Biomedical subjects

P Stinissen

Publications and source records attributed to P Stinissen.

At least 19 recordsLinked to original sources

PubMed2006

The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. METHODS: OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. RESULTS: The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. CONCLUSION: This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).

Arthritis, Rheumatoid↗

PubMed2005

Profiling the autoantibody repertoire by serological antigen selection.

The identification of disease related autoantigens targeted by pathogenic T- and B-cell responses is crucial for the development of improved therapies for autoimmune diseases. To identify immunogenic targets recognized by the humoral immune response, we have recently applied a novel and powerful molecular approach, named 'serological antigen selection' (SAS). This method involves the display of a cDNA expression library on filamentous phage and subsequent selection on patient immunoglobulin G (IgG). In the present study, we have cloned a cDNA repertoire from a multiple sclerosis (MS) patient in pVI phage display vectors and performed selections on pooled MS cerebrospinal fluid (CSF) samples immobilized with anti-human IgG. To further streamline this procedure, we report an optimized SAS procedure in which we have successfully established methods for enrichment of MS-specific candidate antigens. In conclusion, the broad applicability of the SAS method makes it a highly promising method for investigating the autoimmune repertoire.

Antigens↗

PubMed2003

Characterization of three human oligodendroglial cell lines as a model to study oligodendrocyte injury: morphology and oligodendrocyte-specific gene expression.

Oligodendrocytes, the myelin-forming cells of the central nervous system, are the target of pathogenic immune responses in multiple sclerosis. Primary cultures of human oligodendrocytes have been used to unravel the cellular and molecular mechanisms of immune-mediated injury of oligodendrocytes. However, these studies are hampered by the limited availability of viable human brain tissue. The present study was aimed at comparing the morphological and biochemical characteristics of the human oligodendroglial cell lines HOG, MO3.13 and KG-1C. We have determined oligodendrocyte-associated features of these lines and analyzed the degree to which they can be used as a model of human oligodendrocytes arrested at specific developmental stages. The oligodendroglial cell lines all exhibited markers of immature oligodendrocytes, such as CNPase and GalC, but not the astrocytic marker GFAP. Differentiation could be induced in HOG and MO3.13 cells, as was seen through a decrease in proliferation, an increase in process extension without formation of myelin sheets and up-regulation of genes associated with mature oligodendrocytes such as MBP and MOG. Microarray analysis revealed the expression of MAG, MOBP and OMG genes in HOG cells. The KG-1C cells displayed poor growth characteristics in the recommended conditions. In conclusion, our data show that the oligodendroglial cell lines HOG and MO3.13 can be used as a model of human oligodendrocytes "arrested" in an immature developmental stage. Culturing in appropriate medium can induce further differentiation of these cells. These cell lines can therefore be applied as a model to study immune-mediated injury of oligodendrocytes in relation to disease.

Cell Culture Techniques↗

PubMed2003

T cell vaccination in multiple sclerosis patients with autologous CSF-derived activated T cells: results from a pilot study.

Myelin-reactive T cells are considered to play an essential role in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. We have previously studied the effects of T cell vaccination (TCV), a procedure by which MS patients are immunized with attenuated autologous myelin basic protein (MBP)-reactive T cell clones. Because several myelin antigens are described as potential autoantigens for MS, T cell vaccines incorporating a broad panel of antimyelin reactivities may have therapeutic effects. Previous reports have shown an accumulation of activated T cells recognizing multiple myelin antigens in the cerebrospinal fluid (CSF) of MS patients. We conducted a pilot clinical trial of TCV with activated CD4+ T cells derived from CSF in five MS patients (four RR, one CP) to study safety, feasibility and immune effects of TCV. CSF lymphocytes were cultured in the presence of rIL-2 and depleted for CD8 cells. After 5-8 weeks CSF T cell lines (TCL) were almost pure TCR alpha beta+CD4+ cells of the Th1/Th0 type. The TCL showed reactivity to MBP, MOG and/or PLP as tested by Elispot and had a restricted clonality. Three immunizations with irradiated CSF vaccines (10 million cells) were administered with an interval of 2 months. The vaccinations were tolerated well and no toxicity or adverse effects were reported. The data from this small open-label study cannot be used to support efficacy. However, all patients remained clinically stable or had reduced EDSS with no relapses during or after the treatment. Proliferative responses against the CSF vaccine were observed in 3/5 patients. Anti-ergotypic responses were observed in all patients. Anti-MBP/PLP/MOG reactivities remained low or were reduced in all patients. Based on these encouraging results, we recently initiated a double-blind placebo-controlled trial with 60 MS patients to study the effects of TCV with CSF-derived vaccines in early RR MS patients.

