Cladribine tablets after treatment with natalizumab (CLADRINA) - rationale and design.

Background: Individual disease modifying therapies approved for multiple sclerosis (MS) have limited effectiveness and potentially serious side effects, especially when administered over long periods. Sequential combination therapy is a plausible alternative approach. Natalizumab is a monoclonal therapeutic antibody that reduces leukocyte access to the central nervous system that is associated with an increased risk of progressive multifocal leukoencephalopathy and disease reactivation after its discontinuation.

Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.

In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity.

The sequential natalizumab - alemtuzumab therapy in patients with relapsing forms of multiple sclerosis (SUPPRESS) trial - Part I: Rationale and objectives.

Background: Natalizumab is a recombinant humanized monoclonal antibody (mAb) against α4-integrin that is approved for relapsing forms of multiple sclerosis (MS). Natalizumab is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), and with disease reactivation after cessation of treatment that is likely mediated by an accumulation of pro-inflammatory lymphocytes in the blood during therapy. Alemtuzumab is a mAb against CD52 that reduces the number of peripheral lymphocytes.

Clinical trials in multiple sclerosis: past, present, and future.

For the past four decades, multiple sclerosis (MS) has been a focus for clinical trial development and execution. Advances in translational neuroimmunology have led to the development of effective disease-modifying therapies (DMTs) that greatly benefit patients with MS and mitigate their burden of disease. These achievements also stem from continued progress made in the definition and discovery of sensitive disease diagnostic criteria, objective disability assessment scales, precise imaging techniques, and disease-specific biomarkers.

Efficacy of Disease Modifying Therapies in Progressive MS and How Immune Senescence May Explain Their Failure.

The advent of disease modifying therapies (DMT) in the past two decades has been the cornerstone of successful clinical management of multiple sclerosis (MS). Despite the great strides made in reducing the relapse frequency and occurrence of new signal changes on neuroimaging in patients with relapsing remitting MS (RRMS) by approved DMT, it has been challenging to demonstrate their effectiveness in non-active secondary progressive MS (SPMS) and primary progressive MS (PPMS) disease phenotypes. The dichotomy of DMT effectiveness between RRMS and progressive MS informs on distinct pathogeneses of the different MS phenotypes.

CD11cCD88CD317 myeloid cells are critical mediators of persistent CNS autoimmunity.

Natalizumab, a humanized monoclonal antibody (mAb) against α4-integrin, reduces the number of dendritic cells (DC) in cerebral perivascular spaces in multiple sclerosis (MS). Selective deletion of α4-integrin in CD11c cells should curtail their migration to the central nervous system (CNS) and ameliorate experimental autoimmune encephalomyelitis (EAE). We generated CD11c.

The antioxidant MnTBAP does not effectively downregulate CD4 expression in T cells in vivo.

The antioxidant MnTBAP was previously shown to down-regulate the surface expression of CD4 molecule in T cells. This observation obviously holds great potential impact in a number of pathological human conditions, including autoimmunity. Three different single doses of MnTBAP reduced the frequency of CD4 cells.

Limitations of cell-lineage-specific non-dynamic gene recombination in CD11c.CreITGA4 mice.

Background: The Cre-lox system is a non-dynamic method of gene modification and characterization. Promoters thought to be relatively cell-specific are utilized for generation of cell-lineage-specific gene modifications.

Methods: CD11c.

Clinical trials in multiple sclerosis: potential future trial designs.

Clinical trials of new treatments in multiple sclerosis (MS) currently require large sample sizes and long durations in order to yield reliable results. The differential responses of an already heterogeneous population of MS patients to individual disease-modifying therapies (DMTs) will further complicate future trials. MS trials with smaller samples and faster outcomes are conceivable through the substitution of current clinical and MRI outcomes with objectively measureable genomic and proteomic biomarkers.

MAdCAM-1-Mediated Intestinal Lymphocyte Homing Is Critical for the Development of Active Experimental Autoimmune Encephalomyelitis.

Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified.

α4-integrin deficiency in B cells does not affect disease in a T-cell-mediated EAE disease model.

Objective: The goal of this study was to investigate the role of CD 19 B cells within the brain and spinal cord during CNS autoimmunity in a peptide-induced, primarily T-cell-mediated experimental autoimmune encephalomyelitis (EAE) model of MS. We hypothesized that CD19 B cells outside the CNS drive inflammation in EAE.

