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The Journal of Neuroscience, April 1, 2002, 22(7):2690-2700

Pathological CNS Autoimmune Disease Triggered by Traumatic Spinal Cord Injury: Implications for Autoimmune Vaccine Therapy

T. Bucky Jones¹, D. Michele Basso^{1, 2}, Ajeet Sodhi⁵, Jonathan Z. Pan⁵, Ronald P. Hart^{5, 6}, Robert C. MacCallum³, Sunhee Lee³, Caroline C. Whitacre^{1, 4}, and Phillip G. Popovich^{1, 4}

¹ The Neuroscience Graduate Studies Program, ² Division of Physical Therapy, School of Allied Medical Professions, ³ Department of Psychology, College of Social and Behavioral Sciences, and ⁴ Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210, ⁵ Department of Biological Sciences, New Jersey Institute of Technology and Rutgers University, Newark, New Jersey 07102, and ⁶ W. M. Keck Center for Collaborative Neuroscience, Rutgers University, Piscataway, New Jersey 08854

Lymphocytes respond to myelin proteins after spinal cord injury (SCI) and may contribute to post-traumatic secondary degeneration. However, there is increasing evidence that autoreactive T-lymphocytes may also convey neuroprotection and promote functional recovery after CNS injury. To clarify the role of myelin autoreactive lymphocytes after SCI, we performed contusion injuries in the thoracic spinal cord of transgenic (Tg) mice in which >95% of all CD4+ T-lymphocytes are reactive with myelin basic protein (MBP). We observed significantly impaired recovery of locomotor and reflex function in Tg mice compared with non-Tg (nTg) littermates. Measures of functional impairment in Tg mice correlated with significantly less white matter at the injury site, and morphometric comparisons of injured Tg and nTg spinal cords revealed increased rostrocaudal lesion expansion (i.e., secondary degeneration) in Tg mice. Rostrocaudal to the impact site in SCI-nTg mice, demyelination was restricted to the dorsal funiculus, i.e., axons undergoing Wallerian degeneration. The remaining white matter appeared normal. In contrast, lymphocytes were colocalized with regions of demyelination and axon loss throughout the white matter of SCI-Tg mice. Impaired neurological function and exacerbated neuropathology in SCI-Tg mice were associated with increased intraspinal production of proinflammatory cytokine mRNA; neurotrophin mRNA was not elevated. These data suggest that endogenous MBP-reactive lymphocytes, activated by traumatic SCI, can contribute to tissue injury and impair functional recovery. Any neuroprotection afforded by myelin-reactive T-cells is likely to be an indirect effect mediated by other non-CNS-reactive lymphocytes. Similar to the Tg mice in this study, a subset of humans that are genetically predisposed to autoimmune diseases of the CNS may be adversely affected by vaccine therapies designed to boost autoreactive lymphocyte responses after CNS trauma. Consequently, the safe implementation of such therapies requires that future studies define the mechanisms that control T-cell function within the injured CNS.

Key words: protective autoimmunity; neuroprotection; CNS injury; spinal cord injury; myelin basic protein; autoimmune disease

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2272690-11$05.00/0

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