Multiple Sclerosis: Karussis D

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.

Karussis D, Kassis I. · Department of Neurology, Laboratory of Neuroimmunology, Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. · Clin Neurol Neurosurg. · Pubmed #18375051 No free full text.

Abstract: The reported neurodegeneration process in multiple sclerosis may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. Efforts for neuroprotective treatments have not been, so far, successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This may be achieved both by support of the resident CNS stem cells repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases. In this review, we summarize the experience with the use of different types of stem cells in the animal models of MS (EAE) and we describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.

Slavin S, Kurkalli BG, Karussis D. · International Center for Cell Therapy & Cancer (ICTC), Tel Aviv Medical Center, Tel Aviv, Israel. · Clin Neurol Neurosurg. · Pubmed #18325660 No free full text.

Abstract: No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

Goodin DS, Biermann LD, Bohlega S, Boiko A, Chofflon M, Gebeily S, Gouider R, Havrdova E, Jakab G, Karabudak R, Karussis D, Miller A, Pakdaman H, Selmaj K, Sharief M, Anonymous00295. · Department of Neurology, University of California, San Francisco, CA 94121, USA. email: · Curr Med Res Opin. · Pubmed #17908370 No free full text.

Abstract: BACKGROUND: As results from an increasing number of clinical trials with disease-modifying drugs (DMDs) in multiple sclerosis (MS) become available, the challenge for the treating neurologist is how to decide on the appropriate therapy for an individual patient. OBJECTIVE: An International Working Group for Treatment Optimization in MS met to consider how the principles of evidence-based medicine (EBM) should be used to assess the current best evidence regarding the treatment of MS. This report summarizes the outcome from the workshop at which this topic was addressed. RESULTS: Class I evidence from head-to-head studies provides the best tool for direct comparisons of DMDs. However, other EBM approaches to data analysis from placebo-controlled trials can be used to help determine the benefits and risks of a particular DMD relative to placebo by calculating the number needed to treat to achieve a positive outcome, such as avoiding a relapse, and the number needed to harm to produce an additional adverse event, such as having a therapy-related dropout. This provides a structured basis for comparisons between DMDs. CONCLUSION: While such comparisons have their limitations, particularly when drugs with substantially different side-effect profiles are to be compared, they can provide useful information to guide treatment decisions.

Karussis D, Kassis I. · Department of Neurology, Laboratory of Neuroimmunology, Hadassah-Hebrew University Center, Jerusalem, Ein-Karem, IL-91120, Israel. · Expert Rev Neurother. · Pubmed #17868017 No free full text.

Abstract: The reported evidence of neurodegeneration in multiple sclerosis (MS) may explain the lack of efficacy of the currently used immunomodulating modalities and the irreversible axonal damage, which results in accumulating disability. To date, efforts for neuroprotective treatments have not been successful in clinical studies in other CNS diseases. Therefore, for MS, the use of stem cells may provide a logical solution, since these cells can migrate locally into the areas of white-matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin. This is achieved both by support of the resident CNS stem cell repertoire and by differentiation of the transplanted cells into neurons and myelin-producing cells (oligodendrocytes). Stem cells were also shown to possess immunomodulating properties, inducing systemic and local suppression of the myelin-targeting autoimmune lymphocytes. Several types of stem cells (embryonic and adult) have been described and extensively studied in animal models of CNS diseases and the various models of MS (experimental autoimmune encephalomyelitis [EAE]). In this review, we summarize the experience with the use of different types of stem cells in CNS disease models, focusing on the models of EAE and describe the advantages and disadvantages of each stem cell type for future clinical applications in MS.

Karussis D, Kassis I, Kurkalli BG, Slavin S. · Department of Neurology and Laboratory of Neuroimmunology and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Hospital, Ein-Karem, Jerusalem, IL-91120, Israel. · J Neurol Sci. · Pubmed #17610906 No free full text.

