Peripherally-acting MS treatments for a CNS disease

Authors describing the underlying autoimmune mechanisms in MS point out that all MS disease-modifying treatments interfere with the peripheral, not the central, immune system. The authors describe the evidence supporting a principally autoimmune basis for MS. This involves peripheral activation of autoreactive T and B cells specific for central antigens that then migrate to the central nervous system. All disease-modifying treatments act on the peripheral compartment of the immune system by disrupting the sequence of events involved in the development of MS using non-specific immunosuppression or targeting-specific checkpoints. Monoclonal antibodies target macromolecules required for immune system function, mitoxantrone acts as a non-specific immunosuppressant, and beta-interferons block peripheral T-cell activation, pro-inflammatory cytokine release, and translocation of T-cells into the CNS. Together with glatiramer acetate (GA) , these drugs are the mainstay of management of relapsing, remitting MS, writes Dr Hartung and colleagues in their review paper published in the Journal of Neurology. The authors add, "Glatiramer acetate is the only disease-modifying treatment to have an immunomodulatory action directed specifically against the autoimmune process occurring in multiple sclerosis."GA acts in the periphery to recruit GA-specific T cells, which undergo clonal proliferation and drive the immune response towards a TH2 anti-inflammatory response. It has been suggested that GA-reactive T-cells also enter the brain in MS and home-in on areas of active inflammation. Upon activation, anti-inflammatory cytokines are released, which exert a bystander suppressor effect on the inflammatory process. They also release neurotrophic factors that might promote repair to myelin and neurons. "GA thus differs from the other immunomodulatory treatments of MS in that the key immune step that is regulated is within the nervous system at the site of the active inflammatory lesion," the authors say. They add that, although GA's primary action is on immune cells in the periphery and the agent probably never itself enters the CNS, its therapeutic effect may be carried into the site of the lesion by GA-reactive T-cells. "All effective therapies for MS target different steps of the autoimmune process and all act in the periphery to modify the properties, activity or trafficking of different autoreactive lymphocyte populations," the researchers write. Noting a "clear rationale" from studies in animal and patients that MS is "primarily a disease resulting from aberrant systemic immune responses which can be controlled to a large extent by interfering with these" Hartung et al. remark that whether this also pertains to the rarer forms of disease characterized by a relative paucity or absence of inflammatory cells in the CNS "remains to be seen".Reference...