Induction of a non-encephalitogenic type 2 T helper-cell autoimmune responsein multiple sclerosis after administration of an altered peptide ligand ina placebo-controlled, randomized phase II trial
ABSTRACT In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.
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ABSTRACT: Introduction: CD8(+) T cells were originally considered to exert a suppressive role in demyelinating disease because of bias toward the CD4(+) T cell-mediated experimental autoimmune encephalomyelitis, the most common multiple sclerosis (MS) model. However, recent studies of human MS lesion samples and cerebrospinal fluid (CSF) provided compelling evidence about the pathogenic role of CD8(+) T cells. In this article, we discuss the theoretical roles of different CD8(+) T-cell subsets in MS. Areas covered: A revised focus from CD4(+) to CD8(+) T cell-mediated demyelinating disease is summarized. Clonal expansion of CD8(+) T cells in MS lesions and in vitro evidence that CD8(+) T cells injure every central nervous system (CNS) cell type and transect axons are discussed. The role of CD8(+) T cells in two animal models of MS and of regulatory, interleukin (IL)-17-secreting CD8(+) T cells is reviewed. Lastly, an overview about the pathogenic and/or beneficial role of various CD8(+) T-cell subsets is offered. Expert opinion: Growing evidence supports the pathogenic role of CD8(+) T cells. Clonally expanded CD8(+) T cells within MS lesions may damage the nervous system. Revealing the specific antigen is critical to design novel efficient treatments with minimal adverse effects. Increasing evidence exists for the role of regulatory, IL-17-secreting CD8(+) T cells in MS.Expert Opinion on Therapeutic Targets 07/2013; · 4.90 Impact Factor
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ABSTRACT: Introduction: Inhibition of self-reactive T cells through induction of antigen-specific immune tolerance holds the promise of effective treatment of autoimmune pathology with few side effects and preservation of normal immune functions. In multiple sclerosis (MS) several approaches have been tested already in clinical trials or are currently ongoing with the aim to inhibit myelin-reactive immune responses. Areas covered: This article provides an overview of the recent and ongoing strategies to inhibit specific immune responses in MS, including different applications of myelin peptide-based approaches, T-cell vaccination, DNA vaccination and antigen-coupled cells. Expert opinion: Despite difficulties in translation of antigen-specific therapies in MS, novel approaches have the potential to effectively induce immune tolerance and ameliorate the disease. To improve efficacy of treatments, future trials should include patients in the early phases of the disease, when the autoimmune response is predominant and immune reactivity still focused. The target antigens are not fully defined yet, and robust immunomonitoring assays should developed to provide mechanistic proof of concept in parallel to showing efficacy with respect to inhibiting inflammatory disease activity in the central nervous system (CNS).Expert Opinion on Investigational Drugs 10/2013; · 4.74 Impact Factor
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ABSTRACT: In a previous study, we showed that the Ly6G(-)CD11b(+) blood monocytes residing in naïve mice are intrinsically immunosuppressive and that loss of this suppressive function may contribute to the development of autoimmunity in experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis. Here we report that mice treated with a modified superantigen coupled to myelin oligodendrocyte glycoprotein 35-55 (MOG(35-55))peptide (DM-MOG(35-55)) suppressed the development of EAE. The treatment was associated with impaired MOG(35-55)-specific T cell proliferation and a decrease in IL-17 and IFNγ production in the draining lymph nodes. Analysis of circulating blood immune cells showed that the suppressor function of Ly6G(-)CD11b(+) blood monocytes wasreduced in EAE mice, but was restored in mice treated with DM-MOG(35-55). Importantly, adoptive transfer of blood CD11b(+)Ly6G(-) cells isolated from DM-MOG(35-55)-treated mice protected recipient mice from developing EAE. Together, these results show that DM coupled to the auto-antigen MOG(35-55):1) suppresses EAE via antigen-specific suppression of T cell responses, and 2) re-establishes suppressor function ofLy6G(-)CD11b(+) blood monocytes. Auto-antigens coupled to DM could therefore represent a new therapeutic approach for controlling inappropriate inflammation in autoimmune diseases such as multiple sclerosis by inducing antigen-specific T cell suppression.Autoimmunity 02/2013; · 2.77 Impact Factor