Abstract: Bone marrow (BM) derived mesenchymal stem cells (MSCs) (non-hematopoietic, stromal cells) can differentiate under certain circumstances into cells from various neuronal and glial type lineages; they also exert immunomodulatory effects. For potential clinical applications, BM-MSCs offer significant practical advantages over other types of stem cells, since they can be obtained from the adult BM (the patient himself being the donor) and can be easily cultured and expanded posing in parallel a very low risk for development of malignancies. We have shown that BM-MSCs cultured with a cocktail of growth factors (containing FGF and BDNF) differentiate into neuronal/glial lineage cells with a predominance of cells expressing astrocytes' markers. BM-MSCs were effective in suppression of chronic EAE in mice and induced neuroprotection, preserving most of the axons in the CNS of successfully-treated animals. Histopathological studies revealed that MSCs could efficiently migrate into the CNS inflamed tissue (both when administered intravenously and intraventricularly) and differentiated into cells expressing neural-glial lineage markers. Our preclinical results indicate that bone marrow can provide a source of stem cells with a potential for migration into inflamed CNS tissue and differentiation into cells expressing neuronal and glial cell markers. Such an approach may provide a feasible and practical way for in situ immunomodulation, neuroprotection and possibly remyelination/regeneration in diseases like multiple sclerosis. We therefore developed a explorative protocol for the evaluation of this therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

Karussis D, Biermann LD, Bohlega S, Boiko A, Chofflon M, Fazekas F, Freedman M, Gebeily S, Gouider R, Havrdova E, Jakab G, Karabudak R, Miller A, Anonymous00555. · Department of Neurology, Hadassah Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. · Eur J Neurol. · Pubmed #16420394 No free full text.

Abstract: An International Working Group for Treatment Optimization in MS met to recommend evidence-based therapeutic options for the management of suboptimal responses or intolerable side-effects in patients treated with disease-modifying drugs (DMDs) for multiple sclerosis (MS). Several DMDs are now available for the treatment of MS that have been shown to alter the clinical course of the disease by decreasing disease activity and delaying the progression of disability. Nevertheless, many patients continue to experience disease activity whilst on treatment, and recommendations have been made on how the success of therapy in an individual patient can be assessed. However, even after having identified criteria for a suboptimal response to current treatments, clinicians require guidance on how to improve the outcomes. This report summarizes the conclusions from a workshop at which this issue was addressed. We suggest treatment pathways for optimizing therapy for those patients with suboptimal responses to DMDs, and therapeutic options for patients with unacceptable side-effects on their current therapy.

Karussis D, Grigoriadis S, Polyzoidou E, Grigoriadis N, Slavin S, Abramsky O. · Department of Neurology and the Agnes Ginges Center for Neurogenetics, Laboratory of Neuroimmunology, Hadassah University Hospital, Jerusalem, Ein-Karem IL-91120, Israel. · Clin Neurol Neurosurg. · Pubmed #16413962 No free full text.

Abstract: In chronic inflammatory diseases like multiple sclerosis (MS), neuroprotection refers to strategies aimed at prevention of the irreversible damage of various neuronal and glial cell populations, and promoting regeneration. It is increasingly recognized that MS progression, in addition to demyelination, leads to substantial irreversible damage to, and loss of neurons, resulting in brain atrophy and cumulative disability. One of the most promising neuroprotective strategies involves the use of bone marrow derived stem cells. Both hematopoietic and non-hematopoietic (stromal) cells can, under certain circumstances, differentiate into cells of various neuronal and glial lineages. Neuronal stem cells have also been reported to suppress EAE by exerting direct in situ immunomodulating effects, in addition to their ability to provide a potential source for remyelination and neuroregeneration. Preliminary results from our laboratory indicate that intravenous or intracerebral/intraventricular injection of bone marrow derived stromal cells could differentiate in neuronal/glial cells and suppress the clinical signs of chronic EAE. Both bone marrow and neuronal stem cells may therefore have a therapeutic potential in MS. It seems that future treatment strategies for MS should combine immunomodulation with neuroprotective modalities to achieve maximal clinical benefit.

