
Patient-derived xenografts (PDXs) of tumors are increasingly becoming important tools for
translational research in oncology. The NOD.Cg-Prkdcscid
Il2rgtm1Sug/Jic (NOG) mouse is an efficient host for PDXs. Thus as
a basis for future development of methods to obtain PDXs from various disease types, we
have studied the factors that affect the outcome of transplantation of human colorectal
cancer in NOG mice. Of the original donor cases examined, 73% had successful engraftment.
The outcome of donor-matched tissues was consistent in most cases, and was thought to show
that the condition of the host did not affect engraftment. Next we analyzed the tumor
aggressiveness in terms of histology grade of the original tumor and found that they were
related to engraftment. Detailed histopathological examination of the transplanted tissues
strongly indicated that lymphocytes engrafted with the tumor cells affect engraftment. As
a factor related to transplantation of lymphocytes, we studied the human IgG concentration
in the serum of tumor-bearing mice, but there was no tendency for higher concentrations to
result in unsuccessful engraftment. Finally, we studied the type, density and location of
T cells in the original donor tissue to determine the immune contexture and found that the
unsuccessful engraftment cases tended to have an adequate or coordinated immune contexture
compared to successful engraftment cases. From these results, we concluded that the
aggressiveness and the T cell infiltration of the original tumor affect the outcome of
transplantation in the NOG mouse. 相似文献
15.
Kazuya Sakata Masaki Ohmuraya Kimi Araki Chigure Suzuki Satoshi Ida Daisuke Hashimoto Jung Wang Yasuo Uchiyama Hideo Baba Ken-ichi Yamamura 《Experimental Animals》2014,63(1):45-53
Serine protease inhibitor Kazal type 1 (SPINK1; mouse homologue
Spink3) was initially discovered as a trypsin-specific inhibitor in the
pancreas. However, previous studies have suggested that SPINK1/Spink3 is
expressed in a wide range of normal tissues and tumors, although precise characterization
of its gene expression has not been described in adulthood. To further analyze
Spink3 expression, we generated two mouse lines in which either
lacZ or Cre recombinase genes were inserted into the
Spink3 locus by Cre-loxP technology. In
Spink3lacZ mice, β-galactosidase activity was found in
acinar cells of the pancreas and kidney, as well as epithelial cells of the bronchus in
the lung, but not in the gastrointestinal tract or liver.
Spink3cre knock-in mice were crossed with Rosa26 reporter
(R26R) mice to monitor Spink3 promoter activity. In
Spink3cre;R26R mice, β-galactosidase activity was found in
acinar cells of the pancreas, kidney, lung, and a small proportion of cells in the
gastrointestinal tract and liver. These data suggest that Spink3 is widely expressed in
endoderm-derived tissues, and that Spink3cre knock-in mice are
a useful tool for establishment of a conditional knockout mice to analyze Spink3 function
not only in normal tissues, but also in tumors that express
SPINK1/Spink3. 相似文献
16.
Helene Strick-Marchand Mathilde Dusséaux Sylvie Darche Nicholas D. Huntington Nicolas Legrand Guillemette Masse-Ranson Erwan Corcuff James Ahodantin Kees Weijer Hergen Spits Dina Kremsdorf James P. Di Santo 《PloS one》2015,10(3)
Hepatic infections by hepatitis B virus (HBV), hepatitis C virus (HCV) and Plasmodium parasites leading to acute or chronic diseases constitute a global health challenge. The species tropism of these hepatotropic pathogens is restricted to chimpanzees and humans, thus model systems to study their pathological mechanisms are severely limited. Although these pathogens infect hepatocytes, disease pathology is intimately related to the degree and quality of the immune response. As a first step to decipher the immune response to infected hepatocytes, we developed an animal model harboring both a human immune system (HIS) and human hepatocytes (HUHEP) in BALB/c Rag2-/- IL-2Rγc-/- NOD.sirpa uPAtg/tg mice. The extent and kinetics of human hepatocyte engraftment were similar between HUHEP and HIS-HUHEP mice. Transplanted human hepatocytes were polarized and mature in vivo, resulting in 20–50% liver chimerism in these models. Human myeloid and lymphoid cell lineages developed at similar frequencies in HIS and HIS-HUHEP mice, and splenic and hepatic compartments were humanized with mature B cells, NK cells and naïve T cells, as well as monocytes and dendritic cells. Taken together, these results demonstrate that HIS-HUHEP mice can be stably (> 5 months) and robustly engrafted with a humanized immune system and chimeric human liver. This novel HIS-HUHEP model provides a platform to investigate human immune responses against hepatotropic pathogens and to test novel drug strategies or vaccine candidates. 相似文献
17.
