Passive or Active Immunization with Myelin Basic Protein Promotes Recovery from Spinal Cord Contusion

Abstract

Partial injury to the spinal cord can propagate itself, sometimes leading to paralysis attributable to degeneration of initially undamaged neurons. We demonstrated recently that autoimmune T cells directed against the CNS antigen myelin basic protein (MBP) reduce degeneration after optic nerve crush injury in rats. Here we show that not only transfer of T cells but also active immunization with MBP promotes recovery from spinal cord injury. Anesthetized adult Lewis rats subjected to spinal cord contusion at T7 or T9, using the New York University impactor, were injected systemically with anti-MBP T cells at the time of contusion or 1 week later. Another group of rats was immunized, 1 week before contusion, with MBP emulsified in incomplete Freund's adjuvant (IFA). Functional recovery was assessed in a randomized, double-blinded manner, using the open-field behavioral test of Basso, Beattie, and Bresnahan. The functional outcome of contusion at T7 differed from that at T9 (2.9 Ϯ 0.4, n ϭ 25, compared with 8.3 Ϯ 0.4, n ϭ 12; p Ͻ 0.003). In both cases, a single T cell treatment resulted in significantly better recovery than that observed in control rats treated with T cells directed against the nonself antigen ovalbumin. Delayed treatment with T cells (1 week after contusion) resulted in significantly better recovery (7.0 Ϯ 1; n ϭ 6) than that observed in control rats treated with PBS (2.0 Ϯ 0.8; n ϭ 6; p Ͻ 0.01; nonparametric ANOVA). Rats immunized with MBP obtained a recovery score of 6.1 Ϯ 0.8 (n ϭ 6) compared with a score of 3.0 Ϯ 0.8 (n ϭ 5; p Ͻ 0.05) in control rats injected with PBS in IFA. Morphometric analysis, immunohistochemical staining, and diffusion anisotropy magnetic resonance imaging showed that the behavioral outcome was correlated with tissue preservation. The results suggest that T cell-mediated immune activity, achieved by either adoptive transfer or active immunization, enhances recovery from spinal cord injury by conferring effective neuroprotection. The autoimmune T cells, once reactivated at the lesion site through recognition of their specific antigen, are a potential source of various protective factors whose production is locally regulated.

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

“…Therefore, boosting the immune responses to CNS injury under certain conditions may be more beneficial than harmful to functional regeneration (58) . Implantation of activated macrophages (86) or T-lymphocyte mediated immune activity, achieved by either adoptive transfer or active immunization (87)(88)(89)(90) , enhances recovery from spinal cord injury by conferring neuroprotection or regeneration. Although the concept of neuroprotective autoimmunity is intriguing, there is no definitive mechanism that explains its efficacy.…”

Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience

“…A decade ago, our laboratory discovered the importance of the self-reactive T cells in the repair of central nervous system (CNS) injury. 5 The protective capacity of autoimmune cells was further shown in several models of CNS pathology including mechanical injury, 5,6 Alzheimer's disease, 7 Parkinson's disease 8 and imbalances in neurotransmitter levels, 9 as well as non-CNS processes such as skin wound healing. 10 The neuroprotective immune response is a physiological response that is spontaneously evoked after trauma.…”

“…11 Furthermore, immune neuroprotection is antigen-specific, and aimed at antigens expressed at the site of insult. 6,12,13 In addition to the role of CNSspecific T cells in CNS repair, our group has found that adaptive immune cells are key players in CNS maintenance under nonpathological conditions, especially in hippocampal plasticity. 9,14 We showed that autoreactive T cells are needed to support hippocampal-dependent learning and memory tasks, as well as for the regulation of adult hippocampal neurogenesis and neurotrophic factor production, 14 possibly by regulating microglial phenotype.…”

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

“…However, although it is believed to underlie the pathogenesis of MS (13)(14)(15)(16), in other neurodegenerative processes including brain injury (17,18), amyotrophic lateral sclerosis (19), stroke (20), and Alzheimer's disease (AD), T cell infiltration into the CNS has been implicated either as exacerbating neurodegeneration (21)(22)(23) or, in other instances, as beneficial. Regulatory cytokine profiles of certain T cell subsets (24)(25)(26) or the ability of T cells to secrete neurotrophic factors (27,28) have been suggested as mechanisms underlying the beneficial effects of T cell infiltration into the CNS.…”