Multiple Sclerosis: Martino G

Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, Filippi M, Hartung HP, Hertenstein B, Karussis D, Martino G, Tyndall A, van der Meché FG. · Multiple Sclerosis Centre, San Raffaele Scientific Institute, Milan, Italy. · J Neurol. · Pubmed #10896270 No free full text.

Abstract: Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Pluchino S, Zanotti L, Brini E, Ferrari S, Martino G. · Neuroimmunology Unit and Institute of Experimental Neurology (INSpe), DIBIT-San Raffaele Scientific Institute, via Olgettina 58, 20123 Milano, Italy. · Neurosci Lett. · Pubmed #19429143 No free full text.

Abstract: Physiological (spontaneous) and reactive (reparative) regenerative processes are fundamental part of life and greatly differ among the different animals and tissues. While spontaneous regeneration naturally occurs upon cell attrition, reparative regeneration occurs as a consequence of tissue damage. Both spontaneous and reparative regeneration play an important role in maintaining the normal equilibrium of the central nervous system (CNS) as well as in promoting its repair upon injury. Cells play a critical role in reparative regeneration as regenerating structures (cells or tissues) depend on the proliferation without (de)differentiation of parenchymal cells surviving to the injury, proliferation of stem (progenitor) cells resident in the injured tissue, dedifferentiation of mature cells in the remaining tissue, or by the influx of stem cells originating outside the damaged tissue. Considering the central role of stem and progenitor cells in regeneration, a spur of experimental stem cell-based transplantation approaches for tissue (e.g. CNS) repair has been recently generated. This review will focus on the therapeutic efficacy of different sources of somatic stem cells - and in particular on those of neural origin - in promoting CNS repair in a chronic (auto)immune-mediated inflammatory disorder such as multiple sclerosis.

Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M. · Department of Neuroscience, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. · Clin Immunol. · Pubmed #18534912 No free full text.

Abstract: The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.

Muzio L, Martino G, Furlan R. · Neuroimmunology Unit - DIBIT and Institute for Experimental Neurology (INSpe) San Raffaele Scientific Institute, Milan, Italy. · J Neuroimmunol. · Pubmed #17936915 No free full text.

Abstract: The very simplistic view that inflammation in multiple sclerosis (MS) is tout court detrimental has to be profoundly reconsidered. Experimental evidence strongly supports the concept that inflammation in MS is aimed not only at destroying and phagocytosing damaged (infected?) cells (detrimental phase) but also at promoting tissue regeneration or tissue repair via scar formation (resolution or protective phase). Microglia seem to play a crucial role in the different inflammatory phases in MS because they move through multiple functional levels (quantum jumps) either to remove the "danger" signal or to restore the integrity of the central nervous system. The understanding of the molecular signature of any of the quantum microglial states could be useful to better define the cellular and molecular mechanisms underling the different phases of inflammation in MS. This could contribute not only to the design of better therapeutic drugs, but also to the comprehension of the shortcomings of currently used anti-inflammatory drugs.

Pluchino S, Martino G. · Neuroimmunology Unit-DIBIT and Institute of Experimental Neurology, San Raffaele Scientific Institute, Via Olgettina 58, I-20132 Milan, Italy. · J Neurol Sci. · Pubmed #17706971 No free full text.

Abstract: Adult multipotent neural stem/precursor cells (NPCs) have the capacity to self-renew and generate functional differentiated cells (e.g. neurons, astrocytes or oligodendrocytes) within discrete tissue-specific germinal niches, such as the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus of the hippocampus. Due to their intrinsic plasticity NPCs can be considered an essential part of the cellular mechanism(s) by which the central nervous system (CNS) tries to repair itself after an injury and, as a consequence, they also represents an attractive therapeutic tool for the treatment of neurological disorders. Here we will discuss not only the role of NPC-based transplantation therapies in multiple sclerosis (MS) but also recent data suggesting that endogenous NPCs, while contributing to CNS repair in MS, may also become the target of the disease itself.

Comi G, Martino G. · Department of Neurology and Clinical Neurophysiology, Università Vita-Salute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. · Clin Neurol Neurosurg. · Pubmed #16386359 No free full text.

