T Cells Responsive to Myelin Basic Protein in Patients with Multiple Sclerosis

Allegretta, Mark; Nicklas, Janice A.; Subramaniam, Sriram; Albertini, Richard J.

doi:10.1126/science.1689076

Cited by 426 publications

(204 citation statements)

References 22 publications

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“…Daclizumab, a humanized Ab that binds CD25 and blocks its interaction with IL-2 (14), is currently in clinical development for relapsing-remitting multiple sclerosis (RRMS), a T cell-mediated neuroinflammatory disorder (15)(16)(17). Results from a 600-patient, randomized, double-blinded, placebo-controlled trial demonstrated that daclizumab has robust clinical efficacy (18).…”

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confidence: 99%

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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Regulatory T cells (Tregs) mediate immune tolerance to self and depend on IL-2 for homeostasis. Treg deficiency, dysfunction, and instability are implicated in the pathogenesis of numerous autoimmune diseases. There is considerable interest in therapeutic modulation of the IL-2 pathway to treat autoimmunity, facilitate transplantation tolerance, or potentiate tumor immunotherapy. Daclizumab is a humanized mAb that binds the IL-2 receptor α subunit (IL-2Rα or CD25) and prevents IL-2 binding. In this study, we investigated the effect of daclizumab-mediated CD25 blockade on Treg homeostasis in patients with relapsing-remitting multiple sclerosis. We report that daclizumab therapy caused an ∼50% decrease in Tregs over a 52-wk period. Remaining FOXP3+ cells retained a demethylated Treg-specific demethylated region in the FOXP3 promoter, maintained active cell cycling, and had minimal production of IL-2, IFN-γ, and IL-17. In the presence of daclizumab, IL-2 serum concentrations increased and IL-2Rβγ signaling induced STAT5 phosphorylation and sustained FOXP3 expression. Treg declines were not associated with daclizumab-related clinical benefit or cutaneous adverse events. These results demonstrate that Treg phenotype and lineage stability can be maintained in the face of CD25 blockade.

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confidence: 99%

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Huss

Mehta

Sharma

et al. 2015

The Journal of Immunology

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“…The disease is characterized by the presence of perivascular, inflammatory infiltrates that lead to demyelination, traits also characteristic of EAE. 116,117 Auto-reactive T cells are present in the peripheral circulation of both patients with MS and healthy individuals, 118 but only in the patients these cells are able to cross the blood-brain barrier and initiate the inflammatory process. MBP-reactive T cells derived from patients with MS are less dependent on B7-costimulation compared to cells from healthy individuals, and this can be expanded in vitro in the presence of blocking anti-CD28 monoclonal antibodies.…”

Section: Co-stimulatory Blockade Treatments In Human Autoimmune Diseasesmentioning

confidence: 99%

Modulating Co-Stimulation

Viglietta

Khoury

2007

Neurotherapeutics

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Summary:The modulation of co-stimulatory pathways represents a novel therapeutic strategy to regulate autoimmune diseases. Auto-reactive CD4ϩ T cells play a critical role in initiating the immune response leading to inflammation and autoimmune diseases. Blocking co-stimulatory signals prevents T-cell activation, thus diminishing autoimmune responses and possibly preventing the progression of autoimmune disease. Blockade of several co-stimulatory pathways has been investigated in animal models and has led to clinical trials testing specific blocking agents in humans. In this review we will describe the role of co-stimulatory pathways, primarily the CD28-B7 pathway, in autoimmune diseases, and we will present in vivo and in vitro studies supporting the efficacy of co-stimulation blockade in animal models of autoimmune disease. Finally, we will discuss the clinical therapeutic efficacy of blocking monoclonal antibodies in preventing or reducing autoantigen driven T-cell activation in humans with particular attention to the CD28/B7 pathway. Inhibiting co-stimulatory molecule interactions by using monoclonal antibodies seems to be an original approach to regulate autoimmune diseases in humans.

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“…45,46 A primary role for HLA-DRB1 in susceptibility to MS is consistent with a pathogenesis model, which involves a T-cell mediated autoimmune response against the 85-99 peptide of myelin basic protein (MBP). [47][48][49][50] The crystal structure of DRb1501 differs from other non DR2-related DRb molecules in that aromatic residues in the ligand are preferred in the large hydrophobic P4 pocket of the peptide binding domain. 51 For MBP, this pocket is primarily occupied by the aromatic side chain Phe92, acting as an important primary anchor and accounting for its high-affinity binding to the HLA-DRa0101/ DRb1501 heterodimer ( Figure 2).…”

Section: Rr-ms Sp-msmentioning

confidence: 99%

Multiple sclerosis genetics: leaving no stone unturned

2005

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Compelling epidemiologic and molecular data indicate that genes play a primary role in determining who is at risk for developing multiple sclerosis (MS), how the disease progresses, and how someone responds to therapy. The genetic component of MS etiology is believed to result from the action of allelic variants in several genes. Their incomplete penetrance and moderate individual effect probably reflects epistatic interactions, post-transcriptional regulatory mechanisms, and significant environmental influences. Equally significant, it is also likely that locus heterogeneity exists, whereby specific genes influence susceptibility and pathogenesis in some individuals but not in others. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic, and phenotypic information in well-controlled study groups will define a useful conceptual model of pathogenesis and a framework for understanding the mechanisms of action of existing therapies for this disorder, as well as the rationale for novel curative strategies.

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T Cells Responsive to Myelin Basic Protein in Patients with Multiple Sclerosis

Cited by 426 publications

References 22 publications

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

In Vivo Maintenance of Human Regulatory T Cells during CD25 Blockade

Modulating Co-Stimulation

Multiple sclerosis genetics: leaving no stone unturned

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