Journal of Neuroimmunology 216 (2009) 4–7

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Journal of Neuroimmunology

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Conference report

Translational neuroimmunology: A joint meeting of the Israel Society of Neuroimmunology and the Italian NeuroimmunologyAssociation—Conference review

To celebrate ten years of activity for the Israel Society ofNeuroimmunology (ISN) and the Italian Neuroimmunology Associa-tion (AINI; www.aini.it), a meeting was organized by Ariel Miller,Chairperson of ISN, in collaboration with Francesca Aloisi, President ofAINI, on March 31–April 1, 2009 in Tel Aviv. This special eventgathered together about 250 participants, 20 invited speakers fromboth countries and a special guest, Hartmut Wekerle (Germany),former President of the International Society of Neuroimmunology.

The ISN and AINI are among the very few formal nationalneuroimmunology organizations. Both, founded a decade ago, haveexpanded rapidly to become medium-sized societies with about 250members each, essentially physicians and scientists, as well asgraduate students, involved in clinical and basic neuroimmunologicalresearch. During their ten-year activities, the ISN and AINI have aimedto promote scientific research, collaborations, and cultural growth andexchanges within and outside their national boundaries. Organizationof a joint meeting has therefore been the best way to promote cross-fertilization of ideas, strengthen interactions between Israeli andItalian neuroimmunologists, and open new perspectives for collabo-rative educational and research programmes.

Themeeting openedwith awelcome address by Luigi Mattiolo, theItalian Ambassador in Israel, who highlighted the current opportuni-ties of support to scientific projects and technological exchangewithin the cooperation agreement between Italy and Israel.

The topics discussed during the meeting were chosen to representthose that are at the forefront of neuroimmunology research, includingimmune surveillance of the nervous system, neuro-immune regulation,immune dysregulation, gene and environmental influences in neuroin-flammatory diseases, leukocyte trafficking, immunopathologicalmechanisms of nervous tissue damage, neuroprotection and repair incentral and peripheral nervous system diseases, immunomodulationand therapy of neuroinflammatory diseases. The scientific programmecomprised 7 oral sessions, including one dedicated to thememory of Dr.Dvora Teitelbaum, and two poster sessions.

The first session, chaired by Francesca Aloisi (Italy) and Tamir Ben-Hur (Israel), provided an overview of different research approaches tothe study of ‘Immune surveillance and Neuroinflammation’ rangingfrom the search of antigenic triggers in multiple sclerosis (MS) to thecontrol of the immune response in myasthenia gravis (MG), toleukocyte trafficking across endothelial barriers.

Francesca Aloisi (Italy) first reviewed epidemiological, serologicaland immunological evidence supporting a link between Epstein–Barrvirus (EBV) and MS and then summarized recent work performed byher group on B-cell abnormalities and EBV infection in the brain of MSpatients. High frequencies of EBV infected B cells and plasma cells werefound in post-mortem brain tissue fromMS cases with different diseasecourses using in situ hybridization for viral transcripts and immuno-histochemistry for viral latent and lytic proteins. While these findings

doi:10.1016/j.jneuroim.2009.08.006

need to be confirmed in independent studies, perturbedEBV infection intheMS brain has been confirmed by RT-PCR analysis of EBV transcripts.Taken together with accumulation and activation of CD8+ T cells andplasmacytoid dendritic cells in the MS brain, the persistence of anintracerebral pool of EBV infected B cells suggests that MS could resultfrom virus-induced immunopathology.

TalmaBrenner (Israel) highlighted the role of the cholinergic balancein neuroinflammation stressing that since the nervous system is amajorproducer of Acetylcholine (ACh), the immune cholinergic system canmediate neuro-immune interactions, or may serve as an internalregulator of immune responses. Studies on anti-inflammatory effectsof Acetylcholinesterase inhibitors (AChEI) during neuroinflammation inexperimental autoimmune encephalomyelitis (EAE) showed thatAChEIreduce the clinical severity of disease, central nervous system (CNS) andaxonal damage and suppress the reactivity of encephalitogenic T cells,probably by increasing ACh concentration near immune cells andenabling its interaction with α7 nicotinic ACh receptors expressed onthese cells. These findings point to a novel role for AChEI which may berelevant inCNS inflammatorydiseases andemphasize the importanceofthe cholinergic balance in neurological disorders such as Alzheimer'sdisease and MG, in which AChEI are used as therapeutic agents.