Adoptive Transfer↗

PubMed2001

T-cell reactivity to multiple myelin antigens in multiple sclerosis patients and healthy controls.

Myelin proteins, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) are candidate autoantigens in MS. It is not clear whether MS patients show a predominant reactivity to one or several myelin antigens. We evaluated the IFN-gamma production induced by MBP and MOG and selected MBP-, MOG- and PLP-peptides in MS patients and healthy controls using the IFN-gamma ELISPOT assay. Most MS patients and healthy controls showed a heterogeneous anti-myelin T-cell reactivity. Interestingly in MS patients a positive correlation was found between the anti-MOG and anti-MBP T-cell responses. No myelin peptide was preferentially recognized among the peptides tested (MBP 84-102, 143-168, MOG 1-22, 34-56, 64-86, 74-96, PLP 41-58, 184-199, 190-209). In addition the frequency of IL2R+ MBP reactive T-cells was significantly increased in blood of MS patients as compared with healthy subjects, indicating that MBP reactive T-cells exist in an in vivo activated state in MS patients. Most of the anti-MBP T-cells were of the Th1-type because reactivity was observed in IFN-gamma but not in IL-4 ELISPOT-assays. Using Th1 (IL-12) and Th2 (IL-4) promoting conditions we observed that the cytokine secretion pattern of anti-MBP T-cells still is susceptible to alteration. Our data further indicate that precursor frequency analysis of myelin reactive T-cells by proliferation-based assays may underestimate the true frequency of myelin specific T-cells significantly.

Adult↗

PubMed2001

The autoimmune pathogenesis of rheumatoid arthritis: role of autoreactive T cells and new immunotherapies.

OBJECTIVES: To review the role of T lymphocytes in the pathogenesis of rheumatoid arthritis (RA) and discuss the relevance of the components of the trimolecular complex (synovial T cells, autoantigens, and antigen presenting cells) in the pathogenic autoimmune response in RA. METHODS: Currently available experimental data are combined into a hypothetical pathway that may explain some of the events in the RA process. The literature regarding the potential therapeutic strategies that interfere with specific components of the trimolecular complex and other mediators are discussed briefly. RESULTS: T cells are activated in the peripheral blood, cross the endothelial cell wall, and migrate into the joints. Once in the synovial joints, T cells are reactivated by cross-reactive antigens and clonally expand. Clonally expanded T cells accumulate in the diseased joint and secrete proinflammatory cytokines that attract and activate other cells, such as monocytes and macrophages. Treatment with anti-CD4 monoclonal antibodies or anticytokine agents that prevents antigen presentation and/or T-cell activation were effective in RA. Other therapies, such as T-cell vaccination and T-cell receptor peptide vaccination targeting autoreactive T cells, showed clinical improvement, suggesting a pathogenic role of these lymphocytes in disease progression. CONCLUSION: T cells appear to be actively involved in the pathogenesis of RA, but several parts of the pathway are hypothetical and further research is needed.

Arthritis, Rheumatoid↗

PubMed2000

Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins.

