Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study.

Objective: To evaluate the safety and efficacy of a humanized anti-interleukin-6 receptor antibody, tocilizumab (TCZ), in patients with neuromyelitis optica (NMO).

Methods: Seven patients with anti-aquaporin-4 antibody (AQP4-Ab)-positive NMO or NMO spectrum disorders were recruited on the basis of their limited responsiveness to their current treatment. They were given a monthly injection of TCZ (8 mg/kg) with their current therapy for a year.

Differential effects of fingolimod on B-cell populations in multiple sclerosis.

Background: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells.

Objective: To clarify the effects of fingolimod on B-cell populations in patients with MS.

Methods: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts.

Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory disease characterized by recurrent attacks of optic neuritis and myelitis. It is generally accepted that autoantibodies against aquaporin 4 water channel protein play a pathogenic role in neuromyelitis optica. We have recently reported that plasmablasts are increased in the peripheral blood of this autoimmune disease, and are capable of producing autoantibodies against aquaporin 4.

[Pathogenesis of chronic inflammatory demyelinating polyneuropathy].

Chronic inflammatory demyelinating polyneuropathy (CIDP) is considered to be a demyelinating autoimmune disorder in the peripheral nervous system. Concerning cellular immune response, activity of IFN-gamma producing Th1 and IL-17 producing Th17 cells might be accelerated in patients with CIDP, while regulatory function of CD4+ CD25(high) Foxp3+ regulatory T cells might be diminished. Humoral immune responses against several myelin components such as myelin protein zero and gangliosides such as GM1 might be also induced in a part of patients with CIDP.

CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4(+) autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS.

Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab.

Neuromyelitis optica (NMO) is a disabling autoimmune disease associated with an elevation of anti-aquaporin 4 (AQP4) autoantibodies. Here, we present a case with NMO who responded to monthly administration of the anti-IL-6 receptor antibody tocilizumab. The treatment rapidly reduced the elevated numbers of plasmablasts and anti-AQP4 autoantibodies in the patient.

Increase of Ki-67+ natural killer cells in multiple sclerosis patients treated with interferon-β and interferon-β combined with low-dose oral steroids.

Interferon-β (IFN-β) is known to expand regulatory CD56(bright) natural killer (NK) cells in multiple sclerosis (MS). In this cross-sectional study we show that MS patients treated with IFN-β alone or in combination with low-dose prednisolone displayed increased proportion of all NK cell subsets in the active phase of the cell cycle (Ki-67+). There was no difference in NK cell apoptosis markers.

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica.

Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19(int)CD27(high)CD38(high)CD180(-) phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse.

Th17 Cells and autoimmune encephalomyelitis (EAE/MS).

Multiple sclerosis (MS) is a CD4+ T cell-mediated autoimmune disease affecting the central nervous system. It was largely accepted that Th1 cells driven by IL-12 were pathogenic T cells in human MS and experimental autoimmune encephalomyelitis, an animal model of MS. Recent data have established that IL-17-producing CD4+ T cells, driven by IL-23 and referred to as Th17 cells, play a pivotal role in the pathogenesis of EAE.

Cutting edge: Human Th17 cells are identified as bearing CCR2+CCR5- phenotype.

Recent reports have shown that IL-17-producing CD4+ T cells (Th17 cells) belong to a distinct helper T cell lineage and are critically involved in the pathogenesis of autoimmune diseases and allergies. However, the chemokine receptor profile of Th17 cells remains to be clarified. In this study, we report that human Th17 cells are identified as CCR2+CCR5- memory CD4+ T cells.

Differential expression of CD11c by peripheral blood NK cells reflects temporal activity of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease, showing a great degree of variance in temporal disease activity. We have recently demonstrated that peripheral blood NK cells biased for secreting IL-5 (NK2 bias) are associated with the remission state of MS. In this study, we report that MS patients in remission differentially express CD11c on NK cell surface (operationally defined as CD11chigh or CD11clow).

T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients.

To clarify the molecular background underlying the heterogeneity of multiple sclerosis (MS), we characterized the gene expression profile of peripheral blood CD3+ T cells isolated from MS and healthy control (CN) subjects by using a cDNA microarray. Among 1258 cDNAs on the array, 286 genes were expressed differentially between 72 untreated Japanese MS patients and 22 age- and sex-matched CN subjects. When this set was used as a discriminator for hierarchical clustering analysis, it identified four distinct subgroups of MS patients and five gene clusters differentially expressed among the subgroups.

The regulatory role of natural killer cells in multiple sclerosis.

Multiple sclerosis is a chronic demyelinating disease of presumed autoimmune pathogenesis. The patients with multiple sclerosis typically shows alternating relapse and remission in the early stage of illness. We previously found that in the majority of multiple sclerosis patients in a state of remission, natural killer (NK) cells contain unusually high frequencies of the cells expressing CD95 (Fas) on their surface (>36.

IL-7-dependent homeostatic proliferation in the presence of a large number of T cells in gld mice.

In gld mice, CD4 and 8-double-negative (DN) T cells as well as naive and memory-phenotype T cells accumulate in the peripheral lymphoid organs. Although Fas ligand (L) defect accounts for the progressive accumulation of abnormal DN T cells, the existence of other mechanisms which may be involved in the defective homeostasis in gld mice has been unclear. In this study, we analyze T-cell homeostasis in gld mice using adoptive transfer systems.

Positive and negative selection of T cell repertoires during differentiation in allogeneic bone marrow chimeras.

T cells acquire immune functions during expansion and differentiation in the thymus. Mature T cells respond to peptide antigens (Ag) derived from foreign proteins when these peptide Ag are presented on the self major histocompatibility complex (MHC) molecules but not on allo-MHC. This is termed self-MHC restriction.

Tumour necrosis factor-alpha but not lipopolysaccharide enhances preference of murine dendritic cells for Th2 differentiation.

Using murine spleen-derived dendritic cells (DC) and DO11.10 T cells specific for ovalbumin (OVA), the influences of maturational condition and antigen dose on the capability of DC to induce helper T-cell (Th) differentiation were analysed. Immature DC (iDC) with high- or low-dose OVA(323-339) predominantly induced Th1 or Th2 responses in DO11.

Syngeneic mixed lymphocyte reaction (SMLR) with dendritic cells: direct visualization of dividing T cell subsets in SMLR.

Syngeneic mixed lymphocyte reaction (SMLR) has been considered to represent T cell response to self antigens. In this study using stimulator dendritic cells (DC), we analyzed cellular components responding to the syngeneic DC. It was shown that the predominant dividing cells were CD8(+) T cells although the response of CD4(+) T cells was essential for initiation of SMLR.