Immunotherapy Of Multiple Sclerosis Research Articles

Is there a Place for ‘Immuno‘ in the Immunotherapy of Multiple Sclerosis?

Paolo Muraro Imperial College London, UK some T-cell receptor (TCR) transgenic mouse models develop spontaneous a utoimmune disease [11]. However, there are dissenting views on the role of the immune system in the pathogenesis of MS, with some emphasizing the hypothesis of a primary neurodegenerative component [12]. Arguments that have been raised are that CNS pathology in MS is not always associated with inflammation, that it is often difficult to detect T-cell responses to neuroantigens in MS patients (which are also found in healthy control subjects), and that the genetic associations with immune function genes is relatively weak. Furthermore, EAE may not be a perfect model of MS, but rather a model for acute CNS inflammation [13].

Evidenzbasierte Patienteninformation – dargestellt am Beispiel der Immuntherapie bei Patienten mit Multipler Sklerose

The article elucidates consideration of scientific criteria for the development and design of evidence-based patient information (EBPI). Immunotherapy of multiple sclerosis serves as an example. Since in EBPI lack of evidence or ambiguities in available evidence are explicitly communicated, processing of EBPI does not necessarily lead to certainty about benefit and harms of medical interventions. However, only if the information is comprehensive in this respect can the EBPI be regarded as a robust basis for an informed choice. EBPI requires substantial developmental efforts. Regarding the growing number of medical interventions and the half-life of information, the question of responsibility for provision of EBPI is crucial. A vision is drafted in which EBPI is driven by demand of the patients and the public and is provided according to a costs-by-cause principle by those who distribute usual information hitherto. Trained patient advocates can appraise quality of information by use of instruments that consider criteria of EBPI. Critical health literacy should evolve early in school and can later on enhance usefulness of EBPI for people concerned with health issues.

Design and Synthesis of a Cyclic Double Mutant Peptide (cyclo(87−99)[A91,A96]MBP87−99) Induces Altered Responses in Mice after Conjugation to Mannan: Implications in the Immunotherapy of Multiple Sclerosis

Altered peptide ligands that alter immune responses are a promising approach to the immunotherapy of multiple sclerosis. Cyclic peptides are of interest because the limited stability of linear peptides restricts their use in vivo. We designed and synthesized a cyclic double mutant peptide from MBP(87-99)-[cyclo(87-99)[A(91),A(96)]MBP(87-99)]. Immunization of mice, in CFA reduced Th1 responses. However, when conjugated to reduced mannan, a significant further reduction of Th1 responses and moderate Th2 responses were induced.

Recent clinical trials and future therapies

Immunotherapy for multiple sclerosis (MS) has developed extremely successfully during the past decade and a number of new strategies were developed for the treatment of the disease. Examples include therapeutic strategies targeting leukocyte differentiation molecules, costimulatory molecules, anti-adhesion molecules, chemotaxis, novel immunomodulators, autologous stem cell transplantation, anti-infectious therapies and strategies for neuroprotection, neurorepair and remyelination. Here we describe examples of monoclonal antibodies, a novel immunosuppressant and interesting neuroprotective strategies.

Monitoring of multiple sclerosis immunotherapy

Applying microarray technology to identify new diagnostic and prognostic markers in peripheral blood cells (PBC) after therapeutic intervention opens great perspectives regarding patient subclassification. Three recombinant products of the pleiotropic agent interferon beta (rIFN-beta) are available for disease modifying therapy of relapsing remitting multiple sclerosis (RRMS), a complex inflammatory autoimmune disease that targets the central nervous system. They differ according to formulation, route of administration and dosage regimens. The currently, only partially understood mechanism of action of injected rIFN-beta into human organisms needs provision with accessory key molecules; in addition, the significance of established clinical IFN-beta response criteria that distinguish responding from non-responding patients remain unclear.With respect to these major questions, we discuss promising candidates on the gene transcription level, attained from scientific MS literature that included a longitudinal aspect. Reviewed studies were in part carried out with distinct gene interrogating platforms (GeneArrays; RT-PCR), settings (in vitro; ex vivo), and study designs (drug formulations and regimen; inclusion criteria and clinical endpoints), hampering meaningful meta-analysis. Nevertheless, PBC from therapy-naïve MS patients, rIFN-beta treated MS patients, and healthy controls served to characterize facets of both the disease and its treatment. Hence, the field of MS transcriptomics in immunomodulatory therapy is (by far) not adequately understood and should be embedded into systems biology disciplines, yielding multi-layer analyses that deliver timely identification of MS subjects who will profit from applied rIFN-beta therapy.

Review: Escalating immunotherapy of multiple sclerosis

Basic disease-modifying treatment for relapsing forms of active multiple sclerosis (MS) is now available in many countries with high prevalence rates, for this chronic inflammatory disease of the central nervous system. Several lines of evidence support early immunomodulatory treatment with either recombinant interferon-beta or glatiramer acetate, and positive results from phase III trials encourage start of treatment even in patients with clinically isolated syndromes (CIS). However, currently available drugs for basic therapy are only partially effective and patients may still encounter relapses or disease progression. As treatment-refractory, clinically active MS can quickly lead to irreversible neurological disability there is an urgent need for effective escalating strategies. Patients with suboptimal treatment response to basic therapy have been treated with combination therapies, cytotoxic drugs (such as mitoxantrone and cyclophosphamide) or autologous hematopoietic stem cell transplantation. Recently, the monoclonal antibody, natalizumab, was added to this armamentarium. None of these strategies have been vigorously evaluated in large randomized, controlled phase III trials with patients who failed basic therapy. Therefore, the decision to escalate immunotherapy is still based on limited evidence. This article will review potential candidates for intensified immunosuppression and call for innovative study designs to better evaluate escalating immunotherapy in MS.

Future Research Directions in Multiple Sclerosis Therapies

The success of presently available injectable immunomodulatory therapies in treating multiple sclerosis has led to heightened interest in finding even more efficacious and better tolerated therapies. Several oral agents have shown efficacy in phase-II clinical trials and are now entering phase-III pivotal trials. In addition, monoclonal antibodies targeting surface receptors on various cells of the peripheral immune system have also shown efficacy in early studies and will soon be entering phase III. All of these approaches target immune molecules that are not specific for multiple sclerosis (MS) and carry inherent risk of infection and systemic side effects. Novel immunotherapies in preclinical or phases I to IIa testing are attempting to more selectively target pathogenic effector cells and thereby block abnormal immune cell activation without compromising normal healthy immune responses. The induction of tolerance to self-proteins continues to be a goal of MS immunotherapy, but as yet has not been accomplished outside of the laboratory. There is increasing awareness of the need to understand and modulate nonclassical immune targets as well as central nervous system degenerative processes. The roles of vitamins, antimicrobials, and hormones continue to be studied. The mechanisms of neurodegeneration in MS are likely multifactorial and include direct damage by T cells and humoral immunity as well as oxidative stress, glutamate-mediated excitotoxicity, and neuronal and oligodendrocyte apoptosis. Neuroprotective drugs that were once only considered for classical degenerative diseases, such as amyotrophic lateral sclerosis and Parkinson's disease, are now being considered in MS.

T-cell-based immunotherapy in multiple sclerosis: induction of regulatory immune networks by T-cell vaccination

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with presumed autoimmune origin. Pathogenic autoimmune responses in MS are thought to be the result of a breakdown of self tolerance. Several mechanisms account for the natural state of immunological tolerance to self antigens, including clonal deletion of self-reactive T cells in the thymus. However, autoimmune T cells are also part of the normal T-cell repertoire, supporting the existence of peripheral regulatory mechanisms that keep these potentially pathogenic T cells under control. One such mechanism involves active suppression by regulatory T cells. It has been indicated that regulatory T cells do not function properly in autoimmune disease. Immunization with attenuated autoreactive T cells, T-cell vaccination, may enhance or restore the regulatory immune networks to specifically suppress autoreactive T cells, as shown in experimental autoimmune encephalomyelitis, an animal model for MS. In the past decade, T-cell vaccination has been tested for MS in several clinical trials. This review summarizes these clinical trials and updates our current knowledge on the induction of regulatory immune networks by T cell vaccination.

Immunopathogenesis and immunotherapy of multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the CNS that is characterized by inflammation, demyelination and axonal injury. Although the etiology of MS is still unknown, many findings point toward a central role for the immune system in the pathogenesis of the disease. This hypothesis is strongly supported by the beneficial effects of immunomodulatory and immunosuppressive therapy on disease activity. Over the past few years, substantial progress has been made in deciphering the immune response in MS. Although animal models have advanced our knowledge of basic mechanisms of immune responses in the CNS, recent studies have also highlighted the differences between MS and its animal equivalent, experimental autoimmune encephalomyelitis. New immunotherapeutic agents have been developed and evaluated in clinical trials. Here, we review current knowledge of the immunopathogenesis of MS and corresponding animal models of disease, and discuss new immunointerventional treatment strategies based on changing pathogenetic concepts.

Sa.14. Increased Apoptotic Elimination of T-Cells After Immunotherapy for Multiple Sclerosis

Sa.14. Increased Apoptotic Elimination of T-Cells After Immunotherapy for Multiple Sclerosis

Immunopathogenesis and immunotherapeutic approaches in multiple sclerosis

Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-β, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Putative mechanisms of action of statins in multiple sclerosis – comparison to interferon-β and glatiramer acetate

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are widely prescribed as cholesterol-lowering agents. They are promising candidates for future treatment in multiple sclerosis (MS) as they have been shown to exhibit immunomodulatory effects. Recent reports have demonstrated that statins are effective in preventing and reversing chronic and relapsing experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Furthermore, in vitro experiments with human immune cells have documented an immunomodulatory mode of action of statins comparable to that of interferon (IFN)-β. An open label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favourable safety profile. This article reviews data thus far present on the putative mechanisms of action of statins in the immunopathogenesis of MS. Furthermore, the role of statins as potential pharmacotherapy for MS is discussed in the context of the mechanisms of approved immunotherapies in MS, namely IFN-β and glatiramer acetate (GA).

Escalating immunotherapy of multiple sclerosis

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Immunotherapeutic approaches in multiple sclerosis

The progress in understanding the mechanisms of T cell activation, inactivation and modulation has been translated into different immunotherapeutic strategies aiming at treating multiple sclerosis (MS). Key attack points for selective immunointervention in MS include modulation of antigen recognition, costimulation blockade, induction of regulatory cells, deviation to non-pathogenic or protective responses, neutralization of proinflammatory cytokines and administration of anti-inflammatory cytokines. In addition, several attempts have been made using less specific forms of immunointervention. The two resounding successes in the immunotherapy of MS, IFN-failed and glatiramer acetate, contrast with the many attempts, equally based on sound reasoning and promising animal data. Nevertheless, antigen-based immunointervention will continue to be tested clinically, and we will certainly witness the application of more articulate strategies able to selectively target cytokine production by Th1 or Th2 cells or to modify the Th1/Th2 balance. Perhaps, an effective manipulation of pathogenic and protective cells in MS may eventually rely on a combination of antigen- and cytokine-based approaches to selectively target autoreactive T cells and divert them from autoaggression. Most importantly, new avenues are opening, such as the use of chemokine receptor antagonists, and others look very promising, as targeting dendritic cells to favour their capacity to induce regulatory T cells.

Novel approaches and cutting edge immunotherapies in multiple sclerosis.

MS is a chronic inflammatory disease of the central nervous system (CNS). MS is a predominantly CD4+ T cell mediated autoimmune disorder. Recent studies have challenged this existing paradigm by supporting the role of other immune cells and factors (even non-immune) including CNS antigen-driven clonally expanded B cells, autoantibodies, complement and mediators of the innate immune responses in MS lesions. Further expansion of this global CNS dysfunction includes oligodendroglial cell (OGC) loss, attenuated remyelination, axonopathy, and gliosis. The recognition of new "players" directing effector and regulatory functions and further insight into reparative mechanisms occurring at various stages of the disease within a given individual will influence ongoing and future therapeutic trials. The following discussion will encompass evolving concepts in the pathogenesis of MS with a focus on novel immunotherapies. These new approaches reflect targeting of a multifaceted spectrum of immune activity. The immunotherapies will be characterized by their intervening role of specific and/or multiple pathogenic steps including initiation, peripheral activation, molecular co-stimulation and immune effector responses during early, transitional and late phases of disease. Emerging strategies for the enhancement of neuroprotection and reparative mechanisms will also be reviewed. Classification of novel approaches will include the following main types of immunotherapies: (1) targeting of myelin specific T cells: antigen-specific therapies (2) targeting of B cell and autoantibody responses (3) targeting of immunologic steps of disease pathology (4) targeting of reparative stages of disease: neurotrophic and neuroprotective, (5) global therapies: broad-based polydirectional strategies.

Future immunotherapies in multiple sclerosis.

Immunotherapy of multiple sclerosis (MS) will continue to benefit from an increasing understanding of this disease. This knowledge results in newly defined targets for novel therapies. In this article the development of future immunotherapies will be discussed by classifying the approaches into three main types: (1) antigen-specific therapies; (2) agents with a defined target in pathogenic steps of the MS lesion; and (3) therapies with broad immunomodulatory activity. Success in developing new immunotherapies depends on understanding the underlying complexity and heterogeneity of the disease. The current practice of employing a single therapy across a heterogeneous group of MS patients is in part a likely reason for their modest efficacy. The mechanism of action of a single agent may target the appropriate defect in one individual but not others. The therapy of MS in the future will most likely use a combination of agents that are directed at the underlying disease state and stage in the individual patient.

Alphabet soup: a personal, evolving, mostly evidence-based and logical, sequential approach to the "ABCNR" drugs in multiple sclerosis.

With the development of multiple options for immunotherapy in multiple sclerosis, the clinician is faced with the challenge of keeping pace with the literature, acquiring familiarity with the various treatment options and opinions, and then offering the patients the most current and appropriate management. Given the inherent nature of a multifocal and unpredictable disease such as multiple sclerosis, along with the availability of multiple treatment options, it behooves the clinician to develop an evidence-based rationale for how to best manage patients. This article reflects the common questions that arise from referring neurologists regarding my personal approach to the management of patients with multiple sclerosis.

Immunotherapy of multiple sclerosis: Where are we? Where should we go?

Differences in multiple sclerosis patient's disease and their responses to standard drugs indicate that today's therapies need to be more individualized. It is proposed that gene expression profiling in conjunction with magnetic resonance imaging be used to optimize future treatment approaches.

Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-beta therapy in relapsing and secondary-progressive multiple sclerosis patients.

Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood-brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing-remitting (n = 16) and secondary-progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12-month follow-up of 6 patients randomly chosen from each of the 2 groups during interferon beta-1a treatment. Reverse transcription-polymerase chain reaction assessment demonstrated elevated levels of MT1-MMP and MMP-7 mRNA levels in both groups of patients, and no significant differences in MMP-9 levels, compared with healthy controls. Divergent expression of MMP-2 between relapsing-remitting and secondary-progressive patients compared with controls was observed. Interferon-beta treatment was associated with significant suppression of MMP-9 and MMP-7 mRNA in relapsing-remitting patients, though no significant changes were observed in the secondary-progressive group. These results contribute to the understanding of the IFN-beta-mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing-remitting versus secondary-progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis.

Correlations between in vitro effects of preparations of interferon and its inducers on blood cells in patients with multiple sclerosis.

We studied in vitro production of interferon-alpha and interferon-gamma by peripheral blood leukocytes from 15 patients with multiple sclerosis. The priming effects of interferon preparations weakly correlated with interferon-alpha production by leukocytes from patients with multiple sclerosis, but negatively correlated with interferon-gamma production. The effects of interferon inducers in most cases positively correlated with its spontaneous production. We found a weak positive correlation between the priming effect of natural interferon-alpha and the effect of recombinant interferons. There were positive or strong positive correlations between the effects of recombinant interferons on leukocytes from patients with multiple sclerosis. The relationship between the effects of medicinal interferon inducers and interferon preparation varied from negative to strong positive correlations. These data suggest that correlation analysis can be used for dynamic control and elaboration of methods for combined immunotherapy of multiple sclerosis with various interferon preparations or interferon and its inducers.