Differential requirements of naive and memory T cells for CD28 costimulation in autoimmune pathogenesis

Experimental autoimmune encephalomyelitis (EAE) is the most extensively studied animal model of the human disease multiple sclerosis (MS). In EAE, CNS demyelination is induced by immunization with myelin proteins or adoptive transfer of myelin-reactive C D ~ +T cells. Since the antigen specificity of the immune response believed to be responsible for the pathology of MS is not well defined, therapies that target aspects of T cell activation that are not antigen specific may be more applicable to the treatment of MS. As a result, understanding the role of costimulatory molecules in the activation of nai've and memory T cells has become an area of extensive investigation. Naive T cells require two signals for activation. Signal one is provided by engagement of the T cell receptor (TCR) with MHCIpeptide complexes and provides antigen specificity to the immune response. The second signal, termed costimulation, is usually provided by B7 molecules on APC to CD28 molecules expressed on T cells and is antigen-independent. This review will discuss our current understanding of costimulation in the induction and perpetuation of EAE, as well as the potential of costimulaton blockade in the treatment of MS

New and Emerging Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: What is New and What is to Come

The therapeutic landscape for multiple sclerosis (MS) is rapidly changing. Currently, there are eight FDA approved disease modifying therapies for MS including: IFN-β-1a (Avonex, Rebif), IFN-β-1b (Betaseron, Extavia), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), natalizumab (Tysabri), and fingolimod (Gilenya). This review will highlight the experience to date and key clinical trials of the newest FDA approved agents, natalizumab and fingolimod. It will also review available efficacy and safety data on several promising therapies under active investigation including four monoclonal antibody therapies: alemtuzumab, daclizumab, ocrelizumab and ofatumumab and three oral agents: BG12, laquinimod, and teriflunomide. To conclude, we will discuss where each of these new therapies may best fit into treatment algorithms

Chemotherapeutics in the treatment of multiple sclerosis

The likely pathogenic mechanisms of multiple sclerosis (MS) provide a sound rationale for investigating the efficacy of drugs possessing immunosuppressive or immunomodulatory properties. With proven efficacy, safety and tolerability, interferon beta formulations and glatiramer acetate have become the mainstay of initial treatment for patients with relapsing forms of MS. More recently, natalizumab, a humanized monoclonal antibody (mAb) against the cellular adhesion molecule α4-integrin, has been employed for patients with an inadequate response or lack of tolerability to an alternate MS therapy, or as initial therapy for patients with severe disease. Various agents initially developed for oncological indications, either as chemotherapeutics or mAbs, may also have current or future uses in MS treatment. Mitoxantrone is currently the only chemotherapeutic agent approved for treatment of MS in the United States, while in parts of Europe azathioprine is approved and widely used for MS treatment. Other chemotherapeutics that have been tested in MS to date include cyclophosphamide, methotrexate, cladribine, and the mAbs alemtuzumab and rituximab. While there has been varying evidence of efficacy for these compounds, each appears to be associated with serious risks that require careful consideration and management. Given the risks that have been demonstrated for available chemotherapeutic agents and while long-term postmarketing safety data are still not available for those agents in development, it seems prudent to carefully assess the possible use of chemotherapeutics in the treatment of MS. A thorough risk–benefit analysis is becoming increasingly important in the assessment of therapeutic options for this disabling disease