Current Pharmaceutical Design - Volume 18, Issue 29, 2012

Animal models have been used widely in neurology since many decades. They have led to an improved understanding of the pathophysiological processes underlying frequent diseases as multiple sclerosis or Parkinson's disease and enabled the development of highly effective therapeutical approaches. Current developments, drawbacks and limitations of animal models in neurology are discussed with a special focus on the experimental autoimmune encephalomyelitis – model of multiple sclerosis.

Apoptosis is synonymous to programmed cell death, which occurs in response to a plethora of stimuli and employs a series of highly conserved mediators and pathways. Its ambivalent role in immunology is illustrated by the fact that this process not only serves homeostatic functions but also exerts harmful effects including tissue damage. This is particularly true for neuroinflammatory diseases such as multiple sclerosis (MS), the most frequent neurological disease to afflict adolescents in the western world. Considerable insight into the role of apoptosis in MS has been obtained by using its animal model experimental autoimmune encephalomyelitis (EAE). Experiments using the EAE model have revealed that cell death affects both infiltrating lymphocytes and CNS resident cells, and that it contributes to axonal injury as well as the resolution of inflammation. Furthermore, it was discovered that the molecules involved in inducing and regulating this process are the Fas-FasL system, pro- and anti-apoptotic Bcl-2 family members, ‘initiator’ and ‘effector’ caspases, glucocorticoid hormones and various modulatory proteins. The variety of apoptotic mechanisms in combination with their often opposing effects on the disease course highlights the need for a detailed understanding of apoptosis in this context. In the future, this may pave the way to novel approaches aiming at interfering with the apoptotic process to prevent tissue damage or at intentionally inducing cell death in order to ameliorate the disease by deleting autoreactive lymphocytes.

Cellular in vivo imaging can reveal the induction, progression and resolution of nervous system pathology in real-time. In this review, we summarize recent research in the field to illustrate how in vivo imaging has enhanced our understanding of a variety of neurological conditions caused by trauma, degeneration, ischemia or inflammation. Finally, we look ahead and discuss how novel biosensors might help us to follow not only the cellular but also the molecular pathogenesis of neurological diseases in vivo.

The damage of axons and neurons in multiple sclerosis (MS) is well recognised and correlates with neurological disability. The reasons leading to axonal and neuronal injury are diverse and possibly change from an inflammatory mediated mechanism to a neurodegenerative mechanism over the course of the disease. Acute axonal injury is associated with inflammation in the CNS and thus immunomodulatory treatments may also protect neurons from further damage. However, more effective immune treatments also bear the risk for severe side effects. Thus, neuroprotection will become more important to be combined with safe immunomodulation. Although several targets for neuroprotection have been identified experimentally, the translation into clinical treatments proves very difficult. Only few and small trials have investigated substances that may be neuroprotective, however, none had proven to have a substantial effect in MS patients. Clinical trials of remyelination, considered as a natural way of neuroprotection, were likewise not able to achieve clinical benefit. Thus, the development of a neuroprtective treatment in MS will be a major challenge in the decades to come.

Multiple sclerosis (MS) is a chronic immune modulated disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal injury. Currently relapsing remitting type of MS patients are most commonly treated with immune- modulators like interferon β (IFN β) or glatiramer acetate (GA). However, while the majority of patients respond well to therapy others do not. Gene expression profiles in blood samples taken over the course of IFN β treatment can document changes in the biology of the patients in response to the drug and disease activity. During the last decade quite a few of such studies profiling expression in response to IFN β treatment had been done. Here, we combine the results of these studies to outline common differential expression patterns in peripheral blood mononuclear cells (PBMCs) over the course of time under IFN β treatment. We set these profiles into the picture of current knowledge about IFN β pathway, MS immunology and IFN β mechanisms of action. IFN β modulates hundreds of genes. In most of the studies the prominent ones like MX 1, OAS 1, and CXCL 10 had been found to be influenced by IFN β drug treatment. We show examples of short term and long term induced expressional changes, up and down regulated genes (STAT1 and IL8), and explain how under drug treatment feedback loops of type I IFN (IFN α and IFN β) regulated genes may be modulated and changes in expression patterns may result in cytological changes.

