Passive or Active Immunization with Myelin Basic Protein Impairs Neurological Function and Exacerbates Neuropathology after Spinal Cord Injury in Rats

Myelin-reactive T-cells are activated by traumatic spinal cord injury (SCI) in rodents and humans. Despite the historical association of these cells with experimental and clinical neuropathology, recent data suggest a neuroprotective role for myelin-reactive T-cells. Because of the biological and therapeutic implications of these findings, we attempted to reproduce the original neuroprotective vaccine protocols in a model of rat SCI. Specifically, MBP-reactive T-cell function was enhanced in SCI rats via passive or active immunization. Locomotor function was assessed using a standardized locomotor rating scale (Basso–Beattie–Bresnahan scale) and was correlated with myelin and axon sparing. The functional and anatomical integrity of the rubrospinal pathway also was analyzed using the inclined plane test and anatomical tract tracing. MBP-immunized rats exhibited varying degrees of functional impairment, exacerbated lesion pathology, greater rubrospinal neuron loss, increased intraspinal T-cell accumulation, and enhanced macrophage activation relative to SCI control groups. These data are consistent with the conventional view of myelin-reactive T-cells as pathological effector cells.

[1]  B. Winblad,et al.  Reduced susceptibility to Kainic Acid-induced excitoxicity in T-cell deficient CD4/CD8(−/−) and middle-aged C57BL/6 mice , 2004, Journal of Neuroimmunology.

[2]  M. Mochizuki,et al.  Sympathetic ophthalmia: an autoimmune ocular inflammatory disease , 2004, Springer Seminars in Immunopathology.

[3]  R. Hill,et al.  Interferon-γ induces characteristics of central sensitization in spinal dorsal horn neurons in vitro , 2003, Pain.

[4]  H. Keirstead,et al.  Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury , 2003, Experimental Neurology.

[5]  S. Albani,et al.  Heat shock proteins (HSP) for immunotherapy of rheumatoid arthritis (RA) , 2003, Inflammation Research.

[6]  K. Willms,et al.  Effects of cyclosporin-A on immune response, tissue protection and motor function of rats subjected to spinal cord injury , 2003, Brain Research.

[7]  M. Cuzner,et al.  Interleukin-12 induces mild experimental allergic encephalomyelitis following local central nervous system injury in the Lewis rat , 2003, Journal of Neuroimmunology.

[8]  J. Antel,et al.  Vulnerability of Human Neurons to T Cell-Mediated Cytotoxicity1 , 2003, The Journal of Immunology.

[9]  Lawrence Steinman,et al.  Optic Neuritis, A New Variant of Experimental Encephalomyelitis, A Durable Model for All Seasons, Now In Its Seventieth Year , 2003, The Journal of experimental medicine.

[10]  Moses Rodriguez,et al.  Efficient central nervous system remyelination requires T cells , 2003, Annals of neurology.

[11]  E. Yoles,et al.  Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Hart,et al.  Activated/effector CD4+ T cells exacerbate acute damage in the central nervous system following traumatic injury , 2003, Journal of Neuroimmunology.

[13]  P. Lehmann,et al.  Autoreactive T cells promote post-traumatic healing in the central nervous system , 2003, Journal of Neuroimmunology.

[14]  S. Albani,et al.  Heat shock proteins for immunotherapy of rheumatoid arthritis , 2003 .

[15]  Michal Schwartz,et al.  Neuroprotective autoimmunity: Naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  K. Hayes,et al.  Elevated serum titers of proinflammatory cytokines and CNS autoantibodies in patients with chronic spinal cord injury. , 2002, Journal of neurotrauma.

[17]  D. Basso,et al.  Pathological CNS Autoimmune Disease Triggered by Traumatic Spinal Cord Injury: Implications for Autoimmune Vaccine Therapy , 2002, The Journal of Neuroscience.

[18]  E. Check.  Nerve inflammation halts trial for Alzheimer's drug , 2002, Nature.

[19]  D. Basso,et al.  Descending systems contributing to locomotor recovery after mild or moderate spinal cord injury in rats: experimental evidence and a review of literature. , 2002, Restorative neurology and neuroscience.

[20]  E. Agranov,et al.  Vaccination with a Nogo-A-derived peptide after incomplete spinal-cord injury promotes recovery via a T-cell-mediated neuroprotective response: Comparison with other myelin antigens , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Chaplin,et al.  Interleukin-1β Promotes Repair of the CNS , 2001, The Journal of Neuroscience.

[22]  H. Neumann,et al.  Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. , 2001, The American journal of pathology.

