Vaccination with autoantigen protects against aggregated β‐amyloid and glutamate toxicity by controlling microglia: effect of CD4⁺CD25⁺ T cells

Abstract

Neurodegenerative diseases differ in etiology but are propagated similarly. We show that neuronal loss caused by intraocular injection of aggregated b-amyloid was significantly greater in immunodeficient mice than in normal mice. The neurodegeneration was attenuated or augmented by elimination or addition, respectively, of naturally occurring CD4 + CD25 + regulatory T cells (Treg). Vaccination with retina-derived antigens or with the synthetic copolymer glatiramer acetate (Copolymer-1, Cop-1), but not with b-amyloid, reduced the ocular neuronal loss. In mouse hippocampal slices, microglia encountering activated T cells overcame the cytotoxicity of aggregated b-amyloid. These findings support the concept of "protective autoimmunity", show that a given T cell-based vaccination is protective at a particular site irrespective of toxicity type, and suggest that locally activated T cells induce a microglial phenotype that helps neurons withstand the insult. Alzheimer's and other neurodegenerative diseases might be arrested or retarded by vaccination with Cop-1 or related compounds or by treatment with compounds that weaken Treg suppression.

Glatiramer acetate fights against Alzheimer’s disease by inducing dendritic-like microglia expressing insulin-like growth factor 1

“…Therapeutic vaccination with GA boosts the protective autoimmunity (13)(14)(15). A single injection of GA is protective in acute models of CNS insults (13,15), whereas in chronic models occasional boosting rather than daily is required for a long-lasting protective effect (14).…”

“…A single injection of GA is protective in acute models of CNS insults (13,15), whereas in chronic models occasional boosting rather than daily is required for a long-lasting protective effect (14). In a model of chronically elevated intraocular pressure, for example, weekly administration of adjuvant-free GA was found to result in neuroprotection (19).…”

“…Our present results argue against the use of A␤ peptide as a T cell-based therapy for AD. Myelin-related antigens, or antigens (such as GA) that are weakly cross-reactive with myelin, are likely to be the antigens of choice for therapeutic vaccination (15). T cells activated by these antigens upon encountering their relevant antigen-presenting cells supply the cytokines and growth factors to confer microglia with dendritic-like characteristics.…”

“…Here we tested this hypothesis by vaccinating transgenic (Tg) AD (Tg-AD) mice with glatiramer acetate (GA), also known as copolymer 1 (Cop-1), (12). GA can weakly cross-react with CNS-resident autoantigens (13) and can safely simulate the protective and reparative effects of autoreactive T cells (13)(14)(15)(16).…”

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.…”