Methods: We generated CD19.

TLR3 agonism re-establishes CNS immune competence during 4-integrin deficiency.

Objective: Natalizumab blocks 4-integrin-mediated leukocyte migration into the central nervous system (CNS). It diminishes disease activity in multiple sclerosis (MS), but carries a high risk of progressive multifocal encephalopathy (PML), an opportunistic infection with JV virus that may be prompted by diminished CNS immune surveillance. The initial host response to viral infections entails the synthesis of type I interferons (IFN) upon engagement of TLR3 receptors.

PDCB does not promote CNS autoimmunity in the context of genetic susceptibility but worsens its outcome.

Background: Para-dichlorobenzene (PDCB) is an aromatic hydrocarbon contained in mothballs that is potentially neurotoxic. A potential pathogenic role of PDCB in MS pathogenesis has been suggested.

Methods: To determine the ability of chronic PDCB ingestion to induce CNS autoimmunity in a genetically susceptible mammalian species, naive myelin oligodendrocyte glycoprotein peptide (MOG)35-55 T cell receptor (TCR) transgenic mice (2D2) on the C57Bl/6 background were orally gavaged once daily with corn oil control, 125 mg/kg PDCB, or 250 mg/kg PDCB for 45 days.

Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease.

Background: Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown.

IL-12/IL-23p40 Is Highly Expressed in Secondary Lymphoid Organs and the CNS during All Stages of EAE, but Its Deletion Does Not Affect Disease Perpetuation.

Background: Interleukin (IL)-12 and IL-23 are heterodimers that share the p40 subunit, and both cytokines are critical in the differentiation of T helper (Th)1 and Th17 cells, respectively. Th1 and Th17 effector cells have been implicated in the pathogenesis of experimental autoimmune encephalitis (EAE), an animal model of the human central nervous system (CNS) autoimmune demyelinating disorder multiple sclerosis (MS). However, ustekinumab, a monoclonal antibody (mAb) against p40 failed to show efficacy over placebo in a phase II clinical trial in patients with MS.

A Single Amino Acid Substitution Prevents Recognition of a Dominant Human Aquaporin-4 Determinant in the Context of HLA-DRB1*03:01 by a Murine TCR.

Background: Aquaporin 4 (AQP4) is considered a putative autoantigen in patients with Neuromyelitis optica (NMO), an autoinflammatory disorder of the central nervous system (CNS). HLA haplotype analyses of patients with NMO suggest a positive association with HLA-DRB1* 03:01. We previously showed that the human (h) AQP4 peptide 281-300 is the dominant immunogenic determinant of hAQP4 in the context of HLA-DRB1*03:01.

Acute relapse after initiation of Siponimod in a patient with secondary progressive MS.

Sphingosine 1-phosphate (S1P) is a signaling molecule that binds to five G protein-coupled receptors (Proc Natl Acad Sci USA 108:751-756, 2011). Modulation of these receptors has been associated with pleiotropic biological effects in the immune, cardiovascular, and central nervous systems (CNS). The functional S1P receptor antagonist fingolimod was the first member of this class of pharmacotherapeutics to be approved for treatment of relapsing multiple sclerosis (MS).

Testing effects of glatiramer acetate and fingolimod in an infectious model of CNS immune surveillance.

Immune surveillance of the CNS is critical for preventing infections; however, there is no accepted experimental model to assess the risk of infection when utilizing disease-modifying agents. We tested two approved agents for patients with multiple sclerosis (MS), glatiramer acetate and fingolimod, in an experimental model of CNS immune surveillance. C57BL/6 mice were infected with the ME49 strain of the neuroinvasive parasite Toxoplasma gondii (T.

Human aquaporin 4281-300 is the immunodominant linear determinant in the context of HLA-DRB1*03:01: relevance for diagnosing and monitoring patients with neuromyelitis optica.

OBJECTIVE To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1*03:01. DESIGN In this controlled study with humanized experimental animals, HLA-DRB1*03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4.

Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells.

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4-producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23.

Rituximab therapy reduces organ-specific T cell responses and ameliorates experimental autoimmune encephalomyelitis.

Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity.