Biomedical subjects

T Bucky Jones

Publications and source records attributed to T Bucky Jones.

5 recordsLinked to original sources

PubMed2005

Molecular control of physiological and pathological T-cell recruitment after mouse spinal cord injury.

The intraspinal cues that orchestrate T-cell migration and activation after spinal contusion injury were characterized using B10.PL (wild-type) and transgenic (Tg) mice with a T-cell repertoire biased toward recognition of myelin basic protein (MBP). Previously, we showed that these strains exhibit distinct anatomical and behavioral phenotypes. In Tg mice, MBP-reactive T-cells are activated by spinal cord injury (SCI), causing more severe axonal injury, demyelination, and functional impairment than is found in non-Tg wild-type mice (B10.PL). Conversely, despite a robust SCI-induced T-cell response in B10.PL mice, no overt T-cell-mediated pathology was evident. Here, we show that chronic intraspinal T-cell accumulation in B10.PL and Tg mice is associated with a dramatic and sustained increase in CXCL10/IP-10 and CCL5/RANTES mRNA expression. However, in Tg mice, chemokine mRNA were enhanced 2- to 17-fold higher than in B10.PL mice and were associated with accelerated intraspinal T-cell influx and enhanced CNS macrophage activation throughout the spinal cord. These data suggest common molecular pathways for initiating T-cell responses after SCI in mice; however, if T-cell reactions are biased against MBP, molecular and cellular determinants of neuroinflammation are magnified in parallel with exacerbation of neuropathology and functional impairment.

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PubMed2004

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.

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PubMed2003

Rats and mice exhibit distinct inflammatory reactions after spinal cord injury.

Spinal contusion pathology in rats and mice is distinct. Cystic cavities form at the impact site in rats while a dense connective tissue matrix occupies the injury site in mice. Because inflammatory cells coordinate mechanisms of tissue injury and repair, we evaluated whether the unique anatomical presentation in spinally injured rats and mice is associated with a species-specific inflammatory response. Immunohistochemistry was used to compare the leukocytic infiltrate between rats and mice. Microglia/macrophage reactions were similar between species; however, the onset and magnitude of lymphocyte and dendritic cell (DC) infiltration were markedly different. In rats, T-cell numbers were highest between 3 and 7 days postinjury and declined by 50% over the next 3 weeks. In mice, significant T-cell entry was not evident until 14 days postinjury, with T-cell numbers doubling between 2 and 6 weeks. Dendritic cell influx paralleled T-cell infiltration in rats but was absent in mouse spinal cord. De novo expression of major histocompatability class II molecules was increased in both species but to a greater extent in mice. Unique to mice were cells that resembled lymphocytes but did not express lymphocyte-specific markers. These cells extended from blood vessels within the fibrotic tissue matrix and expressed fibronectin, collagen I, CD11b, CD34, CD13, and CD45. This phenotype is characteristic of fibrocytes, specialized blood-borne cells involved in wound healing and immunity. Thus, species-specific neuroinflammation may contribute to the formation of distinct tissue environments at the site of spinal cord injury in mice and rats.

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PubMed2003

Manipulating neuroinflammatory reactions in the injured spinal cord: back to basics.

Recruitment of inflammatory leukocytes to the injured spinal cord is a physiological response that is associated with the production of cytokines and proteinases that are involved in host defense and wound repair. Cells in the spinal cord are mainly post-mitotic and tissue regeneration is poor; thus, these inflammatory mediators can exacerbate the damage to spared tissue and thereby impair spontaneous functional recovery. Although several aspects of immune function might benefit the CNS, experimental studies indicate that acute neuroinflammation aggravates tissue injury. Until the timing and nature of the molecular signals that govern leukocyte recruitment and activation after spinal injury are defined, clinical therapies designed to boost immune cell function should be avoided.

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PubMed2002

Pathological CNS autoimmune disease triggered by traumatic spinal cord injury: implications for autoimmune vaccine therapy.

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.

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