Spinal cord injury (SCI) triggers a neuroinflammatory reaction that can exacerbate tissue damage and promote repair of injured neurons and glia. Exploitation of immune-mediated repair mechanisms and antagonism of degradative immunological cascades has therapeutic value. Unfortunately, these mechanisms and cellular/humoral cascades remain enigmatic. To date, studies of neuroinflammation after SCI have focused largely on neutrophils, microglia and/or macrophages. However, T-lymphocytes also infiltrate the traumatized spinal cord; yet, their roles in processes of secondary degeneration and repair are poorly defined. Given that T-cells directly influence blood-brain barrier integrity, axonal conduction, extracellular matrix composition, macrophage/microglial function and neuronal/glial survival, activated T-cells undoubtedly affect recovery from SCI. We have demonstrated that SCI primes the activation (i.e., proliferation and cytokine production) of peripheral T-cells and that activated T-cells infiltrate the injury site. How and to what extent these cells influence recovery from SCI is not known. Studies in Aim 1 will evaluate T-cell influences on the normal progression of SCI pathology and functional recovery. A systematic manipulation of all T-cells will be accomplished using nude rats and antibody-mediated depletion of T-cells.
In Aim 2, we will determine whether recovery from SCI can be improved by inhibiting CNS myelin-reactive T-cells -- cells that we have previously shown exacerbate pathology and impair functional recovery after SCI. Selective depletion of myelin-reactive T-cells will be accomplished using a clinically feasible oral tolerance paradigm. Newer preliminary data has prompted us to also consider whether other (non-myelin reactive) T-cells can be exploited for therapeutic purposes. Accordingly, studies in Aim 3 will determine whether heat shock protein-reactive T-cells can convey neuroprotection and improve recovery from SCI by suppressing acute neuroinflammation. Studies in Aim 4 will explore a suspected mechanism of T-cell mediated injury after SCI, i.e., activation of recruited macrophages. This will be accomplished by macrophage depleting animals with enhanced myelin-reactive T-cell function. The primary hypothesis to be tested in this proposal is that T-cells exert pathological and neuroprotective effects within the injured spinal cord. This functional diversity depends on the phenotype and antigen-specificity of recruited T-cells as well as the cellular and biochemical milieu at the injury site.
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