Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much bett...Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much better method to study the HLA-A-related principal mechanisms for vaccine development and HLA-Arestricted responses against infection in human.Methods:A recombinant gene encoding the chimeric HLA-A30 monochain was constructed.This HHD molecule contains the following:α1-α2 domains of HLA-A30,α3 and cytoplasmic domains of H-2D~b,linked at its N-terminus to the C-terminus of humanβ2m by a 15-amino-acid peptide linker.The recombinant gene encoding the chimeric HLA-A30 monochain cassette was introduced into bacterial artificial chromosome(BAC)CH502-67J3 containing the HLA-A01 gene locus by Red-mediated homologous recombination.Modified BAC CH502-67J3 was microinjected into the pronuclei of wild-type mouse oocytes.This humanized mouse model was further used to assess the immune responses against influenza A virus(H1N1)pdm09 clinically isolated from human patients.Immune cell population,cytokine production,and histopathology in the lung were analyzed.Results:We describe a novel humanβ2m-HLA-A30(α1α2)-H-2D~b(α3 transmembrane cytoplasmic)(HHD)monochain transgenic mouse strain,which contains the intact HLA-A01 gene locus including 49 kb 5’-UTR and 74 kb 3’-UTR of HLA-A01*01.Five transgenic lines integrated into the large genomic region of HLA-A gene locus were obtained,and the robust expression of exogenous transgene was detected in various tissues from A30-18#and A30-19#lines encompassing the intact flanking sequences.Flow cytometry revealed that the introduction of a large genomic region in HLA-A gene locus can influence the immune cell constitution in humanized mice.Pdm09 infection caused a similar immune response among HLA-A30 Tg humanized mice and wild-type mice,and induced the rapid increase of cytokines,including IFN-γ,TNF-α,and IL-6,in both HLA-A30 humanized Tg mice and wild-type mice.The expression of HLA-A30 transgene was dramatically promoted in tissues from A30-9#line at 3 days post-infection(dpi).Conclusions:We established a promising preclinical research animal model of HLA-A30 Tg humanized mouse,which could accelerate the identification of novel HLA-A30-restricted epitopes and vaccine development,and support the study of HLA-A-restricted responses against infection in humans.展开更多
Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsucc...Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.展开更多
Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the C...Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the Col6a3 gene in mouse models is relevant,but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression.Methods:Here,we present the development,validation and preliminary phenotypic characterization of a novel CRISPR-based knockout mouse model targeting Col6a3 exon 3(Col6a3^(d3/d3)).Results:In this mouse model,Col6a3 mRNA is still expressed at a similar level to wild-type littermates,although the expected protein is undetectable by mass spectrometry.Histological analysis of Col6a3^(d3/d3)quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells,consistent with a myopathy phenotype.Interestingly,Col6a3^(d3/d3)mice are smaller in size,with their fat,muscle,and bone kept proportional compared to wild-type littermates.Conclusions:In summary,we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI-associated diseases.展开更多
The intestinal microbiome has emerged as an important component involved in various diseases.Therefore,the interest in understanding the factors shaping its composition is growing.The gut microbiome,often defined as a...The intestinal microbiome has emerged as an important component involved in various diseases.Therefore,the interest in understanding the factors shaping its composition is growing.The gut microbiome,often defined as a complex trait,contains diverse components and its properties are determined by a combination of external and internal effects.Although much effort has been invested so far,it is still difficult to evaluate the extent to which human genetics shape the composition of the gut microbiota.However,in mouse studies,where the environmental factors are better controlled,the effect of the genetic background was significant.The purpose of this paper is to provide a current assessment of the role of human host genetics in shaping the gut microbiome composition.Despite the inconsistency of the reported results,it can be estimated that the genetic factor affects a portion of the microbiome.However,this effect is currently lower than the initial estimates,and it is difficult to separate the genetic influence from the environmental effect.Additionally,despite the differences between the microbial composition of humans and mice,results from mouse models can strengthen our knowledge of host genetics underlying the human gut microbial variation.展开更多