Bruno Bonetti (Italy) reported on the results obtained using aproteomic approach to identify the autoantigen(s) recognized byserum and cerebrospinal fluid (CSF) IgG from MS patients. Compar-ative analysis of autoreactive spots showed that a restricted numberof neural protein isoforms was specifically recognized by MS IgG.Almost all MS patients had CSF IgG directed to isoforms of one of theoligodendroglial molecules transketolase (TK), CNPase I, collapsinresponse mediator protein 2, and tubulin b4. Interestingly, 50% of MSIgG recognized TK, which was found to localize predominantly inoligodendrocytes in human white matter from normal and MS braintissue samples. This approach sheds new light on the autoimmunerepertoire present in MS patients, revealing novel oligodendroglialand/or neuronal putative autoantigens with potentially importantpathogenic and diagnostic implications.

Ronen Alon (Israel) presented his studies on chemokine signals forlymphocyte adhesion and motility across endothelial barriers. Hefocused on two major integrin receptors, VLA-4 and LFA-1, whichmediate lymphocyte arrest on specific target vascular sites and needto undergo in situ reversible activation at the lymphocyte–endothe-lium interface. Dissecting how endothelial chemokines triggerlymphocyte integrins to support shear-resistant crawling on andacross endothelial barriers, a critical role in this process was found forhigh affinity LFA-1 integrin. Alon proposes that shear forces stabilizeLFA-1–ICAM-1 bonds at high affinity, trigger invasive filopodia on Tcells that promote endothelial invaginations, and thereby allowcrawling lymphocytes to probe the endothelial barrier for chemotacticcues within the endothelial junctions and basolateral compartments.

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These studies predict that multiple cytoskeletal remodeling GTPases ondifferent subsets of T cells contribute to integrin activation bychemokine signals and shear forces, thus placing these enzymes asnovel targets for anti-inflammatory therapy.

The second session, chaired by Michael Sela (Israel) and OdedAbramsky (Israel), was dedicated to the late Dr. Dvora Teitelbaum.Michael Sela heldwords inmemory of Dvora Teitelbaum, describing herfruitful scientific career and focusing on her central role in thedevelopment of copolymer 1 (Cop-1), a drugwhichhashelpedhundredsof thousands of people afflicted with MS. Michael Sela and the otherspeakers in this session described also Teitelbaum's special personality.

Hartmut Wekerle (Germany, the guest of honor of the meeting)focused on the nature of pathogenic autoimmune processes andoutlined recent insights into brain autoimmunity via studies ofexperimentalmodel systems. Using two-photon imaging and functionalapproaches, it was possible to trace the behavior of myelin specific Tcells, the culprits of inflammatory demyelinating disease, on their wayfrom the peripheral immune system into the CNSwhitematter. Tracingof cell-to-cell interactions involved in the multiple milieus crossed byCNS-seeking autoimmune T cells may indicate numerous therapeutictargets which could be of Help in taming the autoaggressive effectors,possibly even before they invade and damage the white matter.

Ruth Arnon (Israel) described the development of Copolimer-1(Cop-1) from basic research to clinical application pointing to thepivotal role that Dr. Teitelbaum had in these studies. Cop-1, firstestablished as a suppressive agent in EAE, was found in clinical trials toslowprogressionof disability and to reduce the relapse rate in relapsing-remitting MS with high safety profile and was subsequently approvedfor the treatment ofMSpatientsworldwide. Thebeneficial effect of Cop-1-induced cells is mediated by different mechanisms, like secretion ofanti-inflammatory cytokines and neurotrophic factors and stimulationof theproliferation andmigration of neural progenitor cells. In EAE, Cop-1was also shown tohave an inhibitory effect ondemyelination andmayeven promote remyelination, as observed in recent studies by electronmicroscopy.

Tamir Ben-Hur (Israel) summarized the prospects of cell therapyfor MS by neural stem cells (NSC). Originally, NSC transplantation wasproposed for cell replacement therapy in diseases such as Parkinson's,Huntington and demyelinating diseases. The beneficial effects oftransplanted neural precursors in models of MS are mediated viamultiple mechanisms, including remyelinating capabilities, immuno-modulatory properties, and neurotrophic and neuroprotective effects.Recent studies show that NSC possess also protective anti-inflamma-tory properties. Selecting the proper cell population, the route of celldelivery and timing of transplantation should be tailored for eachneurological disease in clinical applications. In view of theseconsiderations, MS is an especially good candidate for cell therapysince delivery of neural precursor cells into the ventricular andsubarachnoid space brings them in close proximity to most whitematter tracts that are involved in the disease.

