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  1. Article ; Online: Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis.

    Chae, Wook-Jin / Gibson, Thomas F / Zelterman, Daniel / Hao, Liming / Henegariu, Octavian / Bothwell, Alfred L M

    Proceedings of the National Academy of Sciences of the United States of America

    2010  Volume 107, Issue 12, Page(s) 5540–5544

    Abstract: The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous ... ...

    Abstract The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (Apc(Min/+) mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in Apc(Min/+) mice. CD4 T cells from Apc(Min/+) mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from Apc(Min/+) mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in Apc(Min/+) mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in Apc(Min/+) mice.
    MeSH term(s) Animals ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/pathology ; Cytokines/genetics ; Genes, APC ; Inflammation Mediators/metabolism ; Interleukin-17/deficiency ; Interleukin-17/genetics ; Interleukin-17/physiology ; Intestinal Neoplasms/etiology ; Intestinal Neoplasms/genetics ; Intestinal Neoplasms/immunology ; Intestinal Neoplasms/pathology ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Mutant Strains ; Phenotype ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA, Neoplasm/genetics ; RNA, Neoplasm/metabolism ; Spleen/immunology ; Spleen/pathology ; Thymus Gland/immunology ; Thymus Gland/pathology
    Chemical Substances Cytokines ; Inflammation Mediators ; Interleukin-17 ; RNA, Messenger ; RNA, Neoplasm
    Language English
    Publishing date 2010-03-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0912675107
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  2. Article: Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis

    Chae, Wook-Jin / Gibson, Thomas F / Zelterman, Daniel / Hao, Liming / Henegariu, Octavian / Bothwell, Alfred L.M

    Proceedings of the National Academy of Sciences of the United States of America. 2010 Mar. 23, v. 107, no. 12

    2010  

    Abstract: The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous ... ...

    Abstract The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (ApcMin/⁺ mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in ApcMin/⁺ mice. CD4 T cells from ApcMin/⁺ mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from ApcMin/⁺ mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in ApcMin/⁺ mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in ApcMin/⁺ mice.
    Keywords CD4-positive T-lymphocytes ; atrophy ; carcinogenesis ; colitis ; genes ; interleukin-10 ; interleukin-17 ; intestinal mucosa ; mice ; mutation ; splenomegaly
    Language English
    Dates of publication 2010-0323
    Size p. 5540-5544.
    Publishing place National Academy of Sciences
    Document type Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.0912675107
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  3. Article: Bcl-2 transduction protects human endothelial cell synthetic microvessel grafts from allogeneic T cells in vivo.

    Zheng, Lian / Gibson, Thomas F / Schechner, Jeffrey S / Pober, Jordan S / Bothwell, Alfred L M

    Journal of immunology (Baltimore, Md. : 1950)

    2004  Volume 173, Issue 5, Page(s) 3020–3026

    Abstract: T cell interactions with vascular endothelial cells (EC) are of central importance for immune surveillance of microbes and for pathological processes such as atherosclerosis, allograft rejection, and vasculitis. Animal (especially rodent) models ... ...

    Abstract T cell interactions with vascular endothelial cells (EC) are of central importance for immune surveillance of microbes and for pathological processes such as atherosclerosis, allograft rejection, and vasculitis. Animal (especially rodent) models incompletely predict human immune responses, in particular with regard to the immunological functions of EC, and in vitro models may not accurately reflect in vivo findings. In this study, we describe the development of an immunodeficient SCID/bg murine model combining a transplanted human synthetic microvascular bed with adoptive transfer of human T lymphocytes allogeneic to the cells of the graft that more fully recapitulates T cell responses in natural tissues. Using this model, we demonstrate that transduced Bcl-2 protein in the engrafted EC effectively prevents injury even as it enhances T cell graft infiltration and replication.
    MeSH term(s) Animals ; Blood Vessels ; Endothelial Cells/immunology ; Endothelial Cells/physiology ; Endothelium, Vascular/immunology ; Endothelium, Vascular/physiology ; Humans ; Mice ; Mice, SCID ; Prostheses and Implants ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/immunology ; Proto-Oncogene Proteins c-bcl-2/physiology
    Chemical Substances Proto-Oncogene Proteins c-bcl-2
    Language English
    Publishing date 2004-08-01
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.173.5.3020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Promotion of beta-cell differentiation in pancreatic precursor cells by adult islet cells.