Objective To investigate the influence of m4-1BBL on anti-tumor effects induced by truncated human prostate specific membrane antigen ( tPSMA ) gene in mice. Methods A eukaryotic expression plasmid encoding tPSMA and ...Objective To investigate the influence of m4-1BBL on anti-tumor effects induced by truncated human prostate specific membrane antigen ( tPSMA ) gene in mice. Methods A eukaryotic expression plasmid encoding tPSMA and m4-1BBL ( pDC316-tPSMA-IRES m4-1BBL) ,pDC316-tPSMA and pDC316 were constructed.展开更多
Proper medical treatment of a stroke victim relies on accurate and rapid differentiation between ischemic and hemorrhagic stroke,which in current practice is performed by computerized tomography（CT） or magnetic reso...Proper medical treatment of a stroke victim relies on accurate and rapid differentiation between ischemic and hemorrhagic stroke,which in current practice is performed by computerized tomography（CT） or magnetic resonance imaging（MRI） scans.A panel of micro RNAs could be an extremely useful clinical tool for distinguishing between hemorrhagic and ischemic stroke.This review has shown that blood miRNA profile can distinguish hemorrhagic from ischemic stroke in patients and in experimental animal models.It also seems likely they can differentiate between intracerebral and subarachnoid hemorrhage stroke.The miRNA profile in cerebrospinal fluid could be a useful diagnostic tool for subarachnoid hemorrhagic stroke.Decreased or increased miRNA levels may be needed either as prevention or treatment of stroke.Administration in vivo of miR-130 a inhibitor or miRNA mimic（miR-367,miR-223） in an intracerebral hemorrhage animal model improved neurological outcomes.展开更多
AIM:To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.METHODS:Cell transplantation into mouse livers was conducted using alpha-fetoprotein(AFP)-producing hu-...AIM:To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.METHODS:Cell transplantation into mouse livers was conducted using alpha-fetoprotein(AFP)-producing hu-man gastric cancer cells(h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator(uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient(SCID) mouse line(uPA/SCID mice).Host mice were divided into two groups(A and B).Group A mice were transplanted with h-GCCs alone,and group B mice were transplanted with h-GCCs and h-hepatocytes together.The replacement index(RI),which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section,was estimated by measuring h-AFP and h-albumin concentrations in sera,respectively,as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections.RESULTS:The h-GCCs successfully engrafted,repopulated,and colonized the livers of mice in group A(RI = 22.0% ± 2.6%).These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures,which is a characteristics feature of gastric cancers.The serum h-AFP level reached 211.0 ± 142.2 g/mL(range,7.1-324.2 g/mL).In group B mice,the h-GCCs and h-hepatocytes independently engrafted,repopulated the host liver,and developed colonies(RI = 12.0% ± 6.8% and 66.0% ± 12.3%,respectively).h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies.These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period.The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo.CONCLUSION:A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line.This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.展开更多
In a recent study,Yong-Guang Yang and colleagues developed a severely immunodeficient pig model that supports long-term engraftment and multilineage differentiation of human hematopoietic stem/progenitor cells(HSPCs)....In a recent study,Yong-Guang Yang and colleagues developed a severely immunodeficient pig model that supports long-term engraftment and multilineage differentiation of human hematopoietic stem/progenitor cells(HSPCs).1 This breakthrough addresses key limitations of current humanized mouse models,including their small size and limited lifespan,and offers a promising platform for the large-scale production of human immune cells,potentially functioning as an in vivo bioreactor.展开更多
Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses.However,when human peripheral blood mononuclear cells(PBMCs)are tr...Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses.However,when human peripheral blood mononuclear cells(PBMCs)are transferred into NOG(NOD/Shi-scid,IL-2rg null)mice,severe graft versus host disease(GVHD)hinders long term detailed analysis.Administration of human PBMCs into newly developed murine MHC class I-and class II-deficient NOG(NOG-dKO;NOG-Iab,B2m-double-knockout)mice showed sufficient engraftment of human immune cells with little sign of GVHD.Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab,indicating induction of antigen-specific B cells in the NOG-dKO mice.Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells,indicating the induction of antigen-specific T cells in the NOG-dKO mice.Adoptive cell therapies(ACTs)using melanoma antigen recognized by T cells(MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells.ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice,in which changes in human cancer phenotypes by immune intervention,such as increased CD271 expression,could be evaluated.Therefore,NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.展开更多
Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous eff...Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous efforts have been devoted towards the development of such humanized mouse models. This review is focused on human lymphohematopoietic reconstitution and immune function in humanized mice by cotransplantation of human fetal thymic tissue and CD34＋ cells. The potential use of these humanized mice in translational biomedical research is also discussed.展开更多
Recombinant human prolactin(rhPRL)was administered to huPBL-SCID mice to determine its effects on human immunologic reconstitution and function.The huPBL-SCID mice were given 10 μg i.p.injection of rhPRL every other ...Recombinant human prolactin(rhPRL)was administered to huPBL-SCID mice to determine its effects on human immunologic reconstitution and function.The huPBL-SCID mice were given 10 μg i.p.injection of rhPRL every other day for a total of 10 injections after huPBL were transfered.The results demonstrated that rhPRL improved the engraftment of lymphocytes into thymus,lymph nodes and spleens,showing that the cellularities of these organs increased although the cellularities tended to vary depending on the donor.The amounts of human T cells(HLA-ABC^+/CD3^+)increased greatly in thymus(14.2 folds),spleen(4.16 folds)and lymph nodes(40.18 folds)after rhPRL injections.The amounts of human B cells(HLA-ABC^+/CD19^+)also increased greatly in lymph nodes(42.5 folds)and spleen(5.78 folds).The lymph node cells from the rhPRL-treated huPBL-SCID mice were more sensitive to PHA stimulation([~3H]thymidine incorporation).The supernatant of PHA-stimulated PBL from rhPRL-treated huPBL/SCID chimerism contained more cytokines (IFN-γ and IL-2).The natural cytotoxicity against human sensitive target cells,K562 cells,from spleen and bone marrow of hPBL/SCID chimerism was significantly enhanced by rhPRL administration.The lymph node cells were stimulated with LPS in vitro for 3 days and the lymphocytes from the rhPRL-treated huPBL-SCID mice were more sensitive to mitogen stimulation.Both serum total IgG level and IgM level of rhPRL-treated huPBL/SCID chimerism were increased,and even without DT-rechallenge the base line of DT-specific IgG was elevated after rhPRL treatment in huPBL-SCID mice.Thus,rhPRL stimulation promotes reconstitution of human immune system in huPBL-SCID mice.Cellular & Molecular Immunology.2004;1(2):129-136.展开更多
Introduction:Nail psoriasis is a type of psoriasis involving nail lesions characterized by pitting,onycholysis,longitudinal ridges,and subungual hyperkeratosis.We herein describe a 9-year-old girl with nail psoriasis ...Introduction:Nail psoriasis is a type of psoriasis involving nail lesions characterized by pitting,onycholysis,longitudinal ridges,and subungual hyperkeratosis.We herein describe a 9-year-old girl with nail psoriasis who presented with nail crumbling and was treated with topical cream containing 45μg/g mouse monoclonal antibody to human interleukin-8.Case presentation:A 9-year-old Chinese girl presented with a 6-month history of a rough,thickened fingernail and toenails.Nail plate crumbling,onycholysis,and fissured periungual folds were observed under dermoscopy and ultraviolet dermoscopy.The nails were soaked in warm water,then topical wrapped with Abcream cream overnight.After about 4 months of treatment,the nails significantly improved by both dermoscopy and ultraviolet-dermoscopy evaluattion.Discussion:Due to the different wavelengths of light emitted by polarized light dermatoscope and ultraviolet-dermatoscope,the characteristics of observation will be different.Abcream acts by antagonizing human interleukin-8,inhibiting leukocyte chemotaxis and neovascularization,and regulating the abnormal proliferation and differentiation of keratinocytes.Conclusion:Ultraviolet-dermoscopy is pivotal in evaluating the severity and potency of nail psoriasis.And Abcream can be regarded as a new drug for the treatment of nail psoriasis in children.展开更多
Humanized immune system(HIS)mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions.Although variations are found between models,most HIS mice sho...Humanized immune system(HIS)mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions.Although variations are found between models,most HIS mice show robust human T cell responses.However,there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies,primarily due to defects in terminal B cell differentiation,antibody affinity maturation,and development of primary follicles and germinal centers.In this review,we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice,and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells(FDCs)to facilitate the development of secondary follicles.展开更多
基金supported by the followed funds:National Science and Technology Major Project(2017ZX10304402-001-006,2017ZX10304402-001-012,2016YFD0500208)Shanghai Science and Technology Commission“R&D public service platform and institutional capacity improvement project”(21DZ2291300)+1 种基金Shanghai scientific research projects(19140905300)Shanghai Public Health Clinical Center projects(KY-GW-2019-11,KY-GW-2019-19,and KY-GW-2021-39)。