In a special Teva symposium, chaired by Ariel Miller (Israel), ArnonKarni (Israel) talked on the dual, anti-inflammatory and neuroprotec-tive activities of Cop-1 (Copaxone). These are observed also inexperimental animal models of MS including autoimmune opticneuritis. In these models of autoimmune CNS inflammation, glatirameracetate reduced axonal damage, suppressed secondary apoptotic celldeath of neurons and increased proliferation, migration, and differen-tiation of neuroprogenitors. In addition to a variety of influences on theadaptive and innate immune system described for glatiramer acetate, ithas been shown that human glatiramer acetate-reactive T cells producebrain derived neurotrophic factor (BDNF) that can bemonitored in seraand CSF of patients treated with glatiramer acetate.

Ariel Miller (Israel), the first speaker in the third session on ‘Gene,environment and implications to theranostics’ chaired by Ron Milo(Israel) and Talma Brenner (Israel), discussed issues related totranslation toward ‘Personalized Medicine’ in MS in which ineffective

medication may lead to irreversible dysfunction. Environment andgenetics as well as demographic and chrono-biological indicatorsdetermine disease subtype and activity, and the patient's response tomedication. Novel genomic technologies stimulated pharmacogeneticstudies aimed at identifying genetic factors that affect response totreatment. In light of the rapid advances in the implementation ofTheranostics—the merging of therapeutics and diagnostics, ‘Person-alized Medicine’ for MS seems feasible within the coming years.

Francesca Gilli (Italy) reported on results of a genome-widetranscription analysis aimed at getting better insights into theimmunobiological mechanisms underlying the pregnancy-relateddecrease in disease activity in MS patients. Gene expression profilesof peripheral blood mononuclear cells were evaluated in women(both MS patients and healthy controls) during their pregnancy cycle.MS patients had a deregulated expression of inflammation-relatedgenes before pregnancy and this imbalancewas reverted in the courseof pregnancy. These specific changes in gene expression wereassociated with a decrease in disease activity assessed by occurrenceof relapses during pregnancy. Understanding these findings may helpto develop new and effective therapeutic strategies for MS.

Stefano Sotgiu (Italy) presented new experimental evidence on theinteraction between exogenous and endogenous viruses inMS. EBV andother viruses proposed as causal factors in MS can rapidly transactivatethe expressionof human endogenous retroviral elements such asHERV-W and HERV-K. After strong activation, these otherwise latent andtoleratedHERVcan activate their full immunopathologic potentials. Thispoly-microbial synergism may be relevant in MS phenomenology.

In a session of selected oral presentations, chaired by Nathan Karin(Israel) and Adi Vaknin-Dembinsky (Israel), Rachel Levy (Israel) reportedon the direct and indirect roles of cytosolic phospholipase A2α inneurodegeneration in rat glia–neuron mixed cultures, Dorit Farfara(Israel) talked on the dual role of gamma-secretase in Alzheimer's diseaseand Jacob Rachmilewitz (Israel) presented the implications of PP14regulation of T cell differentiation in the treatment of MS.

The following session, chaired byRenatoMantegazza (Italy) andSaraFuchs (Israel) was dedicated to peripheral neuro-immune modulation.Sonia Berrih-Aknin (Israel) presented her work on pathogenic andregulatory events in the thymus of MG patients. Microarray analysesrevealed overexpression of the chemokines CXCL13 and CCL21 that areinvolved in germinal center formation in hyperplastic MG thymuses,compared to normal thymuses. MG thymuses had increased pro-inflammatory activity which was partially normalized by glucocorti-coids. Pro-inflammatory cytokines upregulated the expression of AChRin thymic epithelial andmyoid cells and the function of regulatoryT cells(Treg) was severely impaired in MG thymuses. These data suggest thatCXCL13 and CCL21, which are produced in excess in the MG thymus,attract peripheral B cells and T cells, which are maintained in achronically activated state in the inflammatory thymic environmentdueto the defective activity of Treg cells. The constant and upregulatedpresence of AChR in the thymus probably contributes to the triggeringand maintenance of the anti-AChR autoimmune response.

Renato Mantegazza (Italy) reported on the possible pathogeneticinteractions between innate immunity and autoimmunity inMG. Toll-like receptor-4 was found to be over-expressed in the MG patholog-ical thymus suggesting pathogen-mediated activation of innateimmunity pathways. Furthermore, virus infection was detected inMG but not in control thymus. Poliovirus (PV) was detected in somepatients with thymitis or thymoma, suggesting a persistent thymicinfection. A perturbed intrathymic EBV infection was insteadconsistently found in MG patients suggesting a role for this virus inchronic B-cell activation, as observed in MS. Hence, a persistent anddysregulated viral infection in the MG thymus could contributesignificantly to the immunological alterations initiating and/orperpetuating the disease.