OBJECTIVE: After implicating Streptococcus pyogenes as causing acute disseminated encephalomyelitis (ADEM) in a child, we wanted to prove that in vivo activation of autoreactive T lymphocytes by superantigens of this Streptococcus contributed to the dramatic demyelination. BACKGROUND: ADEM is a demyelinating disorder of the CNS sharing many similarities with MS. Demyelination in MS is considered to be the result of an autoimmune process mediated by autoreactive T lymphocytes with specificity for myelin antigens. METHODS: Phenotypic analysis and proliferation assays on blood monocytes, as well as isolation of myelin basic protein (MBP)-reactive T-cell lines/clones; and TCR repertorium analysis by PCR-ELISA and cytokine production. RESULTS: 1) The blood T-cell receptor (TCR) repertoire was compatible with in vivo expansion induced by S. pyogenes exotoxins. 2) TCR expression analysis indicated clonal expansion of CD8+ MBP-reactive T cells, suggesting in vivo activation. MBP-reactive T cells showed crossreactivity to S. pyogenes supernatant and exotoxins. 3) Cytokine mRNA quantification of the mononuclear cells revealed a Th2-biased profile. CONCLUSION: In vivo exposure to S. pyogenes may have induced activation of pathogenic myelin reactive T cells, contributing to the dramatic inflammatory demyelination.

Autoimmunity↗

PubMed2000

Myelin reactive T cells after T cell vaccination in multiple sclerosis: cytokine profile and depletion by additional immunizations.

Pathogenic autoreactive T cells can be targeted by T cell vaccination (TCV), a procedure in which patients are immunized with autologous attenuated pathogenic T cells. We reported previously that TCV with myelin basic protein (MBP) reactive T cell clones in multiple sclerosis (MS) patients induced T cell immune responses, resulting in a clonal depletion of MBP reactive T cells in all patients. Five years after TCV, MBP reactive T cells were observed in five out of nine MS patients. These clones had a different clonal origin from those isolated before vaccination. We have studied the cytokine profile, cytotoxicity and epitope specificity of these reappearing clones. Our data indicate that the clones express similar effector functions as those isolated before TCV, suggesting that they also could play a pathogenic role in the disease. We demonstrated that these clones can be depleted by an additional sequence of immunizations. These findings may be relevant to other T cell targeted immunotherapies for MS and other autoimmune diseases.

Clone Cells↗

PubMed2000

Skewed T-cell receptor variable gene usage in the synovium of early and chronic rheumatoid arthritis patients and persistence of clonally expanded T cells in a chronic patient.

OBJECTIVE: Autoreactive T cells may contribute to the pathogenesis of rheumatoid arthritis (RA). We studied the T-cell receptor (TCR) V-gene repertoire in the blood and synovium of early and chronic RA patients using polymerase chain reaction-enzyme-linked immunosorbent assay to evaluate possible differences between these patient groups. RESULTS: Over-represented TCR V genes were observed in the synovium, but not in the blood of all RA patients (n = 38). The number of over-represented V genes was higher in the synovium of chronic RA patients (n = 31) than in that of early RA patients (n = 7). The V-gene profile was different among patients, and similar in the two knees for patients with bilateral synovitis (n = 5). The clonal composition of over-represented TCR BV genes in a patient with early RA and a patient with chronic RA was further studied by CDR3 region sequence analysis. A high level of clonal diversity was found in the joints and the blood of the early RA patient, suggesting a polyclonal T-cell expansion. In the chronic RA patient, predominant clonal expansions were observed in the blood and synovium, and some expanded clones were still present 2 yr later. CONCLUSIONS: The observation of similar T-cell populations in both joints in patients with bilateral synovitis and the persistence of clonally expanded T cells for more than 2 yr in the joints of a chronic RA patient may indicate a pathogenic role for these cells in the disease process.

Amino Acid Sequence↗

PubMed1999

Identification of overrepresented T cell receptor genes in blood and tissue biopsies by PCR-ELISA.