文摘Background:There are remarkable genetic differences between animal major histocompatibility complex(MHC)systems and the human leukocyte antigen(HLA)system.HLA transgenic humanized mouse model systems offer a much better method to study the HLA-A-related principal mechanisms for vaccine development and HLA-Arestricted responses against infection in human.Methods:A recombinant gene encoding the chimeric HLA-A30 monochain was constructed.This HHD molecule contains the following:α1-α2 domains of HLA-A30,α3 and cytoplasmic domains of H-2D~b,linked at its N-terminus to the C-terminus of humanβ2m by a 15-amino-acid peptide linker.The recombinant gene encoding the chimeric HLA-A30 monochain cassette was introduced into bacterial artificial chromosome(BAC)CH502-67J3 containing the HLA-A01 gene locus by Red-mediated homologous recombination.Modified BAC CH502-67J3 was microinjected into the pronuclei of wild-type mouse oocytes.This humanized mouse model was further used to assess the immune responses against influenza A virus(H1N1)pdm09 clinically isolated from human patients.Immune cell population,cytokine production,and histopathology in the lung were analyzed.Results:We describe a novel humanβ2m-HLA-A30(α1α2)-H-2D~b(α3 transmembrane cytoplasmic)(HHD)monochain transgenic mouse strain,which contains the intact HLA-A01 gene locus including 49 kb 5’-UTR and 74 kb 3’-UTR of HLA-A01*01.Five transgenic lines integrated into the large genomic region of HLA-A gene locus were obtained,and the robust expression of exogenous transgene was detected in various tissues from A30-18#and A30-19#lines encompassing the intact flanking sequences.Flow cytometry revealed that the introduction of a large genomic region in HLA-A gene locus can influence the immune cell constitution in humanized mice.Pdm09 infection caused a similar immune response among HLA-A30 Tg humanized mice and wild-type mice,and induced the rapid increase of cytokines,including IFN-γ,TNF-α,and IL-6,in both HLA-A30 humanized Tg mice and wild-type mice.The expression of HLA-A30 transgene was dramatically promoted in tissues from A30-9#line at 3 days post-infection(dpi).Conclusions:We established a promising preclinical research animal model of HLA-A30 Tg humanized mouse,which could accelerate the identification of novel HLA-A30-restricted epitopes and vaccine development,and support the study of HLA-A-restricted responses against infection in humans.
基金National Natural Science Foundation of China,Grant/Award Numbers:82130003,81970158,82000180Zhejiang Provincial Key R&D Projects of Department of Science and Technology,Grant/Award Number:2021C03010Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004。
文摘Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast cancers.However,approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.Methods:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints.Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized mice.The human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and cytokines.To fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 days.Then,human T cells were processed for TCRβ-chain(TRB)sequencing analysis.After the repertoires had been constructed,features such as the fraction,diversity,and immune signature were investigated.Results:The results demonstrated an increase in diversity and clonality of T cells after treatment.The preferential usage and features of TRBV,TRBJ,and the V–J combination were also changed.The stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 expansion.Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.Conclusions:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools.Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.It therefore has the potential to greatly benefit cancer treatment.
文摘Background:Most mutations in the COL6A3 gene lead to collagen VI-related myopathies.This is due to a reduced expression or mislocalization of the COL6A3 protein.Therefore,studying the consequence of knocking out the Col6a3 gene in mouse models is relevant,but the Col6a3 mouse models reported so far do not entirely abolish COL6A3 protein expression.Methods:Here,we present the development,validation and preliminary phenotypic characterization of a novel CRISPR-based knockout mouse model targeting Col6a3 exon 3(Col6a3^(d3/d3)).Results:In this mouse model,Col6a3 mRNA is still expressed at a similar level to wild-type littermates,although the expected protein is undetectable by mass spectrometry.Histological analysis of Col6a3^(d3/d3)quadriceps revealed an abnormally high frequency of muscle cells with internally nucleated muscle cells,consistent with a myopathy phenotype.Interestingly,Col6a3^(d3/d3)mice are smaller in size,with their fat,muscle,and bone kept proportional compared to wild-type littermates.Conclusions:In summary,we performed the validation and preliminary phenotypic characterization of a novel Col6a3 knockout mouse model that could be further characterized and used to study COL6A3 biology and model collagen VI-associated diseases.