Psychoneuroimmunology is a relatively young field of research that investigates interactions between central nervous and immune system. The brain modulates the immune system by the endocrine and autonomic nervous system. Vice versa, the immune system modulates brain activity including sleep and body temperature. Based on a close functional and anatomical link, the immune and nervous systems act in a highly reciprocal manner. From fever to stress, the influence of one system on the other has evolved in an intricate manner to help sense danger and to mount an appropriate adaptive response. Over recent decades, reasonable evidence has emerged that these brain-to-immune interactions are highly modulated by psychological factors which influence immunity and autoimmune disease. For several diseases, the relevance of psychoneuroimmunological findings has already been demonstrated.

Baseline disease-modifying therapies (DMTs) for multiple sclerosis (MS) include three different preparations of interferonbeta (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).

Over the past 25 years, monoclonal antibodies (mAb) have become important elements in the therapeutic concepts for numerous clinical specialities, including oncology, gastroenterology, hemostaseology and endocrinology. One of the most dynamic fields of their use is the treatment of autoimmune diseases. Although the number of existing mAb interfering with the immune system has increased remarkably and many studies have yielded encouraging results in the treatment of neuroimmunological diseases, their clinical use is still limited compared with standard treatments. The only mAb which has been approved for a neuroimmunological disease by now is natalizumab for the treatment of relapsing-remitting multiple sclerosis (RRMS). This article gives an overview on mAb that are currently in use or under investigation for treating neuroimmunological diseases like multiple sclerosis (MS), neuromyelitis optica (NMO), chronic inflammatory demyelinating polyneuropathy (CIDP), inclusion body myositis (IBM), dermatomyositis, polymyositis, opsoclonusmyoclonus syndrome (OMS), multifocal motor neuropathy (MMN), anti-myelin-glycoprotein neuropathy (Anti-MAG), stiff person syndrome and myasthenia gravis (MG).

Autoimmunity is an overreaction of immune competent cells to self structures resulting in an unwanted clinical outcome. Traditional therapeutic strategies, still relevant in many cases, involve broad acting immunosuppressants such as cyclophosphamide with the predictable attendant toxicity. More recent concepts include blockade of specifically defined targets such as TNF-α, with resulting immunomodulation and less toxicity. Both of these strategies require ongoing drug treatment of established disease. A long standing goal, not yet achieved, is the predictable induction of tolerance, obviating the need for chronic treatment. Experimental strategies to achieve this include pre-emptive (preclinical) treatment before chronification is established, total immune ablation and immune “resetting” and autoantigen immunisation.

Autoimmune diseases of the nervous system such as myasthenia gravis, inflammatory demyelinating polyneuropathies, multiple sclerosis and others are still not curable. Yet the introduction of modern immune therapies could significantly improve the prospects of many patients affected by these disorders. In addition to steroids and immunosuppression i.v. immunoglobulins are used for treatment of myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. Interferons, glatiramer acetate, natalizumab and fingolimod are applied in multiple sclerosis. The ever-improving efficacy of the drugs has to be balanced against the increasing risk of possible severe adverse effects.

Paraneoplastic neurological syndromes (PNS) are rare nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumour or its metastases. PNS in adults are mainly associated with lung cancer, especially small cell lung cancer, lymphoma and gynaecological tumours. In some cases an overlapping of different clinical syndromes can be observed. Since autoantibodies directed against tumour and nervous system tissue can be observed, an autoimmune aetiology has been suspected in PNS patients. Currently, one group of patients exhibit surface-binding receptor or ion channel autoantibodies which are thought to be pathogenic and many of these patients respond well to immunotherapies. Another group of PNS is associated with highly specific autoantibodies directed against intracellular onconeuronal antigens. The latter group seem to be T-cell-mediated and do not respond well to immunotherapies. The childhood PNS, especially the neuroblastoma-associated opsoclonus-myoclonus syndrome also respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. The current review summarizes recent developments in physiopathology, diagnosis and treatment of paraneoplastic neurological syndromes.

