The Activation Status of Neuroantigen-specific T Cells in the Target Organ Determines the Clinical Outcome of Autoimmune Encephalomyelitis

The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)–specific T cells in Lewis rats, whereas transfer of S100β- or myelin oligodendrocyte glycoprotein (MOG)–specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein+ T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

[1]  T. Iwanaga,et al.  An immunocytochemical study on the localization of S-100 protein in the retina of rats , 2004, Cell and Tissue Research.

[2]  U. Welsch,et al.  Ultrastructural changes in lactating tissue related to the suppression of milk secretion by concanavalin A , 2004, Cell and Tissue Research.

[3]  H. Wiśniewski,et al.  The distribution of Ia antigen in the lesions of rat acute experimental allergic encephalomyelitis , 2004, Acta Neuropathologica.

[4]  R. Ransohoff,et al.  Chemokine Upregulation Follows Cytokine Expression in Chronic Relapsing Experimental Autoimmune Encephalomyelitis , 2003, Scandinavian journal of immunology.

[5]  H. Weiner,et al.  Targeting monocyte recruitment in CNS autoimmune disease. , 2002, Clinical immunology.

[6]  W. Paul,et al.  Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Jan Bauer,et al.  T‐ and B‐cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis , 2001, Glia.

[8]  H. Lassmann,et al.  Migratory activity and functional changes of green fluorescent effector cells before and during experimental autoimmune encephalomyelitis. , 2001, Immunity.

[9]  B. Rollins,et al.  Absence of Monocyte Chemoattractant Protein 1 in Mice Leads to Decreased Local Macrophage Recruitment and Antigen-Specific T Helper Cell Type 1 Immune Response in Experimental Autoimmune Encephalomyelitis , 2001, The Journal of experimental medicine.

[10]  T. Shike,et al.  Animal models. , 2001, Contributions to nephrology.

[11]  D. Wiest,et al.  On the dynamics of TCR:CD3 complex cell surface expression and downmodulation. , 2000, Immunity.

[12]  J. Goverman,et al.  In Situ Tolerance within the Central Nervous System as a Mechanism for Preventing Autoimmunity , 2000, The Journal of experimental medicine.

[13]  H. Lassmann,et al.  Butyrophilin, a Milk Protein, Modulates the Encephalitogenic T Cell Response to Myelin Oligodendrocyte Glycoprotein in Experimental Autoimmune Encephalomyelitis1 , 2000, The Journal of Immunology.

[14]  H. Neumann,et al.  Neuronal FasL Induces Cell Death of Encephalitogenic T Lymphocytes , 2000, Brain pathology.

[15]  L. Adorini,et al.  Regulation of T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes. , 2000, Immunology today.

[16]  S. Youssef,et al.  Prevention of Experimental Autoimmune Encephalomyelitis by MIP-1α and MCP-1 Naked DNA Vaccines , 1999 .

[17]  S. Bromley,et al.  The immunological synapse: a molecular machine controlling T cell activation. , 1999, Science.

[18]  R. Ransohoff Mechanisms of inflammation in MS tissue: adhesion molecules and chemokines , 1999, Journal of Neuroimmunology.

[19]  H. Wekerle,et al.  Gene transfer into CD4+ T lymphocytes: Green fluorescent protein-engineered, encephalitogenic T cells illuminate brain autoimmune responses , 1999, Nature Medicine.

[20]  M. Schwartz,et al.  Innate and adaptive immune responses can be beneficial for CNS repair , 1999, Trends in Neurosciences.

[21]  H. Kinney,et al.  Early developmental changes in the chemoarchitecture of the human inferior olive: a review. , 1999, Journal of neuropathology and experimental neurology.

[22]  E. Benveniste,et al.  Cytokine regulation of CC and CXC chemokine expression by human astrocytes. , 1999, Journal of neurovirology.

[23]  T. Unger,et al.  Expression of autoimmune disease‐related antigens by cells of the immune system , 1998, Journal of neuroscience research.

[24]  N. Van Rooijen,et al.  Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice. , 1998, Journal of immunology.

[25]  H. Lassmann,et al.  Autoimmunity to Myelin Oligodendrocyte Glycoprotein in Rats Mimics the Spectrum of Multiple Sclerosis Pathology , 1998, Brain pathology.

[26]  Jie Zhu,et al.  Astrocytes induce hyporesponses of myelin basic protein-reactive T and B cell function , 1998, Journal of Neuroimmunology.

[27]  B. Stokes,et al.  Selective chemokine mRNA accumulation in the rat spinal cord after contusion injury , 1998, Journal of neuroscience research.

[28]  C. Brosnan,et al.  Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent. , 1998, Journal of immunology.

[29]  H. Neumann,et al.  Neurotrophins inhibit major histocompatibility class II inducibility of microglia: involvement of the p75 neurotrophin receptor. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[30]  C. Brosnan,et al.  Cytokine Induction of MIP-1α and MIP-1β in Human Fetal Microglia , 1998, The Journal of Immunology.

[31]  C. Brosnan,et al.  Cytokine induction of MIP-1 alpha and MIP-1 beta in human fetal microglia. , 1998, Journal of immunology.

[32]  H. Wekerle,et al.  Neuronal Control of the Immune Response in the Central Nervous System: Linking Brain Immunity to Neurodegeneration , 1998, Journal of neuropathology and experimental neurology.

[33]  B. Pessac,et al.  Myelin Basic Protein‐Related Proteins in Mouse Brain and Immune Tissues , 1998, Journal of neurochemistry.