Dan Xu Toshi Nishimura Sachiko Nishimura Haili Zhang Ming Zheng Ying-Ying Guo Marylin Masek Sara A. Michie Jeffrey Glenn Gary Peltz 《PLoS medicine》2014,11(4)
Background
Seven of 15 clinical trial participants treated with a nucleoside analogue (fialuridine [FIAU]) developed acute liver failure. Five treated participants died, and two required a liver transplant. Preclinical toxicology studies in mice, rats, dogs, and primates did not provide any indication that FIAU would be hepatotoxic in humans. Therefore, we investigated whether FIAU-induced liver toxicity could be detected in chimeric TK-NOG mice with humanized livers.Methods and Findings
Control and chimeric TK-NOG mice with humanized livers were treated orally with FIAU 400, 100, 25, or 2.5 mg/kg/d. The response to drug treatment was evaluated by measuring plasma lactate and liver enzymes, by assessing liver histology, and by electron microscopy. After treatment with FIAU 400 mg/kg/d for 4 d, chimeric mice developed clinical and serologic evidence of liver failure and lactic acidosis. Analysis of liver tissue revealed steatosis in regions with human, but not mouse, hepatocytes. Electron micrographs revealed lipid and mitochondrial abnormalities in the human hepatocytes in FIAU-treated chimeric mice. Dose-dependent liver toxicity was detected in chimeric mice treated with FIAU 100, 25, or 2.5 mg/kg/d for 14 d. Liver toxicity did not develop in control mice that were treated with the same FIAU doses for 14 d. In contrast, treatment with another nucleotide analogue (sofosbuvir 440 or 44 mg/kg/d po) for 14 d, which did not cause liver toxicity in human trial participants, did not cause liver toxicity in mice with humanized livers.Conclusions
FIAU-induced liver toxicity could be readily detected using chimeric TK-NOG mice with humanized livers, even when the mice were treated with a FIAU dose that was only 10-fold above the dose used in human participants. The clinical features, laboratory abnormalities, liver histology, and ultra-structural changes observed in FIAU-treated chimeric mice mirrored those of FIAU-treated human participants. The use of chimeric mice in preclinical toxicology studies could improve the safety of candidate medications selected for testing in human participants. Please see later in the article for the Editors'' Summary 相似文献18.
Establishment of a new model of human multiple myeloma using NOD/SCID/gammac(null) (NOG) mice 总被引:3,自引:0,他引:3
Miyakawa Y Ohnishi Y Tomisawa M Monnai M Kohmura K Ueyama Y Ito M Ikeda Y Kizaki M Nakamura M 《Biochemical and biophysical research communications》2004,313(2):258-262
We developed a new experimental animal model of human multiple myeloma using immunodeficient NOD/SCID/gammac(null) (NOG) mice. A human myeloma cell line, U266, was intravenously inoculated into 20 NOG mice, all of which developed hind leg paralysis and distress around 6 weeks after transplantation. Pathological studies showed that only the bone marrow was infiltrated with U266 cells, and no cells were present in other organs. Osteolytic lesions in cortical bones and loss of trabecular bones were prominent in U266-transplanted NOG mice. In contrast, U266 cells were not detected in CB17scid or NOD/SCID mice 6 weeks after intravenous inoculation. Human IgE, produced by U266 cells, was detected in the serum of U266-transplanted NOG mice by ELISA. The results indicated that this hu-myeloma NOG model might be useful for studying the pathogenesis of myeloma and related osteolytic lesions, and are suggestive of its applicability to the future development of new drugs. 相似文献
19.
Masami Hasegawa Kenji Kawai Tetsuya Mitsui Kenji Taniguchi Makoto Monnai Masatoshi Wakui Mamoru Ito Makoto Suematsu Gary Peltz Masato Nakamura Hiroshi Suemizu 《Biochemical and biophysical research communications》2011,(3):405
To overcome the limitations of existing models, we developed a novel experimental in vivo platform for replacing mouse liver with functioning human liver tissue. To do this, a herpes simplex virus type 1 thymidine kinase (HSVtk) transgene was expressed within the liver of highly immunodeficient NOG mice (TK-NOG). Mouse liver cells expressing this transgene were ablated after a brief exposure to a non-toxic dose of ganciclovir (GCV), and transplanted human liver cells are stably maintained within the liver (humanized TK-NOG) without exogenous drug. The reconstituted liver was shown to be a mature and functioning “human organ” that had zonal position-specific enzyme expression and a global gene expression pattern representative of mature human liver; and could generate a human-specific profile of drug metabolism. The ‘humanized liver’ could be stably maintained in these mice with a high level of synthetic function for a prolonged period (8 months). This novel in vivo system provides an optimized platform for studying human liver physiology, including drug metabolism, toxicology, or liver regeneration. 相似文献
20.
C Stolfi V De Simone A Colantoni E Franzè E Ribichini M C Fantini R Caruso I Monteleone G S Sica P Sileri T T MacDonald F Pallone G Monteleone 《Cell death & disease》2014,5(2):e1073
Initially identified as an inhibitor of transforming growth factor (TGF)-β mainly owing to its ability to bind TGF-β receptor type I and abrogate TGF-β-driven signaling, Smad7 can interact with additional intracellular proteins and regulate TGF-β-independent pathways, thus having a key role in the control of neoplastic processes in various organs. Genome-wide association studies have shown that common alleles of Smad7 influence the risk of colorectal cancer (CRC), even though the contribution of Smad7 in colon carcinogenesis is not fully understood. In this study, we assessed the expression and role of Smad7 in human and mouse models of sporadic CRC. We document a significant increase of Smad7 in human CRC relative to the surrounding nontumor tissues and show that silencing of Smad7 inhibits the growth of CRC cell lines both in vitro and in vivo after transplantation into immunodeficient mice. Knockdown of Smad7 results in enhanced phosphorylation of the cyclin-dependent kinase (CDK)2, accumulation of CRC cells in S phase and enhanced cell death. Smad7-deficient CRC cells have lower levels of CDC25A, a phosphatase that dephosphorylates CDK2, and hyperphosphorylated eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, knockdown of Smad7 associates with inactivation of eIF2α, lower CDC25A expression and diminished fraction of proliferating cells in human CRC explants, and reduces the number of intestinal tumors in Apcmin/+ mice. Altogether, these data support a role for Smad7 in sustaining colon tumorigenesis. 相似文献