IMMUNOMODULATORY EFFECTS OF PHYSICAL EXERCISE IN AN ANIMAL MODEL OF MULTIPLE SCLEROSIS

Einstein O.¹, Fainstein N.², Touloumi O.³, Lagoudaki R.³, Hanya E.⁴, Grigoriadis N.³, Katz A.¹, Ben-Hur T.²

¹Ariel University, Physiotherapy, Ariel, Israel, ²Hadassah-Hebrew University Medical Center, Neurology, Jerusalem, Israel, ³AHEPA University Hospital of Thessaloniki, B' Department of Neurology, Thessaloniki, Greece, ⁴Ariel University, Molecular Biology, Ariel, Israel

Background: Several clinical trials have demonstrated beneficial effects of physical exercise (PE) on patients afflicted with Multiple Sclerosis (MS). Growing evidence links PE and the immune system. Previous studies examined the effects of PE on Experimental Autoimmune Encephalomyelitis (EAE), the animal model of MS, with conflicting results. Some indicated a beneficial effect of exercise on clinical symptoms and pathological parameters in EAE, whereas others did not. There is no conclusive evidence on the beneficial effects of exercise on histopathologic correlates of clinical disease severity, and specifically it is not well understood whether PE mediates beneficial effects in EAE via modulation of the systemic immune system.

Purpose: The purpose of this study is:
(1) To establish the clinical and neuropathological effects of PE in EAE; and
(2) To investigate whether PE ameliorates EAE by modulating the systemic immune system.

Methods: Healthy mice were subjected to a defined moderate-intensity PE program by running on a motorized treadmill (5 sessions/wk for 6 wk). Muscles from exercised and sedentary mice were analyzed for mitochondrial enzyme activities to assess the efficacy of training. To examine the activation state of lymph-node (LN) T cells in vivo, Proteolipid Protein (PLP)-induced transfer EAE model in SJL mice was used. LN T cells from trained- versus sedentary donor mice were transferred to naïve recipient mice to induce EAE. EAE severity was compared between experimental groups by clinical scoring and by histopathological examination of CNS tissues to quantify severity of neuro-inflammation, its pro- versus anti-inflammatory profile and the degree of myelin and axonal loss. To assess the effects of PE on systemic autoimmunity, we examined in vitro the characteristics of LN T cells derived from mice that underwent the PE program prior to PLP immunization, compared with T cells from sedentary mice, using proliferation assays, cell surface marker analysis and cytokine secretion profiles.

Results: Moderate PE significantly increased citrate synthase activity in soleus muscle (exercised mice = 140±4 nmol/min/mg dry wt, n=4; control sedentary mice = 108±9, n=5; P 0.05) and decreased the encephalitogenicity of LN T cells. LN T cells obtained from exercised mice induced a markedly attenuated EAE in recipient mice, as compared to cells derived from sedentary animals. Both a delay in clinical onset and amelioration of severity of symptoms were noted (Total burden of disease score: exercised mice LN T cells derived EAE = 32±2, n=9; control sedentary mice LN T cells derived EAE = 57±13, n=7; P 0.05).

Conclusion(s): These data, obtained by using this unique experimental design, demonstrate beneficial systemic immunomodulatory effects of PE on EAE.

Implications: Revealing the underlying immunomodulatory effects of PE on EAE has a substantial clinical significance for MS patients.

Funding acknowledgements: The work is currently funded by Ariel University

Topic: Neurology

Ethics approval: This work was approved by the institutional animal ethics committee of Ariel university

All authors, affiliations and abstracts have been published as submitted.