[34]  R. Germain,et al.  Single Cell Analysis Reveals Regulated Hierarchical T Cell Antigen Receptor Signaling Thresholds and Intraclonal Heterogeneity for Individual Cytokine Responses of CD4+ T Cells , 1997, The Journal of experimental medicine.

[35]  H. Lassmann,et al.  The thymus and self-tolerance: co-existence of encephalitogenic S100 beta-specific T cells and their nominal autoantigen in the normal adult rat thymus. , 1997, International immunology.

[36]  H. Lassmann,et al.  Experimental autoimmune encephalomyelitis: the antigen specificity of T lymphocytes determines the topography of lesions in the central and peripheral nervous system. , 1997, Laboratory investigation; a journal of technical methods and pathology.

[37]  E. Benveniste Role of macrophages/microglia in multiple sclerosis and experimental allergic encephalomyelitis , 1997, Journal of Molecular Medicine.

[38]  R. Ransohoff,et al.  Synchronous synthesis of alpha- and beta-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. , 1997, The American journal of pathology.

[39]  H. Lassmann,et al.  Induction of experimental autoimmune encephalomyelitis by CD4+ T cells specific for an astrocyte protein, Sl00ß , 1997 .

[40]  M. Zhao,et al.  Thymic expression of myelin basic protein (MBP). Activation of MBP-specific T cells by thymic cells in the absence of exogenous MBP. , 1996, Journal of immunology.

[41]  R. Ransohoff,et al.  Chemokine monocyte chemoattractant protein-1 is expressed by astrocytes after mechanical injury to the brain. , 1996, Journal of immunology.

[42]  C. Benoist,et al.  Checkpoints in the progression of autoimmune disease: lessons from diabetes models. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[43]  R. Ransohoff,et al.  In situ hybridization analysis of glial fibrillary acidic protein mRNA reveals evidence of biphasic astrocyte activation during acute experimental autoimmune encephalomyelitis. , 1996, The American journal of pathology.

[44]  H. Lassmann,et al.  The N-terminal domain of the myelin oligodendrocyte glycoprotein (MOG) induces acute demyelinating experimental autoimmune encephalomyelitis in the Lewis rat , 1995, Journal of Neuroimmunology.

[45]  R. Strieter,et al.  An important role for the chemokine macrophage inflammatory protein-1 alpha in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. , 1995, Journal of immunology.

[46]  I. Kalvakolanu,et al.  Thymic expression of the golli-myelin basic protein gene in the SJL/J mouse , 1995, Journal of Neuroimmunology.

[47]  R. Hohlfeld,et al.  Multiple sclerosis. Immunomodulatory effects of human astrocytes on T cells. , 1994, Brain : a journal of neurology.

[48]  H. Lassmann,et al.  Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia , 1994, The Journal of experimental medicine.

[49]  J. Goverman,et al.  T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis. , 1994, Science.

[50]  H. Lassmann,et al.  Apoptosis of T lymphocytes in experimental autoimmune encephalomyelitis. Evidence for programmed cell death as a mechanism to control inflammation in the brain. , 1993, The American journal of pathology.

[51]  H. Lassmann,et al.  T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system , 1993, European journal of immunology.

[52]  近藤 和也 An immunohistochemical study of thymic epithelial tumors : the distribution of interdigitating reticulum cells and S-100β-positive small lymphocytes , 1992 .

[53]  M. Pender,et al.  Apoptosis in the nervous system in experimental allergic encephalomyelitis , 1991, Journal of the Neurological Sciences.

[54]  W. Hickey,et al.  T‐lymphocyte entry into the central nervous system , 1991, Journal of neuroscience research.

[55]  B. Uitdehaag,et al.  Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages , 1990, The Journal of experimental medicine.

[56]  C. Brosnan,et al.  Homing to central nervous system vasculature by antigen-specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic, and relapsing experimental allergic encephalomyelitis. , 1990, Laboratory investigation; a journal of technical methods and pathology.

[57]  Miller Ad,et al.  Improved Retroviral Vectors for Gene Transfer and Expression , 1989 .

[58]  A. Miller,et al.  Improved retroviral vectors for gene transfer and expression. , 1989, BioTechniques.

[59]  S. Goff,et al.  A safe packaging line for gene transfer: separating viral genes on two different plasmids , 1988, Journal of virology.

[60]  J. Cohen,et al.  Limiting dilution analysis of the frequency of antigen-reactive lymphocytes isolated from the central nervous system of Lewis rats with experimental allergic encephalomyelitis. , 1987, Cellular immunology.

[61]  H. Lassmann,et al.  Cellular immune reactivity within the CNS , 1986, Trends in Neurosciences.

[62]  N. Miyazawa,et al.  An Immunohistochemical Study of Thymic Epithelial Tumors: I. Epithelial Component , 1986, The American journal of surgical pathology.

[63]  F. Michetti,et al.  Detection by S-100 immunolabelling of interdigitating reticulum cells in human thymomas , 1984, Virchows Archiv. B, Cell pathology including molecular pathology.

[64]  C. Brosnan,et al.  The effects of macrophage depletion on the clinical and pathologic expression of experimental allergic encephalomyelitis. , 1981, Journal of immunology.

[65]  E D Day,et al.  Myelin basic protein. , 1981, Contemporary topics in molecular immunology.

[66]  I. Cohen,et al.  The rapid isolation of clonable antigen‐specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis , 1981, European journal of immunology.

[67]  E. Eylar,et al.  [31] Myelin basic proteins , 1974 .