The increasing understanding of autoimmune mechanisms continuously leads to new therapeutic targets and development of novel diagnostic tools in rheumatology. On the other hand, an improved comprehension of mechanisms of action of many drugs and the daily utilization in rheumatology leads to a better understanding of the underlying autoimmune processes. An example for the latter is Bcell depletion using anti-CD20 antibodies, which leads to the concept of B cells not only playing a role as antibody secreting cells but also as important cellular components of autoimmune processes, acting as antigen presenting and cytokine producing cells. Another example is the conventional disease modifying anti-rheumatic drug methotrexate, which has also been used successfully in the clinic first and then, while trying to understand its mechanism of action, led to knew insights in autoimmune mechanisms e.g. revealing the strong anti-inflammatory potential of adenosine. But not only the mechanism of action of different drugs, but also the identification of antibodies against citrullinated proteins (ACPA) as a valuable diagnostic tool resulted in novel concepts regarding the pathophysiology of rheumatoid arthritis. The following review first explains the value of ACPA in the diagnosis of rheumatoid arthritis (RA) and then summarizes the application and mechanism of action of several important substances used in the management of autoimmune disorders. Based on these insights, the authors explain their understanding of the autoimmune process as a continuous repeat of autoantigen presentation – autoreactive effector cell activation – destruction of tissue – liberation of new autoantigens – and again autoantigen presentation, which closes the vicious circle.

Granulumatosis with polyangiitis (wegener's)/GPA microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS) are primary systemic vasculitides which predominantly affect small vessels, showing a high association with a positive C/PR3-ANCA in GPA and P/MPO-ANCA in MPA, so called ANCA-associated vasculitides (AAV). The diagnostic work-up relies on an interdisciplinary approach including imaging techniques and laboratory tests in order to assess disease stage and extent. The golden standard remains the histological proof of a necrotizing, pauci-immune small vessel vasculitis, in GPA additionally non-caseating granuloma is found mainly in the respiratory tract. Treatment is adapted to disease stage and extent and relies on a combination of a cytotoxic plus a tapering regimen of glucocorticosteroids. Induction of remission in “early systemic” disease without organ- and life-threatening organ manifestations and a near normal kidney function can be achieved with methotrexate. In the generalized phase with significant renal dysfunction cyclophosphamide is the mainstay of therapy, in rapidly progressive glomerulonephritis with an imminent dialysis indication plasmapheresis is performed additionally. When remission is achieved, usually after 3-6 months of induction treatment, cyclophosphamide is switched to azathioprine as maintenance of remission drug. Alternative therapies are methotrexate provided the kidney function is normal or Leflunomide in the long-term follow-up the relapse rate in ANCA-associated vasculitis is approximately 50% in 5 years, irrespective of the drug used for maintenance treatment. The relapse rate is significantly higher in GPA than in MPA and CSS.

There are several different diseases in gastroenterology with an important role of immunological mechanisms in their pathogenesis. We know autoimmune diseases with immunological reactions against liver or pancreatic tissue. In addition there are diseases like chronic inflammatory bowel diseases representing inappropriate immunological reactions followed by inflammation and tissue destruction. The research of the last decade has contributed significantly to the understanding of the pathogenesis of diseases based on immunological mechanisms and consequently to the development of novel therapeutic strategies targeting molecules. Chronic inflammatory bowel diseases, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, autoimmune pancreatitis, and celiac disease are the most important diseases with immunological pathogenesis in Gastroenterology. Especially in chronic inflammatory bowel diseases ulcerative colitis and Crohn's disease with immunosuppressive drugs and monoclonal antibodies new preparations are used in therapy. Autoimmune pancreatitis was characterized as an own entity in the last years. Therefore, this review will focus on these diseases.