Grigoriadis N, Grigoriadis S, Polyzoidou E, Milonas I, Karussis D. · Department of Neurology, Laboratory of Experimental Neurology and Neuroimmunology, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilp Kyriakidi str 54636, Thessaloniki, Greece. · Clin Neurol Neurosurg. · Pubmed #16388896 No free full text.

Abstract: Both inflammatory and neurodegenerative components may contribute to the clinical profile of multiple sclerosis (MS) leading to irreversible deficits when they exceed the threshold of compensation. The mechanisms leading to tissue injury in MS are complex. Inflammation appears to be caused by overactive pro-inflammatory T-helper 1 cells, initiating an inflammatory cascade with several cellular and molecular immune components participating in the pathogenetic mechanism. Current treatments are most effective in the inflammatory phase of the disease since they may interfere with various stages of the immune cascade. Recent evidence has emerged that inflammation may not only be destructive, but may also play a part in tissue repair. This has opened up a new aspect of our knowledge of the role of the inflammatory process in MS. Data regarding the role of regulatory cells in particular, imply that specific immunomodulatory strategies that support the function of these particular cellular subpopulations may participate in the downregulation of autoimmune responses in MS.

Burt RK, Cohen B, Rose J, Petersen F, Oyama Y, Stefoski D, Katsamakis G, Carrier E, Kozak T, Muraro PA, Martin R, Hintzen R, Slavin S, Karussis D, Haggiag S, Voltarelli JC, Ellison GW, Jovanovic B, Popat U, McGuirk J, Statkute L, Verda L, Haas J, Arnold R. · Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill 60611, USA. · Arch Neurol. · Pubmed #15956156 links to  free full text

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Karussis D, Slavin S. · Department of Neurology, Hadassah University Hospital, Jerusalem 91120, Israel. · J Neurol Sci. · Pubmed #15261562 No free full text.

Abstract: Acute immunosuppression with lymphocytic agents given at maximally tolerated doses, followed by hematopoietic stem cell rescue achieved by autologous bone marrow or peripheral blood stem cell transplantation (BMT), has proved effective in various experimental models of autoimmunity. The rationale for such an approach in autoimmune diseases is based on the concept of lymphoablation of self-reactive lymphocytes followed by de novo immune system reconstitution, which, in the presence of the autoantigens in the thymus, may reinduce self-tolerance. Our previous work shows that in experimental autoimmune encephalomyelitis (EAE), autologous/syngeneic BMT not only prevents the appearance of paralytic signs, but can also partially reverse chronic disease and induce long-term, antigen-specific tolerance. However, there are serious reservations to be considered when interpreting these data and before applying similar protocols in patients with multiple sclerosis. (1) The model of EAE is not a completely reliable model of multiple sclerosis. (2) In animals with chronic EAE, although further relapses were prevented, the established paralysis was usually not reversible. According to recent data, in chronic multiple sclerosis (MS) lesions, damage caused by axonal loss/transection and cortical/spinal cord atrophy is irreversible and probably amenable to immunotherapy. (3) Long-term, antigen-specific tolerance may be induced with BMT, but not in all cases; in passively induced CR-EAE, many of the mice relapsed upon challenge with myelin antigens, which may indicate that the presence of the immunizing, myelin antigens (on the site of immunization) during the process of immune reconstitution is critical for induction of tolerance. Finally, one should weigh the procedure-related risks (including mortality of up to 5%) of bone marrow or peripheral stem cell transplantation (SCT). A more radical solution for autoimmunity may involve the use of non-myeloablative allogeneic transplantation.

Grigoriadis N, Ben-Hur T, Karussis D, Milonas I. · Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, 1 Stilp. Kyriakidi Str., 54636 Thessaloniki, Greece. · Clin Neurol Neurosurg. · Pubmed #15177770 No free full text.

