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  • 1
    Publication Date: 2012-02-01
    Description: In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 2
    Publication Date: 1998-11-13
    Description: Self tolerance is acquired by the developing immune system. As reported here, particular properties of the neonatal tissue contribute to this process. Neonatal skin, but not adult skin, was accessible for naive CD8 T cells. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a skin-expressed major histocompatibility complex class I antigen only during a neonatal period but not during adulthood. Blockade of T cell migration neonatally prevented tolerance induction. Thus, T cell trafficking through nonlymphoid tissues in the neonate is crucial for the establishment of self tolerance to sessile, skin-expressed antigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alferink, J -- Tafuri, A -- Vestweber, D -- Hallmann, R -- Hammerling, G J -- Arnold, B -- New York, N.Y. -- Science. 1998 Nov 13;282(5392):1338-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tumor Immunology Program, German Cancer Research Center, 69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9812902" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Antigen Presentation ; Bone Marrow Transplantation ; CD8-Positive T-Lymphocytes/*immunology ; Cell Movement ; Graft Rejection ; H-2 Antigens/*immunology ; Keratinocytes/immunology ; Mice ; Mice, Transgenic ; Neoplasm Transplantation ; Neoplasms, Experimental/immunology ; Self Tolerance/*immunology ; Skin/*immunology ; Skin Transplantation ; T-Lymphocytes/*immunology ; Thymus Gland/immunology ; Transplantation Chimera
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2008-04-18
    Description: The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamzah, Juliana -- Jugold, Manfred -- Kiessling, Fabian -- Rigby, Paul -- Manzur, Mitali -- Marti, Hugo H -- Rabie, Tamer -- Kaden, Sylvia -- Grone, Hermann-Josef -- Hammerling, Gunter J -- Arnold, Bernd -- Ganss, Ruth -- England -- Nature. 2008 May 15;453(7193):410-4. doi: 10.1038/nature06868. Epub 2008 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, Western Australia 6000, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18418378" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capillary Permeability ; Cell Hypoxia/physiology ; Female ; Male ; Mice ; Neovascularization, Pathologic/*prevention & control ; Oxygen/metabolism ; Pancreatic Neoplasms/*blood supply/genetics/*immunology/metabolism ; RGS Proteins/*deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 1993-08-06
    Description: Major histocompatibility complex (MHC) class I molecules present peptides derived from nuclear and cytosolic proteins to CD8+ T cells. These peptides are translocated into the lumen of the endoplasmic reticulum (ER) to associate with class I molecules. Two MHC-encoded putative transporter proteins, TAP1 and TAP2, are required for efficient assembly of class I molecules and presentation of endogenous peptides. Expression of TAP1 and TAP2 in a mutant cell line resulted in the delivery of an 11-amino acid oligomer model peptide to the ER. Peptide translocation depended on the sequence of the peptide, was adenosine triphosphate (ATP)-dependent, required ATP hydrolysis, and was inhibited in a concentration-dependent manner.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neefjes, J J -- Momburg, F -- Hammerling, G J -- New York, N.Y. -- Science. 1993 Aug 6;261(5122):769-71.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Netherlands Cancer Institute, Amsterdam.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8342042" target="_blank"〉PubMed〈/a〉
    Keywords: *ATP-Binding Cassette Transporters ; Adenosine Triphosphate/*metabolism ; Amino Acid Sequence ; Animals ; Biological Transport ; Carrier Proteins/*metabolism ; Cell Line ; Cell Membrane Permeability ; Endoplasmic Reticulum/metabolism ; Glycosylation ; Histocompatibility Antigens Class II/*metabolism ; Molecular Sequence Data ; Oligopeptides/*metabolism ; Rats ; T-Lymphocytes, Cytotoxic/*metabolism ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 1995-10-27
    Description: During pregnancy a semiallogeneic fetus survives despite the presence of maternal T cells specific for paternally inherited histocompatibility antigens. A mouse transgenic for a T cell receptor recognizing the major histocompatibility (MHC) antigen H-2Kb was used to follow the fate of T cells reactive to paternal alloantigens. In contrast to syngeneic and third-party allogeneic pregnancies, mice bearing a Kb-positive conceptus had reduced numbers of Kb-reactive T cells and accepted Kb-positive tumor grafts. T cell phenotype and responsiveness were restored after delivery. Thus, during pregnancy maternal T cells acquire a transient state of tolerance specific for paternal alloantigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tafuri, A -- Alferink, J -- Moller, P -- Hammerling, G J -- Arnold, B -- New York, N.Y. -- Science. 1995 Oct 27;270(5236):630-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tumor Immunology Program, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7570020" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Fathers ; Female ; Fetus/*immunology ; Graft Rejection ; H-2 Antigens/*immunology ; *Immune Tolerance ; Male ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Mice, Transgenic ; Neoplasm Transplantation ; Phenotype ; Placenta/immunology ; Pregnancy ; Pregnancy, Animal/*immunology ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 1995-11-24
