Lipid Mediators in Multiple Sclerosis

Uncontrolled or unresolved inflammation is associated with several widely occurring diseases such as multiple sclerosis (MS), which is the most common chronic inflammatory demyelinating disease of the central nervous system and a major cause of disability, triggered by an autoimmune response to myelin that eventually leads to progressive neurodegeneration.Although knowledge on its underlying immunopathogenesis has considerably improved and is mostly believed to be mediated by autoreactive T cells that cause oligodendrocyte death and axonal damage, resulting in demyelination, synaptic alteration, and neuronal loss, there is still an unmet need for new diagnostic and therapeutic options, especially for the progressive forms of MS for which no drugs are still available. In recent years, previously unrecognized metabolites, termed specialized pro-resolving lipid mediators (SPMs), temporally and spatially synthesized from omega-3 polyunsaturated fatty acids, were identified and have emerged as biomarkers and potent mediators that control the magnitude and extent of inflammatory events by activating local resolution programs. Despite emerging data suggest that SPMs might control chronic inflammation, research on these mediators on MS is still absent. Thus, a detailed investigation is needed to identify SPMs as modulators of inflammation and disease progression in MS, which might lead to the development of new disease-modifying treatments.

Hypothesis and Significance:

Our hypothesis is that the underlying mechanism of chronic inflammation in MS could be the failure of activating pro-resolving mechanisms, involving the newly discovered omega-3 essential fatty acids-derived mediators of resolution of inflammation: resolvins, maresins, and protectins. Endogenous mechanisms that curtail excessive inflammation and promptits timely resolution are of considerable interest; our findings that these SPMs (recently identified also in human lymphoidorgans, where most naïve-to-effector T cell differentiation occurs) exert a non-cytotoxic regulatory role on cells central inautoimmunity, acting on the balance between pathogenic Th1/Th17 and tolerogenic Treg cells - typically altered in MS -represents a promising beginning for a new avenue of research for MS. The elucidation of these mechanisms operating invivo to keep acute inflammation within physiologic boundaries as well as to stimulate resolution and prevent chronicinflammation is particularly significant and offers a novel opportunity to manage MS.

Preliminary Data:

Thanks to an ongoing collaboration with Prof. Serhan from Harvard Medical School (the father and inventor of SPMs) we have demonstrated for the first time that specific SPMs modulate adaptive immune responses in human peripheral blood T cells. These SPMs strongly reduce cytokine production from activated T cells, prevent naïve CD4 T-cell differentiation into Th1 and Th17 and enhance the de novo generation and function of Foxp3+ regulatory T (Tregs) cells. These results are supported in vivo in a mouse model deficient elongase 2 (Elovl2-/-), the key enzyme for DHA synthesis (the precursor of resolvins and maresins). These findings suggest that SPMs might act on the balance between pathogenic Th1/Th17 and tolerogenic Treg cells and provide a new evidence for SPM-based therapeutic approaches to modulate T-cell mediated chronic inflammatory and autoimmune diseases.

Specific Aims:

Characterization of the resolution code of inflammation in MS patientsInvestigation of SPMs potential in modulating ex vivo/in vitro T cells in MS patientsExploitation of the therapeutic potential of SPMs in animal models of MS