The analysis of T cell receptor variable (TCR V) gene repertoires in blood or tissues may provide important information when studying immunopathological mechanisms. The overexpression of a TCR gene may indicate the expansion of the corresponding T cell subset. In autoimmune diseases, clonally expanded T cell subsets in the affected organs may represent pathogenic lymphocytes. We describe a simple, rapid and sensitive method to determine the TCR AV and BV gene repertoire using a PCR-ELISA method. RNA is extracted from lymphocytes, transcribed to cDNA, which is then used as a template for PCR with 19 different TCR AV gene and 20 BV gene specific primers as the forward primer, and a digoxigenin (DIG) labeled AC/BC primer as the reverse primer. The DIG labeled PCR amplicons are hybridized with a fluorescein isothiocyanate (FITC) labeled TCR C region specific probe. Finally, the amplicons are quantified by ELISA using anti-FITC coated microtiter plates, and an anti-DIG conjugated peroxidase. Although PCR-ELISA cannot accurately quantify the expression level of a given TCR gene, overrepresented TCR V genes are easily identified by comparing the relative expression levels of each individual V gene in the total V gene repertoire. We demonstrate that this technique can be used to determine TCR profiles in blood and tissue samples containing as few as 50,000 T cells. In combination with CDR3 fragment size analysis, this method is an efficient tool to identify clonally expanded T cell subsets in the synovial biopsies of rheumatoid arthritis patients.

Arthritis, Rheumatoid↗

PubMed1999

Cellular and humoral immune responses against autoreactive T cells in multiple sclerosis patients after T cell vaccination.

Myelin basic protein (MBP)-reactive T cells may play an important role in the autoimmune pathogenesis of multiple sclerosis (MS). MBP-reactive T cells can be specifically targeted by T cell vaccination, a procedure whereby MS patients are immunized with attenuated autologous MBP reactive T cells. T cell vaccination induces immune responses to the vaccine cells together with a depletion of MBP reactive T cells. Forty-nine MS patients were treated with T cell vaccination in an extended phase I trial to study the safety, immune responses and clinical effects of T cell vaccination. In the present paper the immune responses towards the vaccine cells were characterized. Substantial long-term in vitro proliferative responses were observed in all treated patients. Some patients, immunized with different clones, displayed distinct proliferative reactivity against the various vaccine clones, suggesting unequal immunogenic properties of these clones. Reactive TCRalphabeta(+), CD8(+)and CD4(+)T cells, and to a lesser extent, gammadelta T cells and NK cells were observed to in vitro stimulation with the vaccine cells. A small fraction only of CD8(+)T cells expressed cytolytic and inhibitory anti-clonotypic reactivity against the vaccine cells. Stimulation with the vaccine clones predominantly induced expression of pro-inflammatory cytokines in these mixed cultures, although one vaccine clone consistently induced production of IL-4. CD4(+)T cells are the major cytokine-producing cells in these anti-vaccine lines. We could not detect upregulated antibody responses to the vaccine cells in most patients, although a temporary antibody response was observed in one patient. In conclusion, immunization with attenuated autoreactive T cells induces a complex cellular response specifically targeted at the vaccine cells, but no antibody responses. These data provide further insights into the mechanisms of T cell vaccination and improve our understanding of the complex regulatory networks of autoreactive T cells.

Antibody Formation↗

PubMed1999

Lack of association between estrogen receptor genotypes and bone mineral density, fracture history, or muscle strength in elderly women.

The PvuII polymorphism of the estrogen receptor (ESR) gene and its relation to bone mineral density (BMD), fracture history, and muscle strength was studied in 313 postmenopausal (76 +/- 5 years) women of Caucasian origin, of whom 142 had suffered from a fragility fracture after the age of 50 years (14 with fracture of the hip, 38 of the spine, 45 of the wrist, and 85 of other bones). The ESR genotype distribution was similar in women with and without a history of fragility fracture (PP 21%, Pp 43%, pp 36% compared with PP 18%, Pp 47%, pp 35%). We did not find a correlation between the ESR genotypes and BMD at the lumbar spine, the femoral neck, or the proximal forearm. No association was found with grip or quadriceps strength. We further evaluated the relationship between the vitamin D receptor (VDR) and ESR haplotypes and BMD in a random subgroup of 270 elderly women. No differences were found in women with the BBpp versus the bbPP haplotype in the femoral neck (mean difference +/- SD, in Bbpp compared with bbPP groups: -0.05 +/- 0.15 g/cm2), the spine (0.01 +/- 0.13 g/cm2), or the forearm (0.04 +/- 0.08 g/cm2). The significant association of quadriceps strength with VDR genotypes (25% lower in BB compared with bb genotype, p < 0.05) was not influenced by ESR haplotypes. We conclude that in elderly Caucasian women the PvuII ESR polymorphism is not associated with osteoporosis, fracture history, nor muscle strength and does not influence the association of bone density and muscle strength with polymorphism of the VDR.