Abstract: Immunomodulating and immunosuppressive treatments for multiple sclerosis patients are directed against the inflammatory process and are only partially effective. This partial failure could be explained by mechanisms of axonal damage at least partially independent from acute or chronic inflammation. This suggests that there is a need for better use of available treatments and the necessity of alternative new therapeutic options to halt disease progression and enhance recovery mechanisms. Concerning actual treatments, two strategies are quite interesting: early treatment and combination therapy. The former approach is based on converging epidemiological, immunological and pathological studies and is proved by some recent clinical trials. The second one is under evaluation on ongoing clinical trials. Progress in understanding the mechanisms of T cell activation, inactivation and modulation has been translated into new therapeutic strategies aiming at inducing selective immunosuppression. Such an approach is now tested in phase II-III clinical trials.

Pluchino S, Martino G. · Neuroimmunology Unit--DIBIT and Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. · J Neurol Sci. · Pubmed #15896808 No free full text.

Abstract: Spontaneous remyelination occurs in multiple sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture in demyelinated areas of the central nervous system (CNS). As a consequence of this incomplete reparative process, the disease invariably progresses and patchy areas of demyelination-in which axonal damage and/or loss is a constant accompanying factor-increase over time and lead to the accumulation of irreversible neurological deficits. Thus, the development of cell-based therapies aimed to promote multifocal remyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years. However, most of these therapeutic approaches-although consistently able to form new myelin sheaths around the transplantation site-are unrealistic owing to the multifocality of the demyelinating process and the inability to in vitro growth and differentiate large number of myelin-forming cells. Recently, promising cell-replacement therapies based on the use of stem cells have been proposed. However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: (i) the ideal stem cell source for transplantation, (ii) the route of cell administration, (iii) the differentiation and persistence of stem cells into the targeted tissue and, last but not least, (iv) the functional and long-lasting integration of transplanted cells into the host tissue.

Furlan R, Butti E, Pluchino S, Martino G. · Neuroimmunology Unit, DIBIT, Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. · Curr Opin Mol Ther. · Pubmed #15537054 No free full text.

Abstract: Autoimmune diseases are threatening an increasing number of patients in developed countries, representing one of the major causes of disability and an enormous social cost. Current therapies mainly treat the symptoms of autoimmune diseases and are only partially able to interfere with disease evolution, and therefore decrease the degree of physical impairment. Thus, the development of new therapeutic strategies is imperative. This review focuses on gene therapy, as one possible alternative approach to the treatment of autoimmune disorders. The potential of gene therapy to specifically target tissues affected by autoimmune aggression, and its ability to interfere with the destructive pathogenic process while providing functional replacement and fostering reparative mechanisms will be emphasized. Gene therapy studies in experimental models of diabetes, rheumatoid arthritis and multiple sclerosis are reviewed.

Pluchino S, Furlan R, Martino G. · Neuroimmunology Unit - Department of Biotechnology (DIBIT) and Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy. · Curr Opin Neurol. · Pubmed #15167057 No free full text.

Abstract: PURPOSE OF REVIEW: Spontaneous remyelination occurs in the central nervous system of patients with multiple sclerosis. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture. The development of cell-based therapies, aimed at promoting multifocal remyelination, is therefore foreseen. RECENT FINDINGS: Several experimental cell-based strategies aimed at replacing damaged myelin-forming cells have been developed in the last few years. However, most of these therapeutic approaches - although consistently able to form new myelin sheaths at the transplantation site - are unfeasible owing to the mutifocality of the demyelinating process in multiple sclerosis patients and the inability to grow and produce large numbers of differentiated myelin-forming cells in vitro. Stem cell-based therapies that partially overcome these limitations have been proposed recently. SUMMARY: Stem cell-based remyelinating therapies can be considered a plausible alternative strategy in immune-mediated demyelinating disorders. However, before any potential applications in patients with multiple sclerosis can be envisaged, it is necessary to confront the following preliminary, and still unsolved, questions: (1) the ideal stem cell source for transplantation; (2) the most appropriate route of stem cell administration; and, last but not least, (3) the best approach for achieving an appropriate, functional and long-lasting integration of transplanted stem cells into the host tissue.