Limb trauma can lead to the development of a complex regional pain syndrome (CRPS). CRPS is a descriptive term of a variety of different symptoms. According to the current IASP-approved criteria, human CRPS can be diagnosed if a combination of signs is present: continuing pain and hyperalgesia, disproportionate to the initial trauma, skin temperature and colour asymmetry, sweating asymmetry, edema, decreased range of motion, and trophic changes. The diagnosis and treatment of human CRPS can be demanding and the pathophysiology underlying the disease is still under investigation. Immunological aspects are considered to play an important role in the development of CRPS. The impact of elevated pro-inflammatory cytokines systemically as well as locally, increased neurogenic inflammation and auto-antibodies in the pathophysiological development of CRPS are discussed in this review.

Immunosuppressive treatment still is an important element in the management of autoimmune mediated diseases. However, immunosuppressive therapy is often complicated by a narrow therapeutic index and high variability of treatment response. This review discusses the clinical management and monitoring strategies for the use of ciclosporin A, tacrolimus, azathioprine, mycophenolat mofetil, mitoxantrone and some monoclonal antibodies with focus on natalizumab.

Biochemical biomarkers are important candidates for the diagnosis and prognosis of neurological diseases of autoimmune etiology, since they may reflect the presence, nature and intensity of certain immune responses caused by both genetic and environmental processes. Different body fluids such as cerebrospinal fluid (CSF), serum, urine, and tears have been used to identify useful biomarkers. Autoimmune neurological diseases associated with pathology of cell surface structures such as myasthenia gravis, Lambert-Eaton myasthenic syndrome, neuromyotonia, stiff person syndrome, limbic encephalitis, Guillain-Barre syndrome (GBS), and neuromyelitis optica (NMO) are amenable to serum antibody tests which can be used to support the diagnosis. In several of these disorders, new specific autoantibodies have been detected that are directed against proteins complexed with potassium channels in both the central and peripheral nervous system such as contactin-2 associated protein (Caspr2) or the protein leucine-rich, glioma-inactivated 1 (LGI1). Recently, a number of central nervous system disorders like limbic encephalitis and multiple sclerosis (MS) have also been associated with the presence of specific serum autoantibodies. In MS and GBS CSF analysis is still essential to support the diagnosis and to rule out other diseases. We provide an overview over the widening field of autoimmune diseases of the central and peripheral nervous system and discuss the current state of biomarker research and its relevance for clinical practice.

Multiple sclerosis (MS) as a chronic disease presents a vast variability of neurological symptoms. Spasticity is one of the most common symptoms. The principle indication to treat spasticity is disability or handicap of capabilities. All pharmacological methods are attributed to a basic physical management. Different effective treatment schemes have been established. Nevertheless the value of intrathecal triamcinolone acetonid (TCA) in MS is still a controversial issue. Bearing in mind that only limited data are available and due to its invasive application form repeated TCA administration can be recommended as one therapy option in MS with a progressive clinical course and predominantly spinal symptoms.

Intravenous immunoglobulins (IVIg) are used in treatment of a broad spectrum of diseases. Immunoglobulin replacement therapy is the standard treatment for immunodeficiencies with compromised humoural immunity. Use of this method as an immunomodulating therapy ranges from transplantation and treatment of autoimmune-haematological diseases to treatment of various neuroimmunological clinical entities. Limited quantitative availability due to dependence on human donors as a source of IVIg, coupled with high treatment costs, make necessary a highly responsible and evidence-based approach with these agents. Discussion of the indications and currently valid recommendations on use of IVIg in treatment of immunomediated demyelinating diseases of the nervous system is based on existing clinical studies. We describe further neurological indications for use of IVIg as well as mechanisms of action and adverse effects of its use.