Abstract: Multiple sclerosis is no longer considered to simply be an autoimmune demyelinating disease. Axonal destruction is another central pathological feature and a contributor to the accumulating disability of disease progression. The mechanism underlying axonal pathology has not been fully clarified but does not appear to be a simple one. The relationship between axonal damage and other components of the pathological features such as demyelination, inflammation and remyelination are under intense investigation. Experimental data suggest that therapeutic interventions such as the induction of rapid remyelination may lead to the protection of axons. In addition to immunomodulation, future strategies for neuroprotection may be of great importance.

Karussis D, Weiner HL, Abramsky O. · Department of Neurology, Hadassah-Hebrew University Hospital, Medical Center, Ein-Karem, Jerusalem, Israel. · Mult Scler. · Pubmed #10618695 No free full text.

This publication has no abstract.

Kassis I, Grigoriadis N, Gowda-Kurkalli B, Mizrachi-Kol R, Ben-Hur T, Slavin S, Abramsky O, Karussis D. · Department of Neurology and Agnes-Ginges Center for Neurogenetics, Jerusalem, Israel. · Arch Neurol. · Pubmed #18541795 links to  free full text

Abstract: OBJECTIVE: To investigate the therapeutic potential of mesenchymal stromal cells (MSCs) in the chronic model of experimental autoimmune encephalomyelitis (EAE). DESIGN: Mesenchymal stromal cells were obtained from the bone marrow of naïve C57BL and green fluorescent protein-transgenic mice and cultured with Eagle minimum essential medium/alpha medium after removal of adhering cells. Following 2 to 3 passages, MSCs were injected intraventricularly or intravenously into mice in which chronic EAE had been induced with myelin oligodendrocyte glycoprotein 35-55 peptide. RESULTS: In 8 separate experiments, the intravenously and intraventricularly injected green fluorescent protein-positive MSCs were attracted to the areas of central nervous system inflammation and expressed galactocerebroside, O4, glial fibrillary acidic protein, and beta-tubulin type III. The clinical course of chronic EAE was ameliorated in MSC-treated animals (0% mortality; mean [SE] maximal EAE score, 1.76 [1.01] and 1.8 [0.46] in the intraventricular and intravenous groups, respectively, vs 13% and 21% mortality and 2.80 [0.79] and 3.42 [0.54] mean maximal score in the controls). A strong reduction in central nervous system inflammation, accompanied by significant protection of the axons (86%-95% intact axons vs 45% in the controls) was observed in the animals injected with MSCs (especially following intraventricular administration). Mesenchymal stromal cells injected intravenously were detected in the lymph nodes and exhibited systemic immunomodulatory effects, downregulating proliferation of lymphocytes in response to myelin antigens and mitogens. Mesenchymal stromal cells cultured with fibroblast growth factor and brain-derived neurotrophic factor in vitro acquired neuronal-lineage cell morphology and expressed beta-tubulin type III, nestin glial fibrillary acidic protein, and O4. CONCLUSIONS: Our results indicate that stem cells derived from bone marrow may provide a feasible and practical way for neuroprotection, immunomodulation, and possibly remyelination and neuroregeneration in diseases such as multiple sclerosis.

Garin T, Rubinstein A, Grigoriadis N, Nedvetzki S, Abramsky O, Mizrachi-Koll R, Hand C, Naor D, Karussis D. · Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. · J Neurol Sci. · Pubmed #17382349 No free full text.

Abstract: Standard CD44 (CD44s) and its alternatively spliced variants (CD44v) were found to be associated with the metastatic potential of tumor cells, and with cell migration of autoimmune inflammatory cells, including cells involved in experimental autoimmune encephalomyelitis (EAE). The aim of the present study was to evaluate whether induction of anti-CD44 immune reactivity, through cDNA vaccination could down-regulate EAE. Our vaccination technique involved the insertion of CD44s or CD44v cDNA into a silicone tube filled with 2.5 cm long segment of hydroxylated-polyvinyl acetate wound dressing sponge (forming a virtual lymph node) which was implanted under the skin of SJL/J mice immunized with myelin antigens for EAE induction. Animals vaccinated with CD44v cDNA developed significantly less severe EAE when compared with sham vaccinated animals or animals vaccinated with CD44s cDNA. The in vitro proliferation of lymphocytes was preserved regarding myelin antigens and mitogens. Histopathological examinations revealed a significant reduction of EAE lesions and enhanced apoptosis in central nervous system (CNS)-infiltrating cells of the successfully vaccinated animals. Such methods of cDNA vaccination with CD44 could be applicable in inflammatory CNS diseases, like multiple sclerosis.

