Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma

Hirschberg, David L.; Moalem, Gila; He, Jun; Mor, Felix; Cohen, Irun R.; Schwartz, Michal

doi:10.1016/s0165-5728(98)00118-0

Cited by 89 publications

(52 citation statements)

References 31 publications

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“…Another common characteristic of injured CNS is the increased presence of infiltrating immune cells that have been suggested to contribute to the pathology and the spread of damage (2). However, some studies have shown that in the event of an acute injury or chronic neurodegenerative conditions, T cells are recruited by and accumulate in the CNS (41,42), where they rescue neurons from degeneration. Moreover, a well-controlled boost of autoimmune activity following injury increases the number of surviving neurons (43).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, l-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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“…We postulated that one way in which T cells confer neuroprotection occurs via their homing to the site of a lesion (35), where they influence the behavior of the local microglia (36). To gain some insight into the mechanisms underlying the beneficial and the inhibitory effects of Treg on neuronal survival, we carried out an in vitro experiment by using OHSCs.…”

Section: The Treg Neuroprotective Response Is Mediated In Part Throughmentioning

confidence: 99%

Dual effect of CD4⁺CD25⁺regulatory T cells in neurodegeneration: A dialogue with microglia

Kipnis

Avidan

Caspi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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152

107

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autoimmunity ͉ neuroprotection ͉ neurodegenerative conditions ͉ hippocampal slice cultures ͉ immune regulation T he systemic adaptive T cell-dependent immune response plays a key role in the ability of neurons in the central nervous system (CNS) to withstand injurious conditions (1-3). Studies from our laboratory have shown that, after a CNS injury, T cells nonselectively migrate to the site of injury (4), and suggest that homing T cells, which encounter their relevant antigens at the lesion site, are the ones that contribute to the repair. Such T cells become locally activated to produce neurotrophic factors (5) and cytokines, which are capable of affecting the activity of resident microglia and hence the fate of threatened neurons. We further showed that the T cell-dependent protection evoked after an axonal injury, being an anti-self-response (6), is constitutively limited by naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (Treg) (6). It is, however, amenable to therapeutic boosting, either by postinjury immunization with antigens derived from dominant proteins residing in the site of damage or by depletion of Treg (2).Treg comprise Ϸ10% of the CD4 ϩ T cell population, and have been widely viewed as safeguards against the pathogenic effects of autoimmune CD4 ϩ CD25

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“…Thus, systemic injection of activated autoimmune T cells appears to be a feasible cell therapy that offers some advantages. First, these T cells can cross the blood-brain barrier (Hickey et al, 1991) and specifically accumulate at the site of a CNS lesion (Hirschberg et al, 1998). Second, the T cells are capable of continuously releasing various factors at the lesion site as a result of their reactivation at the lesion site upon encountering their antigen.…”

Section: Abstract: Cns; Beneficial Autoimmunity; Myelin Basic Proteimentioning

confidence: 99%

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

et al. 2000

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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.

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Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma

Cited by 89 publications

References 31 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Dual effect of CD4⁺CD25⁺regulatory T cells in neurodegeneration: A dialogue with microglia

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

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Accumulation of passively transferred primed T cells independently of their antigen specificity following central nervous system trauma

Cited by 89 publications

References 31 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Dual effect of CD4+CD25+regulatory T cells in neurodegeneration: A dialogue with microglia

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

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Dual effect of CD4⁺CD25⁺regulatory T cells in neurodegeneration: A dialogue with microglia