基金Binational Science Foundation(BSF)grant number 2015077German Israeli Science Foundation(GIF)grant I-63-410.20-2017,Israeli Science Foundation(ISF)grant 1085/18,and Core Fund Form Tel-Aviv University.
文摘The intestinal microbiome has emerged as an important component involved in various diseases.Therefore,the interest in understanding the factors shaping its composition is growing.The gut microbiome,often defined as a complex trait,contains diverse components and its properties are determined by a combination of external and internal effects.Although much effort has been invested so far,it is still difficult to evaluate the extent to which human genetics shape the composition of the gut microbiota.However,in mouse studies,where the environmental factors are better controlled,the effect of the genetic background was significant.The purpose of this paper is to provide a current assessment of the role of human host genetics in shaping the gut microbiome composition.Despite the inconsistency of the reported results,it can be estimated that the genetic factor affects a portion of the microbiome.However,this effect is currently lower than the initial estimates,and it is difficult to separate the genetic influence from the environmental effect.Additionally,despite the differences between the microbial composition of humans and mice,results from mouse models can strengthen our knowledge of host genetics underlying the human gut microbial variation.
文摘Objective To investigate the influence of m4-1BBL on anti-tumor effects induced by truncated human prostate specific membrane antigen ( tPSMA ) gene in mice. Methods A eukaryotic expression plasmid encoding tPSMA and m4-1BBL ( pDC316-tPSMA-IRES m4-1BBL) ,pDC316-tPSMA and pDC316 were constructed.
文摘Proper medical treatment of a stroke victim relies on accurate and rapid differentiation between ischemic and hemorrhagic stroke,which in current practice is performed by computerized tomography（CT） or magnetic resonance imaging（MRI） scans.A panel of micro RNAs could be an extremely useful clinical tool for distinguishing between hemorrhagic and ischemic stroke.This review has shown that blood miRNA profile can distinguish hemorrhagic from ischemic stroke in patients and in experimental animal models.It also seems likely they can differentiate between intracerebral and subarachnoid hemorrhage stroke.The miRNA profile in cerebrospinal fluid could be a useful diagnostic tool for subarachnoid hemorrhagic stroke.Decreased or increased miRNA levels may be needed either as prevention or treatment of stroke.Administration in vivo of miR-130 a inhibitor or miRNA mimic（miR-367,miR-223） in an intracerebral hemorrhage animal model improved neurological outcomes.
基金Supported by CLUSTER-Yoshizato Project and the National Hospital Organization Nagasaki Medical Center
文摘AIM:To establish an animal model with human hepatocyte-repopulated liver for the study of liver cancer metastasis.METHODS:Cell transplantation into mouse livers was conducted using alpha-fetoprotein(AFP)-producing hu-man gastric cancer cells(h-GCCs) and h-hepatocytes as donor cells in a transgenic mouse line expressing urokinase-type plasminogen activator(uPA) driven by the albumin enhancer/promoter crossed with a severe combined immunodeficient(SCID) mouse line(uPA/SCID mice).Host mice were divided into two groups(A and B).Group A mice were transplanted with h-GCCs alone,and group B mice were transplanted with h-GCCs and h-hepatocytes together.The replacement index(RI),which is the ratio of transplanted h-GCCs and h-hepatocytes that occupy the examined area of a histological section,was estimated by measuring h-AFP and h-albumin concentrations in sera,respectively,as well as by immunohistochemical analyses of h-AFP and human cytokeratin 18 in histological sections.RESULTS:The h-GCCs successfully engrafted,repopulated,and colonized the livers of mice in group A(RI = 22.0% ± 2.6%).These mice had moderately differentiated adenocarcinomatous lesions with disrupted glandular structures,which is a characteristics feature of gastric cancers.The serum h-AFP level reached 211.0 ± 142.2 g/mL(range,7.1-324.2 g/mL).In group B mice,the h-GCCs and h-hepatocytes independently engrafted,repopulated the host liver,and developed colonies(RI = 12.0% ± 6.8% and 66.0% ± 12.3%,respectively).h-GCC colonies also showed typical adenocarcinomatous glandular structures around the h-hepatocyte-colonies.These mice survived for the full 56 day-study and did not exhibit any metastasis of h-GCCs in the extrahepatic regions during the observational period.The mice with an h-hepatocyte-repopulated liver possessed metastasized h-GCCs and therefore could be a useful humanized liver animal model for studying liver cancer metastasis in vivo.CONCLUSION:A novel animal model of human liver cancer metastasis was established using the uPA/SCID mouse line.This model could be useful for in vivo testing of anti-cancer drugs and for studying the mechanisms of human liver cancer metastasis.