Einstein O, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Polyzoidou E, Lavon I, Milonas I, Karussis D, Abramsky O, Ben-Hur T. · Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah--Hebrew University Hospital, Jerusalem, Israel. · Exp Neurol. · Pubmed #16472805 No free full text.

Abstract: Stem cell transplantation was introduced as a mean of cell replacement therapy, but the mechanism by which it confers clinical improvement in experimental models of neurological diseases is not clear. Here, we transplanted neural precursor cells (NPCs) into the ventricles of mice at day 6 after induction of chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Transplanted cells migrated into white matter tracts and attenuated the clinical course of disease. NPC transplantation down-regulated the inflammatory brain process at the acute phase of disease, as indicated by a reduction in the number of perivascular infiltrates and of brain CD3+ T cells, an increase in the number and proportion of regulatory T cells and a reduction in the expression of ICAM-1 and LFA-1 in the brain. Demyelination and acute axonal injury in this model are considered to result mainly from the acute inflammatory process and correlate well with the chronic neurological residua. In consequence to inhibition of brain inflammation, precursor cell transplantation attenuated the primary demyelinating process and reduced the acute axonal injury. As a result, the size of demyelinated areas and extent of chronic axonal pathology were reduced in the transplanted brains. We suggest that the beneficial effect of transplanted NPCs in chronic EAE is mediated, in part, by decreasing brain inflammation and reducing tissue injury.

Gur C, Karussis D, Golden E, Doron S, Ilan Y, Safadi R. · Liver Unit, Hadassah University Hospital, Jerusalem, Israel. · Clin Immunol. · Pubmed #16290121 No free full text.

Abstract: Copaxone modifies TH1 immune response in multiple sclerosis. As Crohn's disease shares TH1 predominance, this study came to investigate the anti-inflammatory response of Copaxone in animal model of colitis. METHODS: Colitis was induced by intra-rectal instillation of TNBS in 2 animal groups; one of them was daily treated intraperitoneally by 300 mug Copaxone starting 48 h post-colitis induction. Both colitis groups were compared to naive group. Eight male C57Bl6 mice were used in each group. At day 12, distal colon was excised for standard scoring, splenocytes were isolated for FACS and serum cytokines were assessed. Splenocytes were in-vitro-stimulated with colitis protein extracts in the presence or absence of Copaxone. Lymphocytes were blocked by either MHC anti-class I or anti-class II antibodies prior to Copaxone administration. RESULTS: Copaxone markedly alleviated macro/microscopic colitis scoring as they decreased from 2.9 +/- 1.1/2.6 +/- 0.8 in colitis group to 1.7 +/- 1/1.5 +/- 0.5 in Copaxone-treated mice (P = 0.03/P = 0.008, respectively) compared to 0 +/- 0/1 +/- 0 in naives (P < 0.001/P < 0.01, respectively). CD4 subsets significantly decreased following Copaxone administration as compared to naive mice (P = 0.05). Although Copaxone-treated mice manifested a block of both serum TH1/TH2 responses, only interferon gamma secreting CD4 cells significantly decreased. NK cells tend to increase following colitis induction (P = 0.08), however, they significantly decreased in Copaxone-treated animals (P = 0.006). NK-T followed NK pattern. Using in vitro studies, Copaxone showed amelioration of T-cell proliferation that was significantly blocked when cells were pre-incubated with anti-MHC class II but not class I antibodies. CONCLUSIONS: Copaxone had class-II-restricted anti-inflammatory effect in our animal colitis model associated with CD4/NK/NKT/TH1/TH2 suppression.

