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*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
To determine how self-tolerance can alter the ability of the immune system to respond against tumor-associated Ags that are also expressed by normal tissue, we designed experiments in which the same protein was expressed both as a tumor Ag and as a transgene product. Unlike conventional BALB/c mice that rejected renal carcinoma cells transfected with the influenza virus hemagglutinin (Renca-HA), transgenic mice that are tolerant of HA due to its expression as a self-Ag on pancreatic islet ß cells, (Ins-HA mice) supported progressive growth of these tumor cells. However, when Ins-HA mice were immunized with a recombinant strain of vaccinia virus expressing the dominant H-2Kd peptide epitope of HA before receiving Renca-HA cells, they too were able to reject the tumor cells. Rejection of Renca-HA cells by immunized Ins-HA mice was found to be associated with the generation of CTL having much lower avidity for target cells presenting the KdHA epitope than CTL from immunized conventional BALB/c mice. Significantly, we show that self-tolerance to the HA Ag is quantitative rather then absolute, and that vaccination of Ins-HA mice can activate low avidity KdHA-specific CD8+ T cells that are able to reject tumor cells expressing high levels of HA, yet these mice remain tolerant of pancreatic islet ß cells expressing HA.
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T. A. Colella, T. N.J. Bullock, L. B. Russell, D. W. Mullins, W. W. Overwijk, C. J. Luckey, R. A. Pierce, N. P. Restifo, and V. H. Engelhard Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy J. Exp. Med., April 3, 2000; 191(7): 1221 - 1232. [Abstract] [Full Text] [PDF]
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B. Ludewig, A. F. Ochsenbein, B. Odermatt, D. Paulin, H. Hengartner, and R. M. Zinkernagel Immunotherapy with Dendritic Cells Directed against Tumor Antigens Shared with Normal Host Cells Results in Severe Autoimmune Disease J. Exp. Med., March 6, 2000; 191(5): 795 - 804. [Abstract] [Full Text] [PDF]
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T. N. J. Bullock, T. A. Colella, and V. H. Engelhard The Density of Peptides Displayed by Dendritic Cells Affects Immune Responses to Human Tyrosinase and gp100 in HLA-A2 Transgenic Mice J. Immunol., March 1, 2000; 164(5): 2354 - 2361. [Abstract] [Full Text] [PDF]
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J. Hernandez, P. P. Lee, M. M. Davis, and L. A. Sherman The Use of HLA A2.1/p53 Peptide Tetramers to Visualize the Impact of Self Tolerance on the TCR Repertoire J. Immunol., January 15, 2000; 164(2): 596 - 602. [Abstract] [Full Text] [PDF]
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C. T. Nugent, D. J. Morgan, J. A. Biggs, A. Ko, I. M. Pilip, E. G. Pamer, and L. A. Sherman Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas J. Immunol., January 1, 2000; 164(1): 191 - 200. [Abstract] [Full Text] [PDF]
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J. Shimizu, S. Yamazaki, and S. Sakaguchi Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity J. Immunol., November 15, 1999; 163(10): 5211 - 5218. [Abstract] [Full Text] [PDF]
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H. T. C. Kreuwel, D. J. Morgan, T. Krahl, A. Ko, N. Sarvetnick, and L. A. Sherman Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8+ T Cell-Mediated Insulin-Dependent Diabetes Mellitus J. Immunol., October 15, 1999; 163(8): 4335 - 4341. [Abstract] [Full Text] [PDF]
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E. M. Sotomayor, I. Borrello, E. Tubb, J. P. Allison, and H. I. Levitsky In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance PNAS, September 28, 1999; 96(20): 11476 - 11481. [Abstract] [Full Text] [PDF]
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A. van Elsas, A. A. Hurwitz, and J. P. Allison Combination Immunotherapy of B16 Melanoma Using Anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation J. Exp. Med., August 2, 1999; 190(3): 355 - 366. [Abstract] [Full Text] [PDF]
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J. J. Molldrem, P. P. Lee, C. Wang, R. E. Champlin, and M. M. Davis A PR1-Human Leukocyte Antigen-A2 Tetramer Can Be Used to Isolate Low-Frequency Cytotoxic T Lymphocytes from Healthy Donors That Selectively Lyse Chronic Myelogenous Leukemia Cancer Res., June 1, 1999; 59(11): 2675 - 2681. [Abstract] [Full Text] [PDF]
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D. J. Morgan, C. Kurts, H. T. C. Kreuwel, K. L. Holst, W. R. Heath, and L. A. Sherman Ontogeny of T cell tolerance to peripherally expressed antigens PNAS, March 30, 1999; 96(7): 3854 - 3858. [Abstract] [Full Text] [PDF]
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J. Lustgarten, J. Marks, and L. A. Sherman Redirecting Effector T Cells Through Their IL-2 Receptors J. Immunol., January 1, 1999; 162(1): 359 - 365. [Abstract] [Full Text] [PDF]
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R. Romieu, M. Baratin, M. Kayibanda, V. Lacabanne, M. Ziol, J.-G. Guillet, and M. Viguier Cutting Edge: Passive But Not Active CD8+ T Cell-Based Immunotherapy Interferes with Liver Tumor Progression in a Transgenic Mouse Model J. Immunol., November 15, 1998; 161(10): 5133 - 5137. [Abstract] [Full Text] [PDF]
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R. M. Tempero, M. L. VanLith, K. Morikane, G. J. Rowse, S. J. Gendler, and M. A. Hollingsworth CD4+ Lymphocytes Provide MUC1-Specific Tumor Immunity In Vivo That Is Undetectable In Vitro and Is Absent in MUC1 Transgenic Mice J. Immunol., November 15, 1998; 161(10): 5500 - 5506. [Abstract] [Full Text] [PDF]
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B. Minev, J. Hipp, H. Firat, J. D. Schmidt, P. Langlade-Demoyen, and M. Zanetti Cytotoxic T cell immunity against telomerase reverse transcriptase in humans PNAS, April 25, 2000; 97(9): 4796 - 4801. [Abstract] [Full Text] [PDF]
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