Autoreactive T cells induce neurotrophin production by immune and neural cells in injured rat optic nerve: Implications for protective autoimmunity

Abstract

Accumulating evidence suggests that activation of the immune system in the central nervous system (CNS) after trauma protects the CNS from damage propagation and facilitates regeneration. Studies by our group have shown that passive transfer of autoimmune T cells specific to myelin basic protein (T(MBP)) can protect injured neurons in the rat CNS from secondary degeneration. In this study, we investigated the effects of T(MBP) treatment on the local immune response (by B cells and macrophages) and on the expression of neurotrophic factors after crush injury of the rat optic nerve. Systemic injection of activated T(MBP) caused an increase in the accumulation of macrophages/microglia and B cells in the injured nerve, which was greater than that seen in the injured optic nerves of untreated animals. This accumulation was accompanied by a transient, but massive, increase in the expression of neurotrophic factors. Immunocytochemical analysis demonstrated differential expression of neurotrophins by resident astrocytes and by infiltrating B cells, T cells, and macrophages. Because postinjury neuronal survival and maintenance are known to be affected by neurotrophins, our findings point to a possible contribution of a neurotrophin-related mechanism to the protective effect conferred by T cell-mediated autoimmunity on injured neurons.

Effects of Olig2-Overexpressing Neural Stem Cells and Myelin Basic Protein-Activated T Cells on Recovery from Spinal Cord Injury

“…Although the concept and safety of clinical therapies have been severely suspected [57][58][59][60], recent reports from ourselves and others have suggested that at least in the experimental allergic encephalomyelitis (EAE)-resistant SD rats, adoptive immunotherapy using MBP-T cells shows a neuroprotective effect on the injured spinal cord [14,61,62]. The protective effect of MBP-T cells may be due to their ability to release neurotrophic factors [63,64], induce microglia to buffer toxic mediators (such as glutamate), and remove growth inhibitors (e.g., by phagocytosis of myelin) [65][66][67][68][69]. In this study, we demonstrated that MBP-T cells were mainly CD3 + CD4 + T cells (>98%).…”

Phagocytosis of neuronal debris by microglia is associated with neuronal damage in multiple sclerosis

“…Phagocytosis of degenerating axons is observed in the entorhinal lesion model in mice (Bechmann and Nitsch, 1997) in which CD95L up regulation is associated with leukocyte apoptosis in areas of axonal damage. Autoreactive T cells secrete neurotrophins, regulate microglia activation and augment regeneration in the CNS (Barouch and Schwartz, 2002;Moalem et al, 1999), arguing against the idea that release of neuronal antigens in brain injury could augment or initiate MS (Goodin et al, 1999). Moreover, in mice experimental brain injury significantly reduces the clinical signs of EAE, considered an animal model of MS (Mutlu et al, 2007).…”

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

“…Once activated, they can serve as a source of cytokines and neurotrophins. In addition, while the local neural cells clear the site of injury of cell debris and other deleterious matter (35,36), the T cells can regulate the local innate response in which resident cells become either antigen-presenting cells or phagocytic, buffering cells (I. Shaked, O. Butovsky, T. Mizrahi, R. Gersner, X. Xiao, P. Soteropoulos, P. Tolias, R. P. Hart, and M.S., unpublished data; and ref. 37).…”

“…Global protection, providing the multiple factors needed for CNS recovery, might be obtained by a therapeutic strategy in which the body's protective (immune system) resources are harnessed. Because T cells are prominent among the immune participants in neuroprotection (13,16), such therapy would presumably recruit a myriad of T cellderived factors (35,36).…”