Martino G. · Neuroimmunology Unit (DIBIT) and Department of Neurology, San Raffaele Scientific Institute, Milan, Italy. · Lancet Neurol. · Pubmed #15157853 No free full text.

Abstract: In the early 20th century, seminal work by Tello and Cajal showed that the CNS has the ability to regenerate itself after injury. In the most recent years, this pivotal observation has been rejuvenated by detailed in vitro and in vivo evidence supporting the idea of an innate self-maintenance programme to sustain brain homoeostasis and repair. These observations support the idea that chronic inflammatory and degenerative disorders of the brain might result from defective repair mechanisms rather than uncontrollable pathogenetic events. Investigation of the molecular and cellular events sustaining intrinsic brain-repair mechanisms and a better understanding of why they fail over time in chronic disorders might, therefore, provide an attractive conceptual framework within which to develop new and efficacious therapies for neurological diseases.

Martino G. · Department of Neuroscience-DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy. · Int MS J. · Pubmed #14561374 links to  free full text

Abstract: The blood-brain barrier limits the therapeutic efficacy of systemic administration of anti-inflammatory and/or neuroprotective molecules to patients affected by immune-mediated inflammatory demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis. Drug delivery to the CNS using non-replicative viral vectors may represent a valid alternative therapeutic strategy. Gene therapy for multiple sclerosis might include different "human-grade" vectors, which could be used to deliver anti-inflammatory molecules as well as neuroprotective agents into the CNS in a flexible and useful way. These potential "therapeutic" vectors would have different life spans, tissue tropism and infectivity rates.

Furlan R, Pluchino S, Martino G. · Neuroimmunology Unit, Department of Neurology, San Raffaele Scientific Institute Via Olgettina, 58 20132 Milan, Italy. · Curr Pharm Des. · Pubmed #12871186 No free full text.

Abstract: Selective interference with immune processes in the central nervous system (CNS) is a very difficult task because of the limitations associated with the delivery of immuno modulatory molecules across the blood brain barrier. Systemic administration of immune-mediators, either by conventional routes or by intramuscularly or intravenous gene therapy, is hampered by severe side effects and alters immune-system functions also in peripheral organs. To overcome these problems, different gene therapy strategies have been developed to deliver immuno modulatory molecules directly within the central nervous system. The use of engineered CNS antigen-specific circulating cells as selective delivery vehicles, the direct injection of gene vectors into the brain parenchyma, or also the ependymal route, have been proposed as possible alternative gene therapy protocols to selectively interfere with immuno-pathological processes in the CNS. We will review the use of these CNS-targeted gene therapy protocols for the treatment of experimental autoimmune encephalomyelitis (EAE), the prototypical experimental immune-mediated disease of the CNS, and therefore discuss the relevance of these results for the therapy of multiple sclerosis (MS) the most common, immune-mediated, demyelinating disease of the CNS in humans.

Furlan R, Pluchino S, Martino G. · Neuroimmunology Unit (DIBIT) and Department of Neurology and Neurophysiology, San Raffaele Scientific Institute, Milan, Italy. · Curr Opin Neurol. · Pubmed #12858077 No free full text.

Abstract: PURPOSE OF REVIEW: Gene therapy protocols aimed to deliver therapeutic molecules into the central nervous system may represent an alternative therapeutic strategy in patients affected by inflammatory demyelinating diseases of the central nervous system where systemic therapies have shown limited therapeutic efficacy possibly owing to the blood-brain barrier, a major obstacle for the entry of therapeutic molecules into the central nervous system. RECENT FINDINGS: Among inflammatory demyelinating diseases of the central nervous system, gene therapy approaches have been so far developed almost exclusively for multiple sclerosis. However, the chronic/relapsing nature of the disease, the restriction to the central nervous system of the pathological process as well as the necessity to inhibit the ongoing inflammatory process but also to foster endogenous remyelinating pathways, have posed several questions which still need to be properly addressed for the development of a successful gene therapy strategy in multiple sclerosis patients. SUMMARY: The gene therapy approaches for multiple sclerosis have been so far developed and tested only in rodents and monkeys with experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. The results of these studies clearly indicate that the delivery of therapeutic genes within the central nervous system is superior to the peripheral delivery. In particular, the intracerebral delivery of genes coding for anti-inflammatory and/or neurotrophic molecules, using gene vectors derived from non-replicative viruses, showed to inhibit not only the detrimental function of blood-borne mononuclear effector cells but also to foster proliferation and differentiation of surviving oligodendrocytes within demyelinated areas. Here, we summarize the most recent findings of this novel area of research.

Martino G, Adorini L, Rieckmann P, Hillert J, Kallmann B, Comi G, Filippi M. · Department of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. · Lancet Neurol. · Pubmed #12849335 No free full text.

Abstract: Inflammation has always been thought of as detrimental in the pathophysiology of multiple sclerosis (MS). However, emerging genetic data, magnetic-resonance-imaging studies, and immunopathological evidence challenge this simplistic view. The evidence leads to the conclusion that inflammation is tightly regulated, and that its net effect may be beneficial in MS, thus explaining some of the results from recent trials of anti-inflammatory agents. We argue that the use of anti-inflammatory drugs to treat MS may not be appropriate in all cases. Precise identification of the inflammatory pathways to be targeted in the different phases of the disease and the timing of such interventions are therefore crucial.

Gironi M, Bergami A, Brambilla E, Ruffini F, Furlan R, Comi G, Martino G. · Department of Neuroscience, San Raffaele Scientific Institute, DIBIT, Milan, Italy. · Neurol Sci. · Pubmed #11205366 No free full text.

Abstract: Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing, among others, autoreactive T cells and activated macrophages. These observations indicate that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that, along with chemokines, adhesion molecules and metalloproteases, modulate at different levels the pathogenic process underlying MS. Due to their central role in MS pathogenesis, "inflammatory" molecules might represent suitable peripheral markers of disease (disease-trait) and/or disease activity (state-trait). However, reliable disease-trait or state-trait immunological markers for MS have not yet been identified. The intrinsic characteristics of these molecules (i.e. autocrine/paracrine activity, short half-life, redundancy) may in part explain their inconsistency as disease markers. Additionally, the unreliability of methodologies and the lack of careful patient stratification can also, at least in part, account for the unsatisfactory results so far obtained.

Martino G, Furlan R, Brambilla E, Bergami A, Ruffini F, Gironi M, Poliani PL, Grimaldi LM, Comi G. · Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milano, Italy. · J Neuroimmunol. · Pubmed #10969174 No free full text.

Abstract: Multiple sclerosis (MS) is considered an immune-mediated disease of the central nervous system (CNS) sustained by a chronic inflammatory process leading to patchy demyelination and axonal loss. However, the inflammatory triggering event as well as the target of the pathogenic process in MS are still partially unknown. We report evidence that a 'local' inflammatory process occurring in the CNS (considered as a reaction of blood vessels in vascularized living tissue to a local injury leading to the accumulation of fluid and blood cells) along with a concomitant, but possibly unrelated, peripheral inflammatory event may trigger a CNS-specific autoimmune reaction cascade sustaining the MS pathogenesis. In the CNS, inflammatory mediators (mainly cytokines) act either as regulatory (i.e. activation of glial cells, shaping the autoimmune response) or effector molecules (i.e. myelinotoxicity, oligodendrotoxicity). In the periphery, inflammatory cytokines induce, in a bystander fashion, activation of monocytes and T cells. Among this latter cell population there are myelin-specific T cells belonging to the normal 'autoimmune' repertoire that home to the CNS where they may trigger the continuous recruitment of effector cells (macrophages) from the periphery. The concept that two concomitant, but possibly unrelated, inflammatory events, occurring in the CNS and in the periphery, represent the crucial elements sustaining MS, might reveal a more comprehensive view (dual signal hypothesis) of the entire etiopathogenic process underlying this disease.

Comi G, Martino G. · Centro de Esclerosis Múltiple, Instituto Científico San Rafael, Milán, Italia. · Rev Neurol. · Pubmed #10935262 No free full text.

Abstract: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of unknown etiology. Its pathological hallmark is the presence within the CNS of inflammatory infiltrates containing few autoreactive T cells and a multitude of pathogenic nonspecific lymphocytes. Based on that, various non-specific immunosuppressive agents have been tested with marginal benefits on the natural evolution of the disease and frequent short- and long-term adverse effects. Moreover, due to their unfavourable profile, these therapies have been usually limited to patients with progressive courses or high clinical activity. The recent approval of IFN beta and Copolymer 1, as therapies able to modify the disease course in relapsing-remitting and secondary progressive, as well as the available immunopathological and clinical data suggesting that the early treatment of MS with safe profile immunomodulatory drugs could be advantageous compared to late treatments, supports the 'putative' relevance of these new drugs in the early treatment of MS patients. However we must wait for the results of ongoing clinical trials to define if such an early treatment has substantial advantages compared to late treatment.

Martino G, Furlan R, Poliani PL. · Departamento de Neurología, Istituto Scientifico San Raffaele, Milán, Italia. · Rev Neurol. · Pubmed #10935253 No free full text.

Abstract: INTRODUCTION: Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing auto-reactive T and B cells and activated macrophages thus indicating that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. DEVELOPMENT: The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that modulate at different levels the pathogenic process underlying MS. Cytokines can 1. Sustain the 'putative' CNS-confined inflammatory process leading to the development of myelin-specific T cells; 2. Activate circulating myelin-specific T cells and shape their repertoire (Th1 versus Th2 pattern); 3. Induce the CNS recruitment of non antigen specific T cells and myelinotoxic effector cells (monocyte/macrophages) from the periphery, and 4. Cause direct oligodendrotoxicity (TNF alpha) or induce the secretion of myelinotoxic substances. The present chapter will focus on the mechanisms sustaining the activity of pro-inflammatory cytokines in MS pathogenesis.

Kieseier BC, Storch MK, Archelos JJ, Martino G, Hartung HP. · Department of Neurology, Karl-Franzens Universität Graz, Austria. · Curr Opin Neurol. · Pubmed #10499177 No free full text.

Abstract: Multiple sclerosis is generally regarded to be a primarily T-cell driven disease. Recent evidence has refocused interest on antibodies. Adhesion molecules, matrix metalloproteinases, chemokines and cytokines, and nitric oxide and oxygen metabolites all participate in the amplification and effector stages of the disease.

Martino G, Hartung HP. · Department of Neurology, San Raffaele Scientific Insitute-DIBIT, Milan, Italy. · Curr Opin Neurol. · Pubmed #10499176 No free full text.

Abstract: Multiple sclerosis is considered to be an autoimmune disease that results from aberrant immune responses to central nervous system antigens. T cells are considered to be crucial in orchestrating an immunopathological cascade that culminates in damage to the myelin sheath, oligodendrocytes and axons.

Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L, Cosi V. · Laboratory of Neuroimmunology, IRCCS, Foundation "Neurological Institute C. Mondino", University of Pavia, via Palestro 3, 27100, Pavia, Italy. · J Neuroimmunol. · Pubmed #11282170 No free full text.

Abstract: The two chemokines, monocyte chemoattractant protein (MCP)-1 and gamma-interferon inducible protein (IP)-10, are thought to be involved in the pathogenesis of multiple sclerosis (MS). We measured MCP-1 and IP-10 levels in serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls. The latter consisted in patients with other inflammatory neurological diseases (OIND) or with non-inflammatory neurological diseases, and healthy controls. CSF MCP-1 levels exceeded those found in serum in all the patients studied as well as in healthy controls. CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml). When detectable, serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml). Among OIND patients, those with HIV-1-associated dementia showed high serum and CSF levels of both MCP-1 and IP-10. Those with encephalitis showed high serum and CSF levels of IP-10 and CSF mononuclear pleiocytosis. We also evaluated the effects of 6-methylprednisolone or IFN-beta1a therapy on circulating MCP-1 and IP-10 levels. Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values. Our findings suggest that (a) MCP-1 could be constitutively produced within the brain; (b) MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse; and (c) current MS therapies do not modify circulating levels of MCP-1 and IP-10.

