Selective targeting of K(2P)5.1 may hold therapeutic promise for MS and putatively other T-cell-mediated disorders.

BackgroundNatalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients.MethodologyA combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs.Principal FindingsBinding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25highCD127lowFoxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment.ConclusionsWe provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD41 Foxp31 regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.Key words: Blood-brain barrier . Brain microvascular endothelial cells . Migration . MS . Regulatory T cells Supporting Information available online IntroductionNaturally occurring CD4 1 Foxp3 1 regulatory T cells (Treg) are essential mediators of peripheral immune tolerance, regulating inflammation in the context of infection, autoimmunity, neoplasia and transplant rejection [1]. In addition to balancing immunity within lymphoid tissues, Treg enter non-lymphoid target sites of inflammation, exerting their anti-inflammatory function there [2][3][4][5]. First, regulatory as well as effector T-cell subsets have to undergo a non-lymphoid homing receptor switch after entering secondary lymphoid tissue [6]. Upon encountering specific antigens provided by dendritic cells in the T-cell area [7], the lymphocytes acquire an activated phenotype, expressing distinct surface markers of non-lymphoid homing à These authors contributed equally to this work. We here combined various murine and human models quantifying transmigratory capacity and locomotion to determine how constitutive, innate Treg motility translates into diapedesis across CNS endothelium. Results Murine Treg exhibit enhanced migratory capacity in vitro and in vivoWe first characterized lymph node-derived regulatory and nonregulatory T-cell subsets with regard to their expression of surface markers indicative for adhesion, migration and activation. In line with previous results for CCR6 [17], murine Treg consistently showed a significantly higher expression for all inspected markers apart from CCR7, where the higher expression was not significant (p 5 0.126), and a significantly lower e...

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To study clinical and paraclinical effects of natalizumab in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP).

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