Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis

Mature T cells initially respond to Ag by activation and expansion, but high and repeated doses of Ag cause programmed cell death and can suppress T cell-mediated diseases in rodents. We evaluated repeated systemic Ag administration in a marmoset model of experimental allergic encephalomyelitis that closely resembles the human disease multiple sclerosis. We found that treatment with MP4, a chimeric, recombinant polypeptide containing human myelin basic protein and human proteolipid protein epitopes, prevented clinical symptoms and did not exacerbate disease. CNS lesions were also reduced as assessed in vivo by magnetic resonance imaging. Thus, specific Ag-directed therapy can be effective and nontoxic in primates.     

DC in multiple myeloma immunotherapy

Therapy for patients with multiple myeloma (MM) is currently unsatisfactory and most patients eventually succumb to relapsed disease. DCs are a subset of leukocytes with the capacity to initiate and control the adaptive immune response against many cancers, including MM. In MM patients, in vivo DC function is often abnormal, however, it appears that it can be restored by in vitro manipulation. This has led to the development of DC immunotherapy for MM patients. We review the background research leading to the recognition of an anti-MM immune response, and discuss abnormalities in DC function, potential tumor-associated Ags, and the results of clinical trials of DC immunotherapy in MM patients.     

IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: Current and future developments

Multiple sclerosis (MS), an autoimmune neurological disorder, is driven by self-reactive T helper (Th) cells. Research on the role of Th17 lymphocytes in MS pathogenesis has made significant progress in identifying various immunological as well as environmental factors that induce the differentiation and expansion of these cells, different subsets of Th17 cells with varying degrees of pathogenicity, and the role of the secreted effector cytokines. While approved therapies for MS offer significant benefit to patients, there remain unmet needs. Ongoing clinical trials aim to translate the advanced knowledge of Th17 cytokines to improved therapies. This review discusses the current status and future developments of research into the role of Th17 and related cytokines in MS pathogenesis and therapy.     

Apoptosis in multiple sclerosis

Several recent studies have provided evidence that apoptosis is an important feature in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. Apoptosis presumably plays a role in the immunoregulation via activation-induced T-cell death (AICD) and in local processes of tissue damage. In this review the dual role of apoptosis in the MS pathogenesis and its relevance regarding therapeutic concepts is discussed.     

Interferons in multiple sclerosis: ten years' experience

Interferons (IFNs) were considered for the treatment of patients with multiple sclerosis (MS) after the demonstration, based on small studies, of the efficacy of type IFN beta in decreasing the frequency of exacerbations in relapsing-remitting multiple sclerosis when administered intrathecally, subcutaneously, or intramuscularly. Three preparations of IFN beta are now approved in Europe and North America: chronologically IFN beta-1b (Berlex/Schering), IFN beta-1a given intramuscularly (Biogen), and IFN beta-1a given subcutaneously (Ares Serono). These treatments have now been in use for more than 10 years, and are supposed to decrease relapse rates. However a lot of questions remain unanswered: it is difficult to compare the various preparations; there remain controversies about the effects of different routes of administration and of different dosage preparations; the role of neutralizing antibodies remains partially understood; and the long term effect on disability has not yet been demonstrated.     

Antigen-specific therapies in multiple sclerosis

Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategies are discussed that are currently employed to selectively block the activation of T-cells reactive against myelin antigens.     

Insulin counter-regulation in multiple sclerosis

Fasting hypoglycemia is frequently observed in patients with Multiple Sclerosis (S.M.) showing orthostatic hypotension and defective thermoregulation, although they never complicate in hypoglycemic coma. The aim of this study was to evaluate glucose homeostasis in S.M. patients. Both insular and counter-insular regulating mechanisms were investigated by determination of glucose, insulin, C-peptide and cortisol plasmatic levels during OGTT, and subsequently by evaluating glucagon plasmatic levels after arginine administration (30 g., i.v.). Our results suggest that the increased susceptibility of S.M. patients to undergo fasting hypoglycemia could be related to some alterations in counter-insular mechanisms, generally included among neurovegetative modifications in S.M. patients and probably due to orthosympathetic function impairment.     

Heat shock protein 70: roles in multiple sclerosis

Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.     

Infectious etiology in multiple sclerosis: the debate continues

‘Demonstrating Infectious Cause: Viral and Bacterial Infections in MS and Related Disorders’ was held in Brighton, UK, 23–25 August 1999.