Furlan R, Bergami A, Lang R, Brambilla E, Franciotta D, Martinelli V, Comi G, Panina P, Martino G. · Neuroimmunology Unit-DIBIT, Dept. of Neuroscience, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. · J Neuroimmunol. · Pubmed #11063825 No free full text.

Abstract: Systemic administration of interferon (IFN)-beta has been recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). The immunological mechanism by which IFN-beta ameliorates MS is still partially unknown. We measured the number of blood circulating CD4(+), CD4(-), CD8(+), and CD8(-) T cells secreting IFN-gamma and IL-4 in 26 RRMS patients followed for up to 9 months of an alternate day s.c. treatment with 8x16 IU of IFN-beta1b. Compared to pre-treatment values, a significant (P<0.05) reduction of CD4(+), CD4(-), CD8(+) and CD8(-) cells producing IFN-gamma and of CD4(+) and CD4(-) cells producing IL-4 was observed in MS patients. The IFN-beta-associated effect was evident soon after the beginning of the treatment and persisted for the entire follow-up period. We did not observe any effect of IFN-beta treatment on the percentage of IL-4-producing CD8(+) and CD8(-) cells nor in that of natural killer (NK) cells producing IFN-gamma. Our results show that IFN-beta treatment in MS patients induces a profound and persistent down-regulation of the number of circulating T cells secreting IFN-gamma and IL-4 thus suggesting a broader rather than a specific immunomodulatory effect of IFN-beta in MS.

Furlan R, Cuomo C, Martino G. · Neuroimmunology Unit - DIBIT and Department of Neuroscience, San Raffaele Scientific Institute, Milan, Italy. · Methods Mol Biol. · Pubmed #19378202 No free full text.

Abstract: Since its first description, experimental autoimmune encephalomyelitis, originally designated experimental allergic encephalitis (EAE), has been proposed as animal model to investigate pathogenetic hypotheses and test new treatments in the field of central nervous system inflammation and demyelination, which has become, in the last 30 years, the most popular animal model of multiple sclerosis (MS). This experimental disease can be obtained in all mammals tested so far, including nonhuman primates, allowing very advanced preclinical studies. Its appropriate use has led to the development of the most recent treatments approved for MS, also demonstrating its predictive value when properly handled. Some of the most exciting experiments validating the use of neural precursor cells (NPCs) as a potential therapeutic option in CNS inflammation have been performed in this model. We review here the most relevant immunological features of EAE in the different animal species and strains, and describe detailed protocols to obtain the three most common clinical courses of EAE in mice, with the hope to provide both cultural and practical basis for the use of this fascinating animal model.

Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D'Amelio M, Cavallucci V, Martorana A, Bergamaschi A, Cencioni MT, Diamantini A, Butti E, Comi G, Bernardi G, Cecconi F, Battistini L, Furlan R, Martino G. · Neurologic Clinic, Department of Neuroscience, Tor Vergata University, 00133 Rome, Italy. · J Neurosci. · Pubmed #19295150 No free full text.

Abstract: Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-alpha from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early gene Arc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

Meloni F, Accapezzato D, Agresti C, Aloisi F, Ristori G, Salvetti M, Furlan R, Martino G, Barnaba V, Paroli M. · Andrea Cesalpino Foundation and Department of Internal Medicine, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. · Clin Immunol. · Pubmed #18753013 No free full text.

Abstract: Evidence suggests that T-cell response to myelin basic protein (MBP) plays an important role in multiple sclerosis (MS). However, the mechanism of generation for MBP immunogenic epitopes is unclear. A series of specific CD4(+) T-cell lines was obtained by stimulating peripheral blood mononuclear cells from MS patients with synthetic peptides spanning the entire MBP sequence. T-cell lines recognizing MBP(8-27), MBP(13-32), and MBP(23-42) peptides, whose sequences are identical for humans and rats, specifically proliferated and produced large amounts of interferon-gamma in response to autologous dendritic cells (DCs) loaded in vitro with apoptotic rat oligodendrocytes. Results suggest that MBP epitopes generated from enzymatic processing of apoptotic glial cells by DCs might be relevant to MS pathogenesis.