Different MOG35–55 concentrations induce distinguishable inflammation through early regulatory response by IL-10 and TGF-β in mice CNS despite unchanged clinical course

Abstract

Multiple sclerosis (MS) shows distinct clinical courses. Experimental autoimmune encephalomyelitis (EAE), a model to study multiple sclerosis, can be induced by different protocols, which show distinct cytokine and antibody production. The factors involved in this heterogeneity remain unclear. The relevance of MOG concentration in triggering a regulatory response in the chronic model of EAE is imprecise. The aim of this study was investigate if 100 or 300 μg of MOG(35-55) could induce different EAE profiles. Modifications in the concentration of MOG were able to change the patterns of chemokines, cytokines, percentage of cells, inflammatory infiltrate and the development of a regulatory response. However, these changes were unable to modify the intensity of response, which explains the chronic progression of the disease in both concentrations. The results presented in this study contribute to understanding the intricate mechanisms that trigger EAE and provide insights into the pathogenesis of various forms of MS.

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair

“…Although both groups displayed similar clinical disease onset, the one MOG injection group exhibited reduced disease severity and a higher level of spontaneous recovery compared to the two MOG injection group. This result, paired with the results of Dias and colleagues (Dias et al, 2015), offer further support that disease course and severity are strongly dependent on the administered dosages and timing of MOG 35–55 injections.…”

“…Even if disease course as measured by onset and clinical scoring is consistent, changes in cytokines, chemokines, immune cell population, and lesion location are dependent on the concentrations used (Dias et al, 2015); (Boullerne et al, 2014); (Hofstetter et al, 2002); (Jee and Matsumoto, 2001) .…”

“…At both concentrations, mice succumbed to chronic disease. However, the 100 µg doses resulted in an earlier increase of inflammatory infiltrate and increased cytokine levels in the CNS after disease induction compared to 300 µg MOG (Dias et al, 2015). Furthermore, active MOG 35–55 peptide fraction purity can influence disease onset and incidence (Boullerne et al, 2014) and it has been reported that PTx dosage has a direct effect on disease incidence, progression, and immune cell profiles (Hofstetter et al, 2002; Jee and Matsumoto, 2001) [Hooke Laboratories, hookelabs.com/protocols/eae AI_C57BL6.html].…”

“…This may be attributable to dissimilar disease timelines or any combination of the aforementioned differences between EAE and MS, but it is also possible that EAE protocol discrepancies contribute to these pre-clinical and clinical incongruences. For example, while the EAE clinical disease may appear similar between studies, differences in protocols lead to dramatically different cellular and subcellular disease profiles (Boullerne et al, 2014; Dias et al, 2015; Hofstetter et al, 2002; Jee and Matsumoto, 2001) potentially biasing pre-clinical drug study results. Irrespective of the origin of these incongruities, these findings support the notion that consistent EAE induction is imperative and that all therapeutics should be verified in multiple MS models prior to progressing to clinical applications.…”

“…This makes, it extremely challenging to meaningfully compare MOG 35–55 -EAE results obtained by independent labs. This discordance is further exacerbated by the fact that induction with different MOG 35–55 peptide doses directly influence EAE pathology (Dias et al, 2015). A study by Dias and colleagues found that female C57BL/6 mice immunized using either 100 or 300 µg of MOG 35–55 peptide presented with variable pathology.…”