Ekstein D, Linetsky E, Abramsky O, Karussis D. · Department of Neurology, The Agnes Ginges Center for Neurogenetics, Hadassah-Hebrew University Hospital, Ein-Karem, Jerusalem, Israel. · Neurology. · Pubmed #16087915 No free full text.

Abstract: Peripheral neuropathy has been reported as a side effect of interferon alpha, but not with interferon beta (IFNbeta) treatment. The authors assessed six patients with multiple sclerosis who developed polyneuropathy, or had exacerbation of previously subclinical neuropathy, during treatment with IFNbeta. In five patients the neuropathy improved after discontinuation of treatment and in two patients it relapsed upon rechallenge.

Karussis D, Michaelson DM, Grigoriadis N, Korezyn AD, Mizrachi-Koll R, Chapman S, Abramsky O, Chapman J. · Department of Neurology, Laboratory of Neuroimmunology and the Agnes Ginges Center for Neurogenetics, Hadassah Medical Center, Hebrew University, Jerusalem, Israel. · Mult Scler. · Pubmed #14582773 No free full text.

Abstract: Experimental autoimmune encephalomyelitis (EAE) was found to have a chronic and significantly worse course in apolipoprotein-E (apoE) deficient female mice when compared with matched controls. Disease measures compared included incidence of EAE (64% versus 31%, P < 0.05, chi2 test), maximal clinical score (average +/- SD 2.81 +/- 2.5 versus 0.75 +/- 1.1, P < 0.01, Mann-Whitney test) and mortality (27.3% versus 0%, P = 0.02, Mann-Whitney test and chi2 test). ApoE deficient mice had significantly increased lymphocyte proliferation responses to both myelin antigens and mitogens and significantly more infiltrating lesions in the central nervous system (CNS) in histopathology. Defective neuronal repair mechanisms and enhanced immune reactivity in apoE deficient mice may explain our findings. Clinical implications for MS are discussed.

Karni A, Kahana E, Zilber N, Abramsky O, Alter M, Karussis D. · Department of Neurology, Barzilai Medical Center, Ashkelon, Israel. · Neuroepidemiology. · Pubmed #12566958 No free full text.

Abstract: A comparison of the incidence rate (IR) and the prevalence rate (PR) of multiple sclerosis (MS) in subgroups of the same ethnic origin, but born and living in different geographical areas, may delineate the relationship between environmental and genetic risk factors for MS. Previous epidemiological studies of MS in Israel did not include the Arab population and used diagnostic criteria that did not include MRI findings. Therefore, we studied the age-adjusted IR and PR of MS in a more recent sample in different population groups, including Arabs, of Greater Jerusalem. We found that the PR of MS in Israeli Jews is higher than previously described. Furthermore, the PR was significantly lower among immigrant Jews from Asia/Africa (A/A) than among native-born Jews of Asian/African origin (I-A/A). Since these groups have similar genetic susceptibilities to MS, the higher PR in the latter is probably due to environmental factors. Our study does not support the effect of latitude on the risk of developing MS since no difference in the PR was found between immigrant Jews from Europe/America (E/A) and native-born Jews of European/American origin (I-E/A). Among Arabs, the PR was similar to that among A/A. Therefore, we hypothesized similarity in environmental etiologic factors for MS between the countries of origin of A/A immigrants and of Arabs communities in Greater Jerusalem. The IR of I-E/A was higher than that of I-A/A and Arabs, although this difference did not reach statistical significance.

Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O. · Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Jerusalem, Israel. · Glia. · Pubmed #12465047 No free full text.