Aged↗

PubMed1999

Autoreactive T lymphocytes in multiple sclerosis: pathogenic role and therapeutic targeting.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), leading to demyelination. Accumulating evidence suggests that MS is an autoimmune disease, mediated by autoreactive T cells with specificity for myelin antigens. The identity of the brain antigens, which are the primary targets of the autoimmune process remains unknown, but myelin basic protein (MBP) is a likely candidate. We will overview some of the experimental evidence, suggesting that MBP reactive T cells hold a central position in the pathogenesis of MS, and discuss how these autoreactive T cells can be therapeutically targeted by T cell vaccination.

Autoimmunity↗

PubMed1998

Gammadelta T cell responses to activated T cells in multiple sclerosis patients induced by T cell vaccination.

To explore the hypothesis that gammadelta T cells may regulate activated alphabeta T cells, we studied gammadelta T cell responses to alphabeta T cell clones in Multiple Sclerosis (MS) patients who received attenuated autologous autoreactive T cells. We recently conducted a pilot study of T cell vaccination with myelin basic protein reactive T cells in MS. Since T cell vaccination upregulates the anti-vaccine T cell responses, we evaluated gammadelta T cell reactivity towards the vaccine in the vaccinated patients. Lymphocytes were stimulated in vitro with irradiated vaccine cells and the responding lines were checked for the presence of gammadelta T cells. Our data demonstrate that in the majority of vaccinated MS patients gammadelta T cells expand upon stimulation with the vaccine cells. The responding gammadelta T cells were predominantly Vdelta1+/Vgamma1+, and represented diverse clonal origins. The gammadelta T cells could not inhibit in vitro proliferation of the vaccine T cells and displayed low cytotoxic reactivity towards the vaccine clones. However, they produced high levels of IL2, TNFalpha and IL10. These results indicate that gammadelta T cells can be stimulated by activated alphabeta T cells, and that these gammadelta T cell responses are upregulated after T cell vaccination. These findings suggest that gammadelta T cells are involved in peripheral mechanisms to control activated autoreactive T cells.

Cells, Cultured↗

PubMed1998

Myelin reactive T cells in the autoimmune pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination. Although it is widely accepted that demyelination in MS results from an active inflammatory process, the cause of the inflammation is still not completely resolved. Findings in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and observations in human MS have led to the hypothesis that MS is an autoimmune disease mediated by autoreactive T cells with specificity for myelin antigens. The identity of the brain antigen(s) which is (are) the primary target(s) of the autoimmune process is not known, but current evidence indicates that myelin basic protein (MBP) is a likely candidate. In this paper we will overview some of the experimental evidence suggesting that MBP reactive T cells hold a central position in the pathogenesis of MS, and discuss some of the currently tested therapeutic strategies in MS which are directed towards the pathogenic MBP reactive T cells. Although there appears to be no direct correlation between anti-MBP T cell responses and clinical disease activity, some recent observations suggest that monitoring of anti-MBP T cell responses could be helpful to study immunological efficacy of experimental immunotherapies in MS.

Autoantibodies↗

PubMed1998

Cytokine mRNA profile of myelin basic protein reactive T-cell clones in patients with multiple sclerosis.

