In children with drug-resistant epilepsy, resective brain surgery may be the only option to obtain seizure freedom but leads to permanent deficits when the zone of resection involves eloquent brain. There is a clear need to find alternative ways to treat children with intractable epilepsy. Controlling brain inflammation may be one important therapeutic strategy. We and others have found activated T cells and other peripheral immune cells in brain tissue removed to control seizures even in cases where an underlying immune disorder is not suspected. We have also identified specific T cell subsets in the blood of patients undergoing resective surgery that are indicative of an active immune response. We hypothesize that recurrent seizures could cause a ?sterile? infection in which activated T cells and other nonresident immune cells are recruited to sites of seizure-induced inflammation. Adjunctive treatment with drugs that block the recruitment of pro-inflammatory peripheral lymphoid and myeloid cells may therefore be therapeutically beneficial. To better understand the involvement of cellular immunity in intractable pediatric epilepsy we will use mass cytometry and a panel of antibodies to distinguish between T cell, innate lymphoid, and myeloid subsets in CD45+ immune cells isolated from resected brain tissue, and blood collected at the time of surgery from a cohort of pediatric epilepsy surgery patients and following their recovery from surgery at 12 weeks, when the effects of the surgery on clinical status are assessed. We will also measure the diversity of ?? and ?? T cells in resected brain tissue and peripheral blood by sequencing the third complementarity regions (CDR3) of rearranged T cell receptor (TCR) ? and ? genes. Showing that there are only a limited number of different ?? and ?? T cell clones in the brain tissue would support the idea of a specific adaptive response. We hypothesize that removal of the epileptogenic area of the brain with a commensurate improvement in seizure status would resolve the sterile infection, and result in a reduction in the frequency of T cell subsets in the blood associated with an active immune response. A decrease in the frequency T cell clones in the peripheral circulation that were originally found in the brain would also be expected.
Surgery remains the only effective treatment for medically refractory seizures in children. The goal of this project is to determine whether T cells and other peripheral immune cells contribute to inflammation in the brains of these patients, which may explain why seizures are not controllable with conventional anti-epileptic drugs.