Abstract: Transplanted neural precursor cells remyelinate efficiently acutely demyelinated focal lesions. However, the clinical value of cell transplantation in a chronic, multifocal disease like multiple sclerosis will depend on the ability of transplanted cells to migrate to the multiple disease foci in the brain. Here, we expanded newborn rat neural precursor cells in spheres and transplanted them intracerebroventricularly or intrathecally in rats. The cells were labeled by the nuclear fluorescent dye Hoechst or by incubation with BrdU to enable their identification at 2 days and 2 weeks after transplantation, respectively. Spheres consisted of PSA-NCAM(+), nestin(+), NG2(-) undifferentiated precursor cells that differentiated in vitro into astrocytes, oligodendrocytes, and neurons. Spheres that were transplanted into intact rats remained mostly in the ventricles or in the spinal subarachnoid space. Following transplantation at peak of experimental autoimmune encephalomyelitis, cells migrated into the brain or spinal cord parenchyma, exclusively into inflamed white matter but not into adjacent gray matter regions. After 2 weeks, many transplanted cells had migrated into distant white matter tracts and acquired specific markers of the astroglial and oligodendroglial lineages. Thus, the inflammatory process may attract targeted migration of transplanted precursor cells into the brain parenchyma.

Karni A, Kohn Y, Safirman C, Abramsky O, Barcellos L, Oksenberg JR, Kahana E, Karussis D, Chapman J, Brautbar C. · Department of Neurology, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem, Israel. · Mult Scler. · Pubmed #10618697 No free full text.

Abstract: A strong association exists between multiple sclerosis (MS) and the DRB1*1501 haplotype, in most populations. Linkage of Multiple Sclerosis (MS) with the MHC or HLA region on chromosome 6p21 has previously been observed in DRB1*1501 positive MS families. A group of 13 Israeli multiplex MS families with a very low frequency of DRB1*1501 haplotype were examined in this study. Association and a linkage test were performed in order to identify a non-DRB1*1501 effect of HLA on susceptibility for MS. MS multiplex families and healthy controls were molecularly typed for six highly polymorphic markers located within the MHC region: DRB1, DQA1 and DQB1, BAT-2, MIB and D6S248. Data analyses included: (a) an association study comparing the patient group with both healthy relative, and healthy control groups (b) a transmission test for linkage disequilibrium (TDT) of the MS-associated alleles in the multiplex families, and (c) multipoint non-parametric linkage (NPL) and parametric LOD score analyses using the GENEHUNTER program. The DRB1*1303 allele was significantly more frequent among the MS patients. There was a trend towards transmission disequilibrium of DRB1*1303, but was not statistically significant. Allele sharing and LOD score analyses revealed no evidence for linkage. The high frequency of DRB1*1303 observed in our family patients provides evidence to support the association with this allele that previously described in sporadic non-Ashkenazi MS patients. Thus, DRB1*1303 may serve as genetic risk factor for MS. Our study exemplifies the genetic heterogeneity in MS as there is a genetic effect of HLA on MS susceptibility in our low frequency DRB1*1501 patients.

Kwon OJ, Karni A, Israel S, Brautbar C, Amar A, Meiner Z, Abramsky O, Karussis D. · Tissue Typing Unit and the Lautenberg Center for General and Tumor Immunology, Hadassah University Hospital, Hebrew University Hadassah Medical School, Jerusalem, Israel. · Arch Neurol. · Pubmed #10328250 links to  free full text