Autoimmune mechanisms involving T-cell responses to (a) myelin autoantigen(s), such as myelin basic protein (MBP), are thought to contribute to the pathogenesis of multiple sclerosis (MS). Cytokines may play a central role in the regulation of the pathogenic autoimmune responses in MS and the mediation of tissue damage in the disease. To study the cytokine expression of myelin reactive T-cells in MS, we determined the cytokine mRNA levels in a panel of blood derived MBP-specific T-cell clones derived from MS patients (33 clones) and normal controls (21 clones), using a novel quantitative RT-PCR method. Our results demonstrate that MBP-specific T-cells, both from MS patients and control subjects, predominantly display a Th1- or Th0-like cytokine pattern. Although MS clones express higher levels of TNFalpha and IL-10 mRNA, these differences do not reach statistical significance. Interestingly, significantly increased TNFalpha and IFNgamma mRNA levels were observed among clones derived from HLA-DR2 positive versus HLA-DR2 negative MS patients. This HLA halpotype is known to be associated with MS. The high levels of TNFalpha and IFNgamma mRNA observed in MBP-reactive T-cell clones from MS patients indicate an important role of these cytokines in the disease process. Our data lend further support to the pathogenic role of MBP-reactive T-cells in MS.

Adult↗

PubMed1997

Cytokine profile of myelin basic protein-reactive T cells in multiple sclerosis and healthy individuals.

Myelin basic protein (MBP)-reactive T cells have been implicated in the autoimmune pathogenesis of multiple sclerosis (MS). In this study, we examined the cytokine profile of 531 primary MBP-reactive T-cell lines and 72 independently established clones from 32 patients with MS and 18 healthy controls (NS) by using highly sensitive enzyme-linked immunosorbent assays. An increased number of primary T-cell lines producing interferon-gamma (IFN gamma) and/or interleukin-4 (IL-4) in response to MBP were found in patients with MS compared with controls. No distinct Th1 or Th2 subtypes could be demonstrated among the MBP-reactive clones. IL-4 was more frequently observed among MS-derived clones. Clones derived from MS patients produced increased levels of IL-2, IL-4, tumor necrosis factor-alpha (TNF alpha), IFN gamma, and IL-10, but not IL-6. It is interesting that MBP-reactive T cells from MS patients expressing the disease-associated HLA-DRB1*15 allele produced increased quantities of TNF alpha, a cytokine suggested to play an important role in inflammation and demyelination. When challenged with either MBP or a bacterial superantigen, the clones expressed similar levels of the proinflammatory cytokine IFN gamma. Our study suggests a functional difference in T-cell responses to MBP in patients with MS compared with healthy individuals, and provides further insights into the role of MBP-reactive T cells and their cytokine profile in the inflammatory processes of MS.

Adult↗

PubMed1997

Autoimmune pathogenesis of multiple sclerosis: role of autoreactive T lymphocytes and new immunotherapeutic strategies.

Accumulating evidence indicates that multiple sclerosis (MS) is an autoimmune disease mediated by autoreactive T lymphocytes with specificity for myelin antigens. Initially, the evidence to support this hypothesis was based mainly on experiments performed in experimental allergic encephalomyelitis (EAE), the animal model of MS. In this model it was demonstrated that T cells reactive to several myelin antigens are encephalitogenic. Many recent immunological and immunohistochemical studies in MS have yielded further data to support this view. For instance, it was demonstrated that activated myelin basic protein (MBP) and proteolipid protein (PLP)-specific T cells accumulate in the central nervous system (CNS), and that clonally expanded MBP-specific T cells persist for several years in the blood of patients with MS. Furthermore, T cells with specificity for MBP were identified in the brain lesions of the patients. It is not yet clear how these autoreactive T cells are activated in the periphery, but several studies have suggested that viral antigens mimicking the myelin epitopes, or superantigens may be involved. Furthermore, we and others have provided evidence showing that the regulatory mechanisms that control autoreactive T cells in healthy subjects are potentially defective in MS patients. In addition to myelin reactive T cells, B cells producing myelin-specific antibodies and gamma delta T cells may also play an important role in the autoimmune cascade. Based on the recent insights in the disease mechanisms, new experimental therapies were developed to target specifically the pathogenic lymphocytes in MS. Some therapies yielded encouraging data in pilot studies, whereas phase III trials of other drugs showed beneficial effects on the disease course. In this article, we overview the most recent data on the role of autoreactive lymphocytes in the pathogenesis of the disease, and discuss some of the recently developed immunotherapeutical strategies in MS.

Adoptive Transfer↗