[23]  E. Agranov,et al.  Posttraumatic therapeutic vaccination with modified myelin self-antigen prevents complete paralysis while avoiding autoimmune disease. , 2001, The Journal of clinical investigation.

[24]  M. Schwartz,et al.  Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. , 2001, Trends in molecular medicine.

[25]  H. Weiner,et al.  Protective Autoimmunity Is a Physiological Response to CNS Trauma , 2001, The Journal of Neuroscience.

[26]  M. Schwartz,et al.  Beneficial immune activity after CNS injury: prospects for vaccination , 2001, Journal of Neuroimmunology.

[27]  Hadas Schori,et al.  Vaccination for Neuroprotection in the Mouse Optic Nerve: Implications for Optic Neuropathies , 2001, The Journal of Neuroscience.

[28]  D. Chaplin,et al.  Interleukin-1beta promotes repair of the CNS. , 2001, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[29]  J. Hardy,et al.  Aβ peptide vaccination prevents memory loss in an animal model of Alzheimer's disease , 2000, Nature.

[30]  L. Noble,et al.  Co-induction of HSP70 and heme oxygenase-1 in macrophages and glia after spinal cord contusion in the rat , 2000, Brain Research.

[31]  P. Srivastava,et al.  Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. , 2000, International immunology.

[32]  A. Evans,et al.  Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial , 2000, Nature Medicine.

[33]  E. Agranov,et al.  Passive or Active Immunization with Myelin Basic Protein Promotes Recovery from Spinal Cord Contusion , 2000, The Journal of Neuroscience.

[34]  I. Bechmann,et al.  Axonal Damage Induced by Invading T Cells in Organotypic Central Nervous System Tissue in vitro: Involvement of Microglial Cells , 2000, Brain pathology.

[35]  W. Brück,et al.  Tumour necrosis factor alpha mRNA expression in early multiple sclerosis lesions: Correlation with demyelinating activity and oligodendrocyte pathology , 2000, Glia.

[36]  E. Agranov,et al.  Autoimmune T cells as potential neuroprotective therapy for spinal cord injury , 2000, The Lancet.

[37]  J. Hardy,et al.  A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. , 2000, Nature.

[38]  Roland Martin,et al.  Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7 , 1999, Journal of Neuroimmunology.

[39]  M. Schwartz,et al.  The remedy may lie in ourselves: prospects for immune cell therapy in central nervous system protection and repair , 1999, Journal of Molecular Medicine.

[40]  Jingwu Z. Zhang,et al.  T cell responses to myelin basic protein in patients with spinal cord injury and multiple sclerosis , 1999, Journal of Neuroimmunology.

[41]  L. Steinman,et al.  The Immunobiology of Multiple Sclerosis: An Autoimmune Disease of the Central Nervous System , 1999, Neurobiology of Disease.

[42]  V. Sanders,et al.  Exacerbation of Facial Motoneuron Loss after Facial Nerve Transection in Severe Combined Immunodeficient (scid) Mice , 1999, The Journal of Neuroscience.

[43]  John T. Chang,et al.  Regulation of Interleukin (IL)-12 Receptor β2 Subunit Expression by Endogenous IL-12: A Critical Step in the Differentiation of Pathogenic Autoreactive T Cells , 1999, The Journal of experimental medicine.

[44]  Geoffrey A. Donnan,et al.  Activated Macrophages and Microglia Induce Dopaminergic Sprouting in the Injured Striatum and Express Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor , 1999, The Journal of Neuroscience.

[45]  H. Eng,et al.  Synthesis of β-Tubulin, Actin, and Other Proteins in Axons of Sympathetic Neurons in Compartmented Cultures , 1999, The Journal of Neuroscience.

[46]  Irun R. Cohen,et al.  Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy , 1999, Nature Medicine.

[47]  Radhey S. Gupta,et al.  Heat shock proteins and experimental autoimmune encephalomyelitis II: environmental infection and extra-neuraxial inflammation alter the course of chronic relapsing encephalomyelitis , 1998, Journal of Neuroimmunology.

[48]  G. Kollias,et al.  Oligodendrocyte apoptosis and primary demyelination induced by local TNF/p55TNF receptor signaling in the central nervous system of transgenic mice: models for multiple sclerosis with primary oligodendrogliopathy. , 1998, The American journal of pathology.

[49]  R. Rudick,et al.  Axonal transection in the lesions of multiple sclerosis. , 1998, The New England journal of medicine.

[50]  R. McCarron,et al.  Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[51]  H. Hartung,et al.  IMMUNOLOGICALLY INDUCED ELECTROPHYSIOLOGICAL DYSFUNCTION: IMPLICATIONS FOR INFLAMMATORY DISEASES OF THE CNS AND PNS , 1997, Progress in Neurobiology.

