Immunomodulation by poly-YE reduces organophosphate-induced brain damage

Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4+ T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.

Highlight
► Down-regulation of Tregs activity by the copolymer poly-YE, facilitates recruitment of CD4+ T cells into nerve-agent poisoned brain, and results in neuroprotection with a wide therapeutic window of 24 h.