基金supported the Natural Science Foundation of Jilin Province(YDZJ202201ZYTS101).
文摘In a recent study,Yong-Guang Yang and colleagues developed a severely immunodeficient pig model that supports long-term engraftment and multilineage differentiation of human hematopoietic stem/progenitor cells(HSPCs).1 This breakthrough addresses key limitations of current humanized mouse models,including their small size and limited lifespan,and offers a promising platform for the large-scale production of human immune cells,potentially functioning as an in vivo bioreactor.
基金This work was supported by Grants-in-aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology(MEXT)of Japan(22220007,26221005 and 15K09783)the Project for Development of Innovative Research on Cancer Therapeutics(P-DIRECT)and the Project for Cancer Research And Therapeutic Evolution(P-CREATE)from Japan Agency for Medical Research and Development(AMED)+2 种基金a grant from Tokyo Biochemical Research Foundationa Keio University Grant-in-Aid for Encouragement of Young Medical Scientistsa Grant-in-Aid from the Keio Medical Association.
文摘Immunodeficient mice engrafted with human peripheral blood cells are promising tools for in vivo analysis of human patient individual immune responses.However,when human peripheral blood mononuclear cells(PBMCs)are transferred into NOG(NOD/Shi-scid,IL-2rg null)mice,severe graft versus host disease(GVHD)hinders long term detailed analysis.Administration of human PBMCs into newly developed murine MHC class I-and class II-deficient NOG(NOG-dKO;NOG-Iab,B2m-double-knockout)mice showed sufficient engraftment of human immune cells with little sign of GVHD.Immunization with influenza vaccine resulted in an increase in influenza-specific human IgG Ab,indicating induction of antigen-specific B cells in the NOG-dKO mice.Immunization with human dendritic cells pulsed with HLA-A2 restricted cytomegalovirus peptide induced specific cytotoxic T cells,indicating the induction of antigen-specific T cells in the NOG-dKO mice.Adoptive cell therapies(ACTs)using melanoma antigen recognized by T cells(MART-1)-specific TCR-transduced activated T cells showed strong tumor growth inhibition in NOG-dKO mice without any sign of GVHD accompanied by preferential expansion of the transferred MART-1-specific T cells.ACTs using cultured human melanoma infiltrating T cells also showed anti-tumor effects against autologous melanoma cells in NOG-dKO mice,in which changes in human cancer phenotypes by immune intervention,such as increased CD271 expression,could be evaluated.Therefore,NOG-dKO mice are useful tools for more detailed analysis of both the induction and effector phases of T-cell and B-cell responses for a longer period than regular NOG mice.
文摘Small animal models with functional human lymphohematopoietic systems are highly valuable for the study of human immune function under physiological and pathological conditions. Over the last two decades, numerous efforts have been devoted towards the development of such humanized mouse models. This review is focused on human lymphohematopoietic reconstitution and immune function in humanized mice by cotransplantation of human fetal thymic tissue and CD34＋ cells. The potential use of these humanized mice in translational biomedical research is also discussed.
基金supported by 0utstanding Young Scientist Award and Key Project by Natural Science Foundation of China(#30125038,#30230340)Key Basic Science Program by Ministry of Science and Technology of China(#2001CB510009)Foundation of Chinese Academy of Science(#KSCX2-2-08).