[52]  H. Weiner,et al.  Increased interleukin 12 production in progressive multiple sclerosis: induction by activated CD4+ T cells via CD40 ligand. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[53]  B. Stokes,et al.  Cellular inflammatory response after spinal cord injury in sprague‐dawley and lewis rats , 1997, The Journal of comparative neurology.

[54]  C. Whitacre,et al.  Concept of autoimmunity following spinal cord injury: Possible roles for T lymphocytes in the traumatized central nervous system , 1996, Journal of neuroscience research.

[55]  Michael S. Beattie,et al.  Graded Histological and Locomotor Outcomes after Spinal Cord Contusion Using the NYU Weight-Drop Device versus Transection , 1996, Experimental Neurology.

[56]  L Steinman,et al.  Multiple Sclerosis: A Coordinated Immunological Attack against Myelin in the Central Nervous System , 1996, Cell.

[57]  M. Fehlings,et al.  The relationships among the severity of spinal cord injury, residual neurological function, axon counts, and counts of retrogradely labeled neurons after experimental spinal cord injury , 1995, Experimental Neurology.

[58]  D. Basso,et al.  A sensitive and reliable locomotor rating scale for open field testing in rats. , 1995, Journal of neurotrauma.

[59]  D. Hafler,et al.  Clonal expansion and persistence of human T cells specific for an immunodominant myelin basic protein peptide. , 1994, Journal of immunology.

[60]  J. Antel,et al.  Oligodendrocyte lysis by CD4+ T cells independent of tumor necrosis factor , 1994, Annals of neurology.

[61]  T. Olsson,et al.  Autoreactive T and B cell responses to myelin antigens after diagnostic sural nerve biopsy , 1993, Journal of the Neurological Sciences.

[62]  Y. Qin,et al.  Perforin and tumor necrosis factor alpha in the pathogenesis of experimental allergic encephalomyelitis: comparison of autoantigen induced and transferred disease in Lewis rats. , 1993, Journal of autoimmunity.

[63]  S. Anderton,et al.  Inflammation activates self hsp60‐specific T cells , 1993, European journal of immunology.

[64]  M. Beattie,et al.  Spinal cord injury produced by consistent mechanical displacement of the cord in rats: behavioral and histologic analysis. , 1992, Journal of neurotrauma.

[65]  K. Kristensson,et al.  Facial nerve transection causes expansion of myelin autoreactive T cells in regional lymph nodes and T cell homing to the facial nucleus. , 1992, Autoimmunity.

[66]  L. Kappos,et al.  Myelin basic protein‐specific T lymphocyte lines from MS patients and healthy individuals , 1990, Neurology.

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

[68]  H. J. G. Gundersen,et al.  The new stereological tools: Disector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[69]  H. J. G. GUNDERSEN,et al.  Some new, simple and efficient stereological methods and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[70]  N. Strominger,et al.  Morphometric and experimental studies of the red nucleus in the albino rat , 1987, The Anatomical record.

[71]  J. Cohen,et al.  A quantitative immunohistochemical comparison of actively versus adoptively induced experimental allergic encephalomyelitis in the Lewis rat. , 1987, Cellular immunology.

[72]  J. Saint-Cyr,et al.  Assessment of spinal cord injury by counting corticospinal and rubrospinal neurons , 1987, Brain Research.

[73]  D. Carrigan.  Chronic, relapsing encephalomyelitis associated with experimental measles virus infection , 1987, Journal of medical virology.

[74]  D. C. Sterio.  The unbiased estimation of number and sizes of arbitrary particles using the disector , 1984, Journal of microscopy.

[75]  S. Leong,et al.  Origin of the rubrospinal tract in neonatal, developing, and mature rats , 1983, The Journal of comparative neurology.

[76]  C H Tator,et al.  Objective clinical assessment of motor function after experimental spinal cord injury in the rat. , 1977, Journal of neurosurgery.

[77]  M. Prochazka,et al.  Studies of immunologic reactions after brain injury. II. Antibodies against brain tissue lipids after blunt head injury in man. , 1971, International surgery.

[78]  R. Swanborg,et al.  Purification of an organ-specific thermostable antigen found in bovine brain. , 1970, Immunology.

[79]  T. Rivers,et al.  OBSERVATIONS ON ATTEMPTS TO PRODUCE ACUTE DISSEMINATED ENCEPHALOMYELITIS IN MONKEYS , 1933, The Journal of experimental medicine.