Thl7在多发性硬化中发病机制及相关治疗进展

多发性硬化（MS）是以中枢神经系统白质炎性脱髓鞘病变为主要特点的T细胞介导的自身免疫性疾病,其具体发病机制不明。目前认为遗传因素在发病中起主要作用,环境中的某种因素如病毒的感染的刺激也可能引发疾病。以往认为CD4^＋自身反应性Th1与Th2之间功能紊乱是主要机制,但最新研究表明Th17细胞在MS的发病过程中起主要作用。本文则对近期有关Th17细胞在MS发病中的研究及进展作一概括论述,并提出较为新的针对Th17细胞可能的治疗方式。     

Macrophages and the regulation of self-reactive T cells

Macrophages are professional scavengers of apoptotic and necrotic cells, and hence constantly take up self antigens. Paradoxically, macrophages are also professional antigen-presenting cells, which would seem to invite autoimmune disorders. Moreover, macrophages are effector cells in the tissue-destruction phase of autoimmune disorders, where they encounter additional self antigens in the stimulatory context of chronic inflammation. This review examines the array of immunosuppressive mechanisms which may help macrophages suppress unwanted T cell responses, and considers the consequences of a breakdown in these negative-regulatory systems in autoimmunity.     

Teriflunomide for oral therapy in multiple sclerosis

Teriflunomide, the active metabolite of an approved antirheumatic drug, is an emerging oral therapy for multiple sclerosis (MS). Next to the inhibition of pyrimidine biosynthesis and proliferation of activated lymphocytes, it seems to have multiple anti-inflammatory and immunomodulating effects. Phase II and III clinical trials in relapsing MS demonstrated favorable safety and tolerability of the drug, as well as clinical efficacy, with a significant reduction of relapse rate, comparable with those of the available injectable immunomodulatory agents. While multiple other studies with teriflunomide are currently ongoing, its exact place in future treatment algorithms for MS is difficult to predict. It may be a good alternative for patients wishing to have an oral treatment with relatively large data regarding long-term safety.     

多发性硬化的免疫抑制治疗

<正>多发性硬化是发生在中枢神经系统的一种自身免疫性疾病,复发率高,致残率高。其主要病理变化是免疫活性细胞浸润,分泌炎性细胞因子,导致神经纤维的髓鞘脱失,轴索变性,胶质增生,瘢痕形成。多发性硬化的确切病因不明,研究认为遗传和环境因素参与致病。在环境因素中,外来入侵微     

Venom therapy in multiple sclerosis

To date many people with multiple sclerosis (MS) seek complementary and alternative medicines (CAM) to treat their symptoms as an adjunct to conventionally used therapies. Among the common CAM therapies, there is a renewed interest in the therapeutic potential of venoms in MS. The efficacy of this therapeutic method remains unclear. However, venom-based therapy using bee, snakes and scorpions venom and/or sea anemones toxin has been recently developed because current investigations have identified the various components and molecular mechanism of the effects of venoms under in vitro and in vivo conditions. The aim of this review is to describe the recent findings regarding the role of venoms and their components in treatment of MS disease and that whether venom therapy could be recommended as a complementary treatment or not.     

多发性硬化的药物治疗研究进展

多发性硬化(MS)的药物治疗方案近年来发生了显著的变化:从作用于全身副作用较大的激素类药物发展为针对特定免疫细胞的靶向药物;从经sc、im或iv等非肠胃途径给药发展为方便的口服药物。在诸多治疗方案中,免疫调节类药物、神经保护类药物和干细胞移植疗法目前在临床上占主导地位。随着对MS病理学研究的发展,免疫调节类药物已逐步被人们所认识。按免疫调节类药物直接靶向的免疫细胞的不同对药物进行分类,对药物的作用特点、临床使用情况、毒副作用等进行综述,同时对神经保护剂和干细胞移植疗法做简要阐释。     

Benefit-risk assessment of interferon-b therapy for relapsing multiple sclerosis

IFN-β therapy has a central place in the management of relapsing multiple sclerosis, as demonstrated by the pivotal studies of three IFN-β treatment regimens. However, questions remain concerning the optimal choice of preparation and dose regimen. The benefit?risk ratio for a given preparation is an important consideration in optimising treatment for an individual patient. Of the three IFN-β preparations currently available, all have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while benefit on progression measures (disability and total lesion burden) has been less consistent. Available data across studies suggest that dose and/or dose frequency are important determinants of efficacy, a finding supported by direct comparative data on different IFN-β preparations. The added benefit of high-dose, high-frequency IFN-β therapy is not achieved at the cost of compromised safety or tolerability, indicating that three-times-weekly treatment offers a superior benefit?risk ratio to once-weekly treatment. The potential advantages of IFN-β therapy may be enhanced by regular monitoring of efficacy and safety in order to maintain patients on therapy beyond the first few months when side effects are most apparent.     

Development of interferon-beta as a therapy for multiple sclerosis

The introduction of interferon (IFN) therapy represents a milestone in multiple sclerosis (MS) treatment. This class of drugs is part of an evolving area of MS therapy that utilises immunomodulating agents to alter the immune processes thought to be integral to the development of MS. IFN-beta has been developed in three different formulations that have proven benefit in reducing exacerbations in relapsing-remitting MS. Two of the formulations consist of the naturally-occurring amino acid sequence of IFN-beta and are referred to as IFN-beta(1a). One is delivered intramuscularly (IM IFN-beta(1a)), and the second form of IFN-beta(1a) is delivered subcutaneously (SC IFN-beta(1a)). The third formulation of IFN-beta, known as IFN-beta(1b), consists of a modified amino acid sequence containing a cysteine to serine mutation at amino acid 17 and a deletion of the amino terminal methionine. This review describes the evolution of IFNs as therapeutics for MS.     

Benefit-risk assessment of interferon-beta therapy for relapsing multiple sclerosis

IFN-beta therapy has a central place in the management of relapsing multiple sclerosis, as demonstrated by the pivotal studies of three IFN-beta treatment regimens. However, questions remain concerning the optimal choice of preparation and dose regimen. The benefit-risk ratio for a given preparation is an important consideration in optimising treatment for an individual patient. Of the three IFN-beta preparations currently available, all have shown benefit on activity measures (relapses and active lesions apparent on magnetic resonance imaging), while benefit on progression measures (disability and total lesion burden) has been less consistent. Available data across studies suggest that dose and/or dose frequency are important determinants of efficacy, a finding supported by direct comparative data on different IFN-beta preparations. The added benefit of high-dose, high-frequency IFN-beta therapy is not achieved at the cost of compromised safety or tolerability, indicating that three-times-weekly treatment offers a superior benefit-risk ratio to once-weekly treatment. The potential advantages of IFN-beta therapy may be enhanced by regular monitoring of efficacy and safety in order to maintain patients on therapy beyond the first few months when side effects are most apparent.     

Glatiramer acetate therapy for multiple sclerosis: a review

The past decade has witnessed a revolution in the treatment of multiple sclerosis (MS), the most common demyelinating disorder of the human CNS. After being considered as an untreatable disease for more than a century, six disease-modifying treatments have been approved between 1993 and 2006. Glatiramer acetate (GA) is a worldwide drug approved for the treatment of relapsing-remitting MS in 1996. The drug is a synthetic copolymer of four amino acids based on the composition of myelin basic protein, one of several putative autoantigens implicated in the pathogenesis of MS. Three separate double-blind, placebo-controlled trials have established its efficacy in relapsing-remitting MS. Observations from an ongoing study, the longest prospective study in MS therapeutics so far, suggest that the effect of GA in reducing the relapse rate and neurological disability is maintained over a 10-year period. Independent investigators have identified several putative immunological mechanisms of action of GA, with the unique observation of the generation of GA-reactive T-helper 2 (anti-inflammatory) polarised lymphocytes within days to weeks of initiating therapy and sustaining an anti-inflammatory milieu for years in the peripheral immune system and, presumably, in the CNS. Emerging data from immunological and imaging studies quantifying axonal injury in the brain point towards neuroprotective abilities of GA. Combined with its remarkable safety and tolerability, long-term efficacy and neuroprotective effect, GA presents it self as a first-line choice in relapsing-remitting MS, and holds immense promise in developing its potential as a combination therapy in MS, as well as extending its indications to other neurodegenerative diseases.     

Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects

T cells are important mediators of autoimmune inflammation in relapsing–remitting multiple sclerosis (RRMS). Previous studies found that deferiprone, an iron chelator, suppressed disease activity in a mouse model of multiple sclerosis, and inhibition of T cell proliferation was implicated as a putative mechanism. The objective of the present study was to examine the effects of deferiprone on suppressing in vitro responses of T cells from control and RRMS subjects. Peripheral blood T cells were co-stimulated with anti-CD3+anti-CD28 and cultured with or without interleukin 2 (IL-2). Proliferating CD4+ T cells from control and RRMS subjects, cultured with or without IL-2, decreased in response to 75 μM deferiprone, although the extent of decreased proliferation of CD4+ T cells from RRMS subjects was less than for control subjects. Proliferating CD8+ T cells from control subjects, cultured with or without IL-2, also decreased in response to 75 μM deferiprone, and this decrease was seen in proliferating CD8+ T cells from RRMS cultured with IL-2. CD4+CD25+ and CD8+CD25+ cells from control subjects, cultured with or without IL-2, declined in 75 μM deferiprone, but the decrease was smaller than for the CD4+ and CD8+ proliferative responses. CD4+CD25+ and CD8+CD25+ cells from RRMS subjects showed more variability than for control subjects, but CD4+CD25+ cultured with IL-2 and CD8+CD25+ cells cultured without IL-2 significantly declined in 75 μM deferiprone. CD4+FoxP3+ and CD4+CD25+FoxP3+ cells tended to remain constant or increase. In summary, deferiprone induced declines in proliferative responses at a dosage that is within peak serum pharmacological concentrations.     

