Focused ultrasound therapy of cervical lymph nodes in rats for alleviating EAE

Abstract

Multiple sclerosis (MS) is a prevalent neurological disease among adults worldwide (∼2.5 million cases). Disease modifying therapies are only modestly effective for slowing long-term progression of pathological and disability outcomes, underscoring the importance of considering other approaches for managing MS. One approach to treating MS is to reduce the load of lymphocytes that could enter the central nervous system (CNS). Most pharmaceuticals work by downgrading the immune system, but have numerous adverse side effects. We hypothesize that using focused ultrasound (FUS) to heat the cervical lymph nodes, which house the lymphocytes that primarily service the CNS, will reduce the lymphocyte load and alleviate MS with minimal side effects. In our pilot study, FUS was used to produce hyperthermia in cervical lymph nodes of rats having experimental autoimmune encephalomyelitis (EAE), the animal model of MS, in order to alleviate severity of EAE. EAE was induced in rats through injection of myelin oligodendrocyte glycoprotein (MOG (1–125)) and EAE disability scores, on a scale of 0 to 5, were recorded over 21 days post injection. At the onset of EAE symptoms, one set of rats was treated with FUS while another set of rats was sham treated. Specifically, rats were treated at day 9 and day 12 post MOG injection. During therapy, a focused ultrasound transducer (f/3) operating at 0.5 MHz was positioned over the jaw of a rat with the focus of the transducer placed above the skin surface to heat the superficial cervical lymph nodes just under the skin surface. A temperature of 43–44 °C was induced via FUS in the lymph nodes of the rats for 20 minutes on both the right and left side of the jaw. A thermocouple was used to record the temperature near the lymph nodes during exposures. An EAE remittance score was tallied for all rats, defined as the reduction in the EAE score achieved after the maximum EAE score was reached. On average the EAE remittance score for FUS treated rats was 1.14 ± 0.48 versus 0.33 ± 0.27 for sham treated rats. These differences were statistically significant (p = 0.037). Remittance of the EAE disability scores were highly correlated with the last therapy application. Therefore, FUS treatment of cervical lymph nodes in rats with EAE resulted in a significant reduction in EAE score, which was not observed in sham treated rats. This pilot study is the first ever FUS treatment of EAE in a rat model.