    Chen, Wei / Begum, Salma / Opare-Addo, Lynn / Garyu, Justin / Gibson, Thomas F / Bothwell, Alfred L M / Papaioannou, Virginia E / Herold, Kevan C

    Endocrinology

    2008  Volume 150, Issue 2, Page(s) 570–579

    Abstract: It is thought that differentiation of beta-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify beta-cell differentiation have not been ... ...

    Abstract It is thought that differentiation of beta-cell precursors into mature cells is largely autonomous, but under certain conditions differentiation can be modified by external factors. The factors that modify beta-cell differentiation have not been identified. In this study, we tested whether adult islet cells can affect the differentiation process in mouse and human pancreatic anlage cells. We assessed beta-cell proliferation and differentiation in mouse and human pancreatic anlage cells cocultured with adult islet cells or betaTC3 cells using cellular, molecular, and immunohistochemical methods. Differentiation of murine anlage cells into beta-cells was induced by mature islet cells. It was specific for beta-cells and not a general feature of endodermal derived cells. beta-Cell differentiation required cell-cell contact. The induced cells acquired features of mature beta-cells including increased expression of beta-cell transcription factors and surface expression of receptor for stromal cell-derived factor 1 and glucose transporter-2 (GLUT-2). They secreted insulin in response to glucose and could correct hyperglycemia in vivo when cotransplanted with vascular cells. Human pancreatic anlage cells responded in a similar manner and showed increased expression of pancreatic duodenal homeobox 1 and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A and increased production of proinsulin when cocultured with adult islets. We conclude that mature beta-cells can modify the differentiation of precursor cells and suggest a mechanism whereby changes in differentiation of beta-cells can be affected by other beta-cells.
    MeSH term(s) Adult ; Animals ; Antigens, Surface/physiology ; Cell Communication/physiology ; Cell Differentiation/physiology ; Cells, Cultured ; Coculture Techniques/methods ; Green Fluorescent Proteins/genetics ; Humans ; Insulin-Secreting Cells/physiology ; Islets of Langerhans/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Mice, Transgenic ; Stem Cells/physiology
    Chemical Substances Antigens, Surface ; Green Fluorescent Proteins (147336-22-9)
    Language English
    Publishing date 2008-10-09
    Publishing country United States
    Document type Evaluation Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2008-1009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: An implantable vascularized protein gel construct that supports human fetal hepatoblast survival and infection by hepatitis C virus in mice.

    Harding, Martha J / Lepus, Christin M / Gibson, Thomas F / Shepherd, Benjamin R / Gerber, Scott A / Graham, Morven / Paturzo, Frank X / Rahner, Christoph / Madri, Joseph A / Bothwell, Alfred L M / Lindenbach, Brett D / Pober, Jordan S

    PloS one

    2010  Volume 5, Issue 4, Page(s) e9987

    Abstract: Background: Widely accessible small animal models suitable for the study of hepatitis C virus (HCV) in vivo are lacking, primarily because rodent hepatocytes cannot be productively infected and because human hepatocytes are not easily engrafted in ... ...

    Abstract Background: Widely accessible small animal models suitable for the study of hepatitis C virus (HCV) in vivo are lacking, primarily because rodent hepatocytes cannot be productively infected and because human hepatocytes are not easily engrafted in immunodeficient mice.
    Methodology/principal findings: We report here on a novel approach for human hepatocyte engraftment that involves subcutaneous implantation of primary human fetal hepatoblasts (HFH) within a vascularized rat collagen type I/human fibronectin (rCI/hFN) gel containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVEC) in severe combined immunodeficient X beige (SCID/bg) mice. Maturing hepatic epithelial cells in HFH/Bcl-2-HUVEC co-implants displayed endocytotic activity at the basolateral surface, canalicular microvilli and apical tight junctions between adjacent cells assessed by transmission electron microscopy. Some primary HFH, but not Huh-7.5 hepatoma cells, appeared to differentiate towards a cholangiocyte lineage within the gels, based on histological appearance and cytokeratin 7 (CK7) mRNA and protein expression. Levels of human albumin and hepatic nuclear factor 4alpha (HNF4alpha) mRNA expression in gel implants and plasma human albumin levels in mice engrafted with HFH and Bcl-2-HUVEC were somewhat enhanced by including murine liver-like basement membrane (mLBM) components and/or hepatocyte growth factor (HGF)-HUVEC within the gel matrix. Following ex vivo viral adsorption, both HFH/Bcl-2-HUVEC and Huh-7.5/Bcl-2-HUVEC co-implants sustained HCV Jc1 infection for at least 2 weeks in vivo, based on qRT-PCR and immunoelectron microscopic (IEM) analyses of gel tissue.
    Conclusion/significance: The system described here thus provides the basis for a simple and robust small animal model of HFH engraftment that is applicable to the study of HCV infections in vivo.
    MeSH term(s) Animals ; Cell Survival ; Cell Transplantation/methods ; Coculture Techniques ; Collagen ; Disease Models, Animal ; Endothelial Cells/transplantation ; Endothelial Cells/virology ; Fibronectins ; Gels/chemistry ; Hepacivirus ; Hepatitis C ; Hepatocytes/cytology ; Hepatocytes/transplantation ; Hepatocytes/virology ; Humans ; Mice ; Mice, SCID ; Proto-Oncogene Proteins c-bcl-2/genetics ; Rats ; Transplantation, Heterologous ; Umbilical Veins/cytology
    Chemical Substances Fibronectins ; Gels ; Proto-Oncogene Proteins c-bcl-2 ; Collagen (9007-34-5)
    Language English
    Publishing date 2010-04-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0009987
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  6. Article ; Online: Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac-/-, Balb/c-Rag1-/-gammac-/-, and C.B-17-scid/bg immunodeficient mice.