Miriam Souroujon (Israel) discussed the role of the autoimmuneregulator gene (AIRE) and of Treg inMGrendering the latter as potential

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targets for immunointervention. Aire−/− mice were shown to expresslow thymic mRNA levels of AChR and mouse strains susceptible toexperimental autoimmune myasthenia gravis (EAMG) have lowerthymic levels of Aire and AChR compared to resistant strains.Surprisingly, EAMG induced in 2 month-old mice was milder in Aire−/−

than in wt mice whereas induction of EAMG in 5 month-old mice led tosignificantly sicker Aire−/− mice compared to wt mice. There was alink between peripheral Treg and the course of EAMG in Aire−/−mice.The key role of Treg in MG is also suggested by lower numbers andfunctional impairment of Treg in MG patients. EAMG rats have alsolower numbers of peripheral Treg as compared with healthy controls.Moreover, administration of ex vivo generated Treg from healthydonors to myasthenic rats had a suppressive effect on EAMG.

Carlo Antozzi (Italy) reported on the efficiency and clinical efficacyof selective IgG immunoadsorption in neurological antibody-mediat-ed disorders, either with protein A or polyclonal sheep anti-humanIgG. The technique can be particularly helpful in the management oftreatment-resistant patients with autoimmune ion channel disordersthat are typically IgG-mediated diseases. This selective approach, thatremoves only circulating immmunoglobulins, is also being tested indisorders of the CNS such as multiple sclerosis and Rasmussen'sencephalitis. The observed effects underline the importance and needfor further studies on the potential role of B cells in inflammatorydisorders of the CNS. Antozzi proposes that immunoadsorption can bea clinical as well as a powerful research tool.

Itzhak Wirguin (Israel) presented accumulating evidence linkingCampylobacter jejuni (Cj) infection with Guillain–Barré syndrome(GBS) and attributing immune-mediated neuropathic damage to anti-ganglioside antibodies generated by molecular mimicry between Cjlipooligosaccharides (LOS) and nerve gangliosides. Although repeatedimmunization by Cj LOS induced a chronic motor neuropathy in rabbitsthe underlying mechanisms in GBS are still poorly understood.

The first speaker in the sixth session chaired by Dimitrios Karussis(Israel) and Robert Furlan (Italy) and entitled “From neuroinflamma-tion to neurodegeneration” was Michal Schwartz (Israel) whodiscussed the concept of peripheral immune cells as players in CNSrepair and maintenance. T cells and blood monocytes are needed forrepair, and microglia and infiltrating monocytes contribute specifi-cally to the repair process in an acute spinal cord injury model.Boosting immunity was shown to be therapeutic for chronicneurodegenerative diseases by circumventing age-related loss ofbrain plasticity and psychological dysfunction such as depression,which are associated with reduced neurogenesis and BDNF.

Robert Furlan (Italy) reported on the fortunate collaborationbetween the group of Diego Centonze in Rome, dealing with basicelectrophysiology, and the team coordinated by Gianvito Martino inMilan. This two-headed research revealed that in EAE it is possible todetect changes in synaptic activity of striatal neurons as early as7 days post-immunization, in the pre-clinical stage. The observedchanges are both pre- and post-synaptic and involve glutamatergic aswell as GABAergic neurons. Synaptic alterations are the consequenceof the signaling cascade following pro-inflammatory cytokine releasein the striatum, and may represent a link between neuroinflamma-tion, neurodegeneration and cognitive impairment.

Dan Frenkel (Israel) presented an immunotherapeutic approach tocerebral amyloid angiopathy due to amyloid accumulation in thevessel walls leading to dementia. Overexpression of TGF-ß1 under anastrocyte promoter in mice results in cerebrovascular amyloidaccumulation. Nasal vaccination with a proteosome-based adjuvant,Protollin, potently decreases vascular amyloid in 13-month-old TGF-ß1 expressingmice following six weeks of treatment, prevents furtherbrain damage and leads to significant improvement in cognition.

The last session was dedicated to stem cells and future therapies inimmune-mediated neurological diseases and was chaired by RonitGalili Mosberg (Israel) and Arnon Karni (Israel). Dimitrios Karussis(Israel) presented data on the potential of bone marrow-derived

mesenchymal stem cells (BM-MSC) that possess powerful neuro-trophic and immunomodulatory properties for treatment of MS andneurodegenerative diseases. A trial including 13 MS and 14 amyo-trophic lateral sclerosis patients showed that intrathecal administra-tion of BM-MSC is feasible and relatively safe. Treatment resulted inimmediate immunomodulatory effects and led to clinical benefits insome patients suggesting that further controlled studies and longerobservation periods are required to evaluate the long term safety andpotential clinical efficacy of treatment with BM-MSC.