文摘Recombinant human prolactin(rhPRL)was administered to huPBL-SCID mice to determine its effects on human immunologic reconstitution and function.The huPBL-SCID mice were given 10 μg i.p.injection of rhPRL every other day for a total of 10 injections after huPBL were transfered.The results demonstrated that rhPRL improved the engraftment of lymphocytes into thymus,lymph nodes and spleens,showing that the cellularities of these organs increased although the cellularities tended to vary depending on the donor.The amounts of human T cells(HLA-ABC^+/CD3^+)increased greatly in thymus(14.2 folds),spleen(4.16 folds)and lymph nodes(40.18 folds)after rhPRL injections.The amounts of human B cells(HLA-ABC^+/CD19^+)also increased greatly in lymph nodes(42.5 folds)and spleen(5.78 folds).The lymph node cells from the rhPRL-treated huPBL-SCID mice were more sensitive to PHA stimulation([~3H]thymidine incorporation).The supernatant of PHA-stimulated PBL from rhPRL-treated huPBL/SCID chimerism contained more cytokines (IFN-γ and IL-2).The natural cytotoxicity against human sensitive target cells,K562 cells,from spleen and bone marrow of hPBL/SCID chimerism was significantly enhanced by rhPRL administration.The lymph node cells were stimulated with LPS in vitro for 3 days and the lymphocytes from the rhPRL-treated huPBL-SCID mice were more sensitive to mitogen stimulation.Both serum total IgG level and IgM level of rhPRL-treated huPBL/SCID chimerism were increased,and even without DT-rechallenge the base line of DT-specific IgG was elevated after rhPRL treatment in huPBL-SCID mice.Thus,rhPRL stimulation promotes reconstitution of human immune system in huPBL-SCID mice.Cellular & Molecular Immunology.2004;1(2):129-136.
基金This research was supported by the Project for Disciplines of Excellence(No.ZYJC18033)the HX-Academician Project(No.HXYS19003)of West China Hospital,Sichuan University China.
文摘Introduction:Nail psoriasis is a type of psoriasis involving nail lesions characterized by pitting,onycholysis,longitudinal ridges,and subungual hyperkeratosis.We herein describe a 9-year-old girl with nail psoriasis who presented with nail crumbling and was treated with topical cream containing 45μg/g mouse monoclonal antibody to human interleukin-8.Case presentation:A 9-year-old Chinese girl presented with a 6-month history of a rough,thickened fingernail and toenails.Nail plate crumbling,onycholysis,and fissured periungual folds were observed under dermoscopy and ultraviolet dermoscopy.The nails were soaked in warm water,then topical wrapped with Abcream cream overnight.After about 4 months of treatment,the nails significantly improved by both dermoscopy and ultraviolet-dermoscopy evaluattion.Discussion:Due to the different wavelengths of light emitted by polarized light dermatoscope and ultraviolet-dermatoscope,the characteristics of observation will be different.Abcream acts by antagonizing human interleukin-8,inhibiting leukocyte chemotaxis and neovascularization,and regulating the abnormal proliferation and differentiation of keratinocytes.Conclusion:Ultraviolet-dermoscopy is pivotal in evaluating the severity and potency of nail psoriasis.And Abcream can be regarded as a new drug for the treatment of nail psoriasis in children.
基金supported by the National Key Research and Development Program of China(2021YFA1100700)the National Natural Science Foundation of China(81941008)+3 种基金the Natural Science Foundation of Jilin Province,China(20200201191JC)the Department of Human Resource and Social Security of Jilin Province(2022DJ02)the Science Development of Jilin Province,China(20230505029ZP)the Bethune Medical Department of Jilin University(2022JBGS01)。
文摘Humanized immune system(HIS)mice have been developed and used as a small surrogate model to study human immune function under normal or disease conditions.Although variations are found between models,most HIS mice show robust human T cell responses.However,there has been unsuccessful in constructing HIS mice that produce high-affinity human antibodies,primarily due to defects in terminal B cell differentiation,antibody affinity maturation,and development of primary follicles and germinal centers.In this review,we elaborate on the current knowledge about and previous attempts to improve human B cell development in HIS mice,and propose a potential strategy for constructing HIS mice with improved humoral immunity by transplantation of human follicular dendritic cells(FDCs)to facilitate the development of secondary follicles.