    Lepus, Christin M / Gibson, Thomas F / Gerber, Scott A / Kawikova, Ivana / Szczepanik, Marian / Hossain, Jaber / Ablamunits, Vitaly / Kirkiles-Smith, Nancy / Herold, Kevan C / Donis, Ruben O / Bothwell, Alfred L / Pober, Jordan S / Harding, Martha J

    Human immunology

    2009  Volume 70, Issue 10, Page(s) 790–802

    Abstract: Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer ...

    Abstract Immunodeficient mice bearing components of a human immune system present a novel approach for studying human immune responses. We investigated the number, phenotype, developmental kinetics, and function of developing human immune cells following transfer of CD34(+) hematopoietic stem cell (HSC) preparations originating from second trimester human fetal liver (HFL), umbilical cord blood (UCB), or granulocyte colony-stimulating factor-mobilized adult blood (G-CSF-AB) delivered via intrahepatic injection into sublethally irradiated neonatal NOD-scid/gammac(-/-), Balb/c-Rag1(-/-)gammac(-/-), and C.B-17-scid/bg mice. HFL and UCB HSC provided the greatest number and breadth of developing cells. NOD-scid/gammac(-/-) and Balb/c-Rag1(-/-)gammac(-/-) harbored human B and dendritic cells as well as human platelets in peripheral blood, whereas NOD-scid/gammac(-/-) mice harbored higher levels of human T cells. NOD-scid/gammac(-/-) mice engrafted with HFL CD34(+) HSC demonstrated human immunological competence evidenced by white pulp expansion and increases in total human immunoglobulin following immunization with T-dependent antigens and delayed-type hypersensitivity-infiltrating leukocytes in response to antigenic challenge. In conclusion, we describe an encouraging base system for studying human hematopoietic lineage development and function utilizing human HFL or UCB HSC-engrafted NOD-scid/gammac(-/-) mice that is well suited for future studies toward the development of a fully competent humanized mouse model.
    MeSH term(s) Animals ; Fetal Blood/immunology ; Granulocyte Colony-Stimulating Factor/immunology ; Granulocyte Colony-Stimulating Factor/metabolism ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Hemocyanins/immunology ; Humans ; Hypersensitivity, Delayed/immunology ; Hypersensitivity, Delayed/pathology ; Immunoglobulins/blood ; Influenza A Virus, H5N1 Subtype/immunology ; Liver/embryology ; Liver/immunology ; Lymph Nodes/cytology ; Lymph Nodes/immunology ; Lymphocyte Subsets/immunology ; Lymphocyte Subsets/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Radiation Dosage ; Spleen/cytology ; Spleen/immunology ; Thymus Gland/cytology ; Thymus Gland/immunology ; Whole-Body Irradiation
    Chemical Substances Immunoglobulins ; Granulocyte Colony-Stimulating Factor (143011-72-7) ; Hemocyanins (9013-72-3) ; keyhole-limpet hemocyanin (FV4Y0JO2CX)
    Language English
    Publishing date 2009-06-12
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 801524-7
    ISSN 1879-1166 ; 0198-8859
    ISSN (online) 1879-1166
    ISSN 0198-8859
    DOI 10.1016/j.humimm.2009.06.005
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