Fingolimod blocks pathway from the brain

Mohammad MG, et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J Clin Invest. 2014 [Epub]

In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leucocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.

The rostral migratory stream (RMS) is a specialized migratory route found in the brain of some animals along which neuronal precursors that originated in the subventricular zone (SVZ) of the brain migrate to reach the main olfactory bulb (OB). The importance of the RMS lies in its ability to refine and even change an animal's sensitivity to smells, which explains its importance and larger size in the rodent brain. This study shows that Dendritic cells migrate along the RMS pathway and down into cervical lymph nodes. There lymph glands are found in the neck. This study talks about a (new?) pathway of how immune cells leave the brain, which was first reported a few decades ago (Phillips MJ, et al. Role of cervical lymph nodes in autoimmune encephalomyelitis in the Lewis rat. J Pathol. 1997; 182:457-64. and Vos AF, et al. Tansfer of central nervous system autoantigens and presentation in secondary lymphoid organs.de  J Immunol. 2002). 

This study indicates that Dendritic cells, which are specialised antigen presenting cells that can stimulate immune responses in lymph glands, travel from the brain into the lymph gland. Some will say this is how new antigen specificities are generated. However, in this study,they reported that fingolimod, which blocks egress of white blood cells from lymph glands, actually makes things worse and can make resistant animals sensitive. They suggest that this treatment blocks migration of dendritic cells into lymph glands. Whilst it is known that systemic delivery  of fingolimod blocks the development of EAE in essentially every published study, local delivery into the RMS apparently made things worse by an effect on the formation of Tregs and so could block the generation of autoimmunity.
So this work contradicts some views of how relapsing immunity autoimmunity may be generated and adds a note of caution about fingolimod (Gilenya) use. Should it put neuros off. The balance of delivery of fingolimod will be that disease is blocked.

It will be interesting to see if this work is repeated.

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