Oral laquinimod therapy in relapsing multiple sclerosis

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Early treatment reduces the number of relapses, limits progression of disability, and improves quality of life; however, existing therapies are only partially effective and require parenteral administration. Objective: To review current experience with laquinimod as a novel immunomodulatory therapy for MS. Results: Laquinimod is a new quinolonecarboxamide that has demonstrated efficacy in animal models of several autoimmune diseases, including MS. It shows immunomodulatory effects, likely through Th1/Th2 shift, but does not lead to immunosuppression. Laquinimod is metabolized in the liver, primarily by the CYP3A4 enzyme. Phase II studies in relapsing MS demonstrate a dose-response effect on disease activity, measured by number of active lesions on brain magnetic resonance imaging, and show favorable tolerability and safety based on clinical and laboratory indicators. Two Phase III studies currently in progress are evaluating the efficacy of laquinimod 0.6 mg/day in relapsing MS. The drug was granted a fast track review by the FDA in 2009. Conclusion: Laquinimod is a novel, orally administered immunomodulator that has advanced to the pre-submission stage and may become an alternative to the current injectable first-line treatments for relapsing MS.     

Chemokine receptor antagonism as a new therapy for multiple sclerosis

New information about the role of tissue inflammation in the pathogenesis of multiple sclerosis (MS) has driven a search for effective and specific therapeutics that address leukocyte trafficking. These developments in understanding MS are complemented by advances in clarifying the molecular mechanisms of leukocyte extravasation and providing the knowledge base needed to modulate tissue inflammation. Of particular interest are the chemokines and their receptors. Chemokines constitute a large family of chemoattractant peptides that regulate the vast spectrum of leukocyte migration events. This review discusses MS and proposes that identifying the chemokines and receptors involved in the inflammation associated with this disorder may lead to therapeutic intervention.     

Chemokine receptor antagonism as a new therapy for multiple sclerosis

New information about the role of tissue inflammation in the pathogenesis of multiple sclerosis (MS) has driven a search for effective and specific therapeutics that address leukocyte trafficking. These developments in understanding MS are complemented by advances in clarifying the molecular mechanisms of leukocyte extravasation and providing the knowledge base needed to modulate tissue inflammation. Of particular interest are the chemokines and their receptors. Chemokines constitute a large family of chemoattractant peptides that regulate the vast spectrum of leukocyte migration events. This review discusses MS and proposes that identifying the chemokines and receptors involved in the inflammation associated with this disorder may lead to therapeutic intervention.     

Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab

Immunologists have long hypothesized that particular 'molecular addresses' govern lymphocyte entry to a given organ. In 1992, alpha4beta1 integrin was identified as the key molecule involved in homing to inflamed regions of the brain. An antibody to alpha4beta1integrin blocked paralysis in an animal model of multiple sclerosis, and the humanized monoclonal antibody natalizumab, which binds alpha4beta1 integrin, reduced relapses 66% in clinical trials in multiple sclerosis. Three months after its expedited approval by the FDA, natalizumab was removed from the market after two cases of deadly progressive multifocal leukoencephalopathy were reported among the few thousand patients who had taken this drug in those clinical trials.     

Pharmacogenomics of multiple sclerosis: in search for a personalized therapy

Background: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that affects young adults and provokes severe disability, imposing a high health and social burden. Current therapies for MS include interferon-β, glatiramer acetate, natalizumab and chemotherapy. These therapies decrease the number of relapses and partially prevent disability accumulation. However, their efficacy is only moderate, they have common adverse effects and impose a high cost to health systems. The identification of biomarkers will allow responders and non-responders to therapy to be identified, increasing the efficacy and adherence to therapy, and the pharmaco-economic profile of theses drugs. Objectives and Conclusion: In this review we examine the pharmacogenetic studies that have evaluated the clinical response to interferon-β, and to a lesser extent, glatiramer acetate and natalizumab. Finally, we discuss how systems biology can be used to integrate biological and clinical data in order to develop personalized medicine for MS.     

Immune therapy of multiple sclerosis - future strategies

Baseline disease-modifying therapies (DMTs) for multiple sclerosis (MS) include three different preparations of interferon-beta (IFN-β) and glatiramer acetate (GA). These substances reduce relapse rates, side-effects are tolerated by most patients and - after more than 15 years of experience - the long-term safety profile for these drugs can be appraised as very good. In 2006, the therapeutic tool kit was augmented by the first monoclonal antibody, natalizumab, approved as monotherapy for treatment-refractory highly active MS. The restriction to these patient groups results from the rare, but fatal risk of JC virus-induced progressive multifocal leukoencephalopathy (PML). The first oral agent (fingolimod) was approved in 2010 for the United States and in 2011 for Europe. As a further option for therapy escalation the chemotherapeutic agent mitoxantrone is approved for non-responding relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS). The use of mitoxantrone is limited by severe cardiotoxicity and the risk of treatment related acute leukemia. However, despite the fact that therapeutic options for MS have significantly been widened over the past decade new treatment options and more convenient modes of application are needed to enhance efficacy and improve adherence to therapy. This article will review recent developments in MS treatments focusing on oral agents (cladribine, fingolimod, BG00012, teriflunomide and laquinimod) and novel monoclonal antibodies (alemtumzumab, daclizumab, ocrelizumab, ofatumumab).