Abstract: OBJECTIVE: To look for HLA class II alleles and haplotypes conferring susceptibility to multiple sclerosis (MS) in the Jewish population of Israel. DESIGN: Population-based cohort of clinically definite patients with MS tested prospectively over 7 years. SETTING: Referral center in a neurology clinic at a university hospital in the greater Jerusalem area in Israel. PATIENTS: A total of 162 consecutive patients with clinically definite MS from the 2 main ethnic Jewish groups in Israel: 104 Ashkenazi (80 with a relapsing remitting or secondary progressive and 24 with a primary chronic progressive course of the disease) and 58 non-Ashkenazi (36 with a relapsing remitting or secondary progressive course and 22 with a primary chronic progressive course of the disease), matched with 132 Ashkenazi and 120 non-Ashkenazi healthy controls. MAIN OUTCOME MEASURES: The relationship between the various HLA class II alleles and haplotypes and MS, as defined by the polymerase chain reaction and sequence-specific oligonucleotide probe hybridization, among the Ashkenazi and the non-Ashkenazi Jewish sections and with respect to the different clinical courses of the disease. RESULTS: The haplotype DRB1*1501, DQA1*0102, DQB1*0602 was found to be associated with MS among both Ashkenazi and non-Ashkenazi patients (P<.001 and P =.04, respectively). Among the non-Ashkenazi patients, a new association of haplotypes DRB1*1303, DQA1*05, and DQB1*030 with MS was detected (P = .03). The MS susceptibility alleles, DRB 1* 1501, DQA1*0102, and DQB1*0602 , were found in association with the Ashkenazi patients (P<.001, P=.02, and P=.01, respectively); DRB1*1501 and DRB1*1303 were more frequently observed among the non-Ashkenazi patients (P = .03, P = .04, respectively). On subdivision of the patients into clinical subgroups, associations of DRB1*0801, DQA1*0102, DQA1*0401, and DQB1*0602 with primary chronic progressive MS among the Ashkenazi patients were evident (P = .03, P = .04, P = .04 and P = .05, respectively), whereas DRB1* 1501, DRB1*03011, and DQB1*0602 were associated with relapsing remitting or secondary progressive among the non-Ashkenazi patients (P = .05, P = .05, and P = .03, respectively). CONCLUSIONS: This study, unlike previous ones, is the first to show a significant association between HLA class II alleles and MS in the Jewish population. The association with the HLA-DR2-related haplotype is similar to that among non-Jewish white patients with MS. Moreover, our data support the possibility that DRB1*1501 is the susceptibility allele responsible for the association between this haplotype and MS in the Jewish population. Our study also underscores differences in HLA profiles between Ashkenazi and non-Ashkenazi patients, and between the different clinical courses of the disease. The latter may indicate that the clinical courses of MS are influenced by the genetic background.

Karussis D, Vourka-Karussis U, Mizrachi-Koll R, Abramsky O. · Department of Neurology, Hadassah Hebrew University Hospital, Jerusalem, Israel. · Mult Scler. · Pubmed #10096098 No free full text.

Abstract: Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. We have previously shown that treatment of EAE-mice with high doses of cyclophosphamide (CY) (350 mg kg), followed by syngeneic bone marrow transplantation (SBMT), completely abrogates the clinical paralytic signs and even prevents the appearance of new relapses in the chronic-relapsing model of the disease. In the present study we examined whether this treatment protocol induces long term tolerance and whether this tolerance is antigen-specific. EAE was induced by immunization with spinal cord homogenate (MSCH) in complete Freund's adjuvant (CFA). The treatment with CY and SBMT was performed on day 6 post immunization. Treated and untreated mice were rechallenged with MSCH, or a non-relevant antigen (OVA) in CFA at various stages after the first paralytic attack. In contrast to previous data showing that animals recovering from acute EAE are usually refractory to re-induction of the disease, repeated injections of MSCH at different sites from the initial immunization, followed by i.v. injection of inactivated Bordetella bacteria, 2, 4 and 6 months after the initial EAE-induction, caused a severe and usually lethal relapse in all the untreated, control animals. Mice treated with CY and SBMT were resistant to all rechallenges with the same encephalitogenic inoculum. Following the second rechallenge, peripheral lymph node cells were examined in vitro for their proliferative responses to myelin antigens or to OVA. Lymphocytes obtained from CY+SBMT treated mice did not proliferate in vitro in response to myelin basic protein (MBP), but proliferated against OVA, when immunized with this antigen, after SBMT. Adoptive transfer of lymphocytes from tolerant mice to naive recipients did not transfer resistance to EAE-induction. Our results indicate that high doses of CY, followed by SBMT, induce long term antigen-specific tolerance presumably by a mechanism of clonal deletion or anergy.

Moreh E, Gartsman I, Karussis D, Rund D, Hiller N, Meiner Z. · No affiliation provided · Mult Scler. · Pubmed #18505773 No free full text.

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