Luca Muzio (Italy) showed that the subventricular zone (SVZ) ofthe adult forebrain is a site of intense inflammation during EAE. Theseareas of the forebrain contain the neural stem cell niches which maysustain both tissue homeostasis and tissue repair of the diseasedCNS. However, these areas appeared substantially derangedduring neuroinflammation. Analysis of bone marrow chimeric micerevealed a large influx of T cells, B cells and macrophages in the SVZ.Consequently, the morphology of the periventricular lining wasaltered and the growth fraction of proliferating neural stem cells wasseverely impaired. Molecular analysis of laser capture-mediated SVZmicrodissections revealed that a subset of cells within the healthy SVZconstitutively express the pro-inflammatory chemoattractant CXCL10,which can promote early T-cell recruitment into these areas. Oncewithin the SVZ, effector immune cells promote the expression of pro-inflammatory and detrimental signals that can contribute to SVZderangement.

Nathan Karin (Israel) presented data in EAE suggesting a potentialuse of regulatory chemokines for treatment of MS. CXCL12 (stromalderived factor-1 alpha) redirects the polarization of effector Th1 cellsinto CD4+CD25-Foxp3- IL-10high antigen-specific regulatory T cells in aCXCR4 dependentmanner, and by doing so acts as a regulatorymediatorrestraining the autoimmune inflammatory process. Administration ofCXCL12-Ig fusion protein suppresses EAE in wild type, but not in IL-10deficient mice and anti-IL-10 neutralizing antibodies can reverse thissuppression. The beneficial effect included selection of CD4+CD25-Foxp3-IL-10high (Tr1) antigen-specific T cells that could adoptivelytransfer disease resistance, and suppression of Th17 selection.

Ron Milo (Israel) closed the meeting by giving a comprehensiveoverview on clinical trials that are in progress for MS—a complex ofmulti-faceted processes that provides a multitude of targets fortherapeutic intervention. Several new oral therapies (FTY720,cladribine, oral fumarate, laquinimode, teriflunomide) have shownefficacy and good tolerability in recently completed phase II and IIIclinical trials in relapsing MS, and their marketing is awaited. Otheroral agents are being tested in various stages of MS, or in combinationwith approved immunomodulators. New monoclonal antibodiesdemonstrate impressive efficacy; however, safety issues and newemerging adverse effects raise concern over their future widespreaduse. These “double-edged sword” agents need further thoroughevaluation and may be limited to restricted populations of MSpatients. The successful completion of several large clinical trials withinterferons and glatiramer acetate in clinically isolated syndromesemphasizes the importance of early treatment of MS. New strategiessuch as T-cell vaccination, DNA vaccination, anti-sense agents, andstem-cell transplantation look promising and other studies approachunmet needs and new directions in the treatment of MS. Several oldand new compounds are being tested for disablingMS symptoms. Thisvibrant scene is bringing new hope for better disease control, newoptions for progressive disease, and novel approaches to alleviatedisturbing symptoms associated with functional impairment ofpatients with immune-mediated neurological diseases.

At the end of the meeting, besides appreciation of the excellentorganization and stimulating scientific environment, the generalfeeling was that this event has paved the way for future jointinitiatives with a broader participation of young researchers andstudents from both countries as well as strengthened the bi-nationalbridges at both professional and personal levels.

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Acknowledgments

The meeting was organized with the generous support of the ItalianMinistry of Foreign Affairs and the Italian Embassy in Tel Aviv, IsraelMinistry of Health, and with the contribution of Teva Pharmaceuticals,Novartis, Zotal, Bayer-Schering Pharma, Biogen-Idec, Merck-SeronoIsrael, and Medison Pharma, Israel.

Representative photos attached.

Ariel MillerDepartment of Neurology, Division of Neuroimmunology,

Carmel Medical Center, Rappaport Faculty of Medicine and ResearchInstitute, Technion-Israel Institute of Technology,

Haifa 34362, IsraelCorresponding author.

E-mail address: milleras@netvision.net.il.

Miriam C. SouroujonDepartment of Natural Sciences, The Open

University, Raanana 43107, IsraelE-mail address: miriso@openu.ac.il.

Francesca AloisiDepartment of Cell Biology and Neuroscience,

Istituto Superiore di Sanità, Viale Regina Elena 299,00161, Rome, Italy

E-mail address: francesca.aloisi@iss.it.

12 August 2009