    Description: The assembly and transport of major histocompatibility complex (MHC) class II molecules require interaction with the invariant chain. A fragment of the invariant chain, CLIP, occupies the peptide-binding groove of the class II molecule. At endosomal pH, the binding of CLIP to human MHC class II HLA-DR molecules was counteracted by its amino-terminal segment (residues 81 to 89), which facilitated rapid release. The CLIP (81-89) fragment also catalyzed the release of CLIP(90-105) and a subset of other self-peptides, probably by transient interaction with an effector site outside the groove. Thus, CLIP may facilitate peptide loading through an allosteric release mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kropshofer, H -- Vogt, A B -- Stern, L J -- Hammerling, G J -- New York, N.Y. -- Science. 1995 Nov 24;270(5240):1357-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Immunology, German Cancer Research Center, Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/7481823" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Antigens, Differentiation, B-Lymphocyte/chemistry/*metabolism ; Binding Sites ; Cell Line ; HLA-DR3 Antigen/*metabolism ; Histocompatibility Antigens Class II/chemistry/*metabolism ; Humans ; Hydrogen-Ion Concentration ; Lysine/chemistry ; Molecular Sequence Data ; Peptide Fragments/metabolism ; Proline/chemistry ; Protein Conformation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 1994-02-04
    Description: Antigen-specific immunosuppression requires an understanding of the parameters that control peripheral T cell tolerance. A liver-specific inducible promoter was used to drive the expression of the major histocompatibility complex antigen Kb in transgenic mice. Minute amounts of Kb, expressed exclusively on hepatocytes, induced tolerance by partial down-regulation of the T cell receptor (TCR) on the self-reactive CD8+ cells. Contact of these tolerant T cells with high concentrations of Kb after induction led to complete down-regulation of TCR. Thus, tolerant T cells are susceptible to further tolerogenic signals and reach different levels of tolerance depending on antigen dose.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ferber, I -- Schonrich, G -- Schenkel, J -- Mellor, A L -- Hammerling, G J -- Arnold, B -- New York, N.Y. -- Science. 1994 Feb 4;263(5147):674-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Somatic Genetics, Deutsches Krebsforschungszentrum, Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/8303275" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Ly/analysis ; C-Reactive Protein/genetics ; Dose-Response Relationship, Immunologic ; Down-Regulation ; H-2 Antigens/genetics/*immunology ; Immune Tolerance/*immunology ; Lipopolysaccharides/immunology ; Liver/*immunology ; Mice ; Mice, Inbred CBA ; Mice, Transgenic ; Promoter Regions, Genetic ; Receptors, Antigen, T-Cell/genetics/immunology ; T-Lymphocytes/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    International journal of immunogenetics 16 (1989), S. 0 
    ISSN: 1744-313X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: We have used the 3-Methylcholanthrene induced T-10 fibrosarcoma tumour cell system (H-2b xH-2k)F1 to elucidate the possible correlation between metastatic potential, expression of individual H-2 antigens and susceptibility to NK cells.Transfection of the non-metastatic and NK sensitive IC9 cells (Db+, Dk-, Kb-, Kk-) with the H-2Dk gene, altered the metastatic phenotype of the parental cells, yet had no effect on the susceptibility of these tumour cells to lysis by NK and did not elicit a specific CTL response in syngeneic hosts. Variants of the metastatic and NK resistant IE7 clone (Db+, Dk+, Kb-, Kk-), lacking H-2Dk, were selected by treatment with monoclonal anti H-2Dk antibodies and complement. These variants were sensitive to NK and poorly or non metastatic. Retransfection of ‘Dk′loss’ variants with the H-2Dk gene, resulted in the isolation of several clones expressing a wide range of metastatic phenotypes but maintained sensitivity to NK. These results indicate that the H-2D region of the MHC and or closely linked genes may be involved in the complex interrelationship between target susceptibility to NK and metastasis.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    International journal of immunogenetics 13 (1986), S. 0 
    ISSN: 1744-313X
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Biology , Medicine
    Notes: Approximately 50% of fibrosarcomas induced with methylcholanthrene A were found to be defective in H-2 expression. In tumours which lack H-2K antigens, H-2 gene transfection was used to restore H-2K expression. The de novo expression of H-2K reduced tumorigenicity and abolished the formation of metastases in syngeneic mice. Expression of H-2K seems to render the tumour cells immunogenic and leads to effective recognition of the tumour cells by the host immune system.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Palo Alto, Calif. : Annual Reviews
    Annual Review of Immunology 9 (1991), S. 297-322 
    ISSN: 0732-0582
    Source: Annual Reviews Electronic Back Volume Collection 1932-2001ff
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
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