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Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Objective Two pilot studies were conducted to evaluate safety, tolerability, and efficacy of two doses of Protiramer (TV-5010) in patients with relapsing–remitting multiple sclerosis. Background Both glatiramer acetate and TV-5010 are synthetic copolymers comprised the same four amino acids in a defined molar ratio. TV-5010 has higher average molecular weight than Glatiramer acetate and might be hypothesized that glatiramoids with higher molecular weight might be more immunoreactive than lower molecular weight peptides, thus increasing therapeutic potential and allowing for less frequent dosing. Methods In the two separate studies, after a 10 week pretreatment period, TV-5010 was given subcutaneously once weekly at 15 mg and 30 mg for 36 weeks. The primary end point was a reduction in the number of magnetic resonance imaging active lesions (i.e., T1-weigthed gadolinium-enhancing and new T2-weighted lesions) between the pretreatment period and the end of study. Results Both TV-5010 doses were generally well tolerated. The treatment with TV-5010 at a dose of 15 mg/wk did not show any significant effect. In contrast, in patients treated with at a dose of 30 mg/wk, a significant reduction in the mean number of gadolinium-enhancing (−58.8%; P = 0.0013) and new T2-W (−50%; P = 0.0002) lesions was observed. However, a large decrease in the mean number of both gadolinium-enhancing (−55%) and new T2-W (−40%) lesions during the pretreatment period made difficult the interpretation of the efficacy assessments. Conclusions Further studies are needed to confirm these preliminary data on safety and efficacy of TV-5010 at a weekly dose of 30 mg.

Natalizumab (Tysabri(A (R))) is highly efficacious in controlling disease activity in relapsing multiple sclerosis (MS) patients. As it is one of the more recent therapies for MS, there remains a need for long-term safety and efficacy data of natalizumab in a clinical practice setting. The Tysabri observational program (TOP) is an open-label, multicenter, multinational, prospective observational study, aiming to recruit up to 6,000 patients with relapsing-remitting MS from Europe, Canada and Australia. The objectives of this study are to collect long-term safety and efficacy data on disease activity and disability progression. We report here the interim results of the 563 patients included in TOP between December 2007 and 2012 from Belgium. This patient cohort was older at baseline, had longer disease duration, higher neurological impairment, and a higher baseline annualized relapse rate, when compared to patients included in the pivotal phase III AFFIRM trial. Nevertheless, the efficacy of natalizumab was comparable. The annualized relapse rate on treatment was reduced by 90.70 % (p < 0.0001) with a cumulative probability of relapse of 26.87 % at 24 months. The cumulative probabilities of sustained disability improvement and progression at 24 months were 25.68 and 9.01 %, respectively. There were no new safety concerns over the follow-up period. Two cases of progressive multifocal leukoencephalopathy were diagnosed. Our results are consistent with other observational studies in the post-marketing setting.

Accumulating evidence indicates that multiple sclerosis, a chronic inflammatory disease of the central nervous system, has an autoimmune origin. Since T cells reactive to myelin basic protein (MBP) are thought to play an important role in the pathogenesis of this disease, it was assumed that inactivation or depletion of this pathogenic T cell subset may have therapeutic effects in multiple sclerosis. We have recently reported that T cell vaccination, i.e. immunisation with attenuated autologous MBP-reactive T cell clones, leads to the depletion of the MBP-reactive T cells. Furthermore, this approach induced favourable clinical effects in the treated patients, encouraging further studies of T cell vaccination in multiple sclerosis.

Activated autoreactive T cells are potentially pathogenic and regulated by clonotypic networks. Experimental autoimmune diseases can be treated by inoculation with autoreactive T cells (T cell vaccination). In the present study, patients with multiple sclerosis were inoculated with irradiated myelin basic protein (MBP)-reactive T cells. T cell responses to the inoculates were induced to deplete circulating MBP-reactive T cells in the recipients. Regulatory T cell lines isolated from the recipients inhibited T cells used for vaccination. The cytotoxicity of the CD8+ T cell lines was restricted by major histocompatibility antigens. Thus, clonotypic interactions regulating autoreactive T cells in humans can be induced by T cell vaccination.

Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon beta) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon beta alone on the accumulation of disability. Patients with relapsing-remitting multiple sclerosis on interferon beta for at least 6 months were randomized to interferon beta + inosine or interferon beta + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (

Suppressor T cell (Ts) lines specific for myelin basic protein (MBP)-reactive helper T cell (Th) clones were generated from two patients with multiple sclerosis (MS) following a primary culture of peripheral blood mononuclear cells (PBMC) with MBP and cyclosporine A (CsA). These suppressor T cell lines were maintained in culture by alternate stimulation with MBP and antigen-presenting cells (APC). The Ts lines expressed preferentially the CD4 phenotype (5/6 Ts lines tested) and exhibited potent antigen-specific suppressor activity on the proliferation of MBP-specific Th clones and not on the T cell lines with other antigen specificity. For some Ts lines, a Ts-to-Th ratio of 1 was sufficient to inhibit the proliferation of MBP-specific T cells by 90%. The suppressor T cells obtained were weakly responsive to MBP and required the presence of the autologous PBMC for proliferation. Furthermore, proliferation of these suppressor T cell lines was restricted by HLA-DR molecules (for CD4+ Ts lines) and HLA class I (for a CD8+ Ts line). The suppressor T cell lines generated and the techniques described in this study may be helpful in our understanding of the events involved in the immune regulation in MS and other autoimmune diseases.

A panel of 17 myelin basic protein (MBP)-specific T lymphocyte clones were generated from four multiple sclerosis (MS) patients. All T cell clones expressed CD4 phenotype and 14 clones exhibited substantial cytotoxic activity on MBP-coated target cells. T cell recognition sites of the clones on human MBP were identified by using MBP fragments and synthetic peptides. Despite the fact that at least three epitopes were defined, these T cell clones displayed a striking bias to the C-terminal peptide 149–171 independent of differences in HLA-DR and DQ expression. In addition, the T cell responses of the clones appeared to be restricted by HLA-DR molecules irrespective of peptide specificities. The present study suggests an immunodominant property of the C-terminal peptide for HLA-DR-restricted T cell responses to MBP. However, its association with encephalitogenicity in humans and its potential pathologic importance in MS await further clarification.

Accumulating evidence indicates an immunosuppressive role for CD4(+)CD25(+) regulatory T cells (Tregs) in autoimmune diseases. Although an impaired Treg function in patients with relapsing-remitting multiple sclerosis (RR-MS) has been reported recently, no information is available so far about Treg function in the progressive stage of the disease. In the present study, the phenotypic and functional characteristics of CD4(+)CD25(+) T cells isolated from the peripheral blood of patients with RR-MS and secondary progressive multiple sclerosis (SP-MS) were investigated. No significant quantitative or phenotypic abnormalities in CD4(+)CD25(+) T cells from RR- and SP-MS patients were detected. However, whereas a reduced suppressor function of CD4(+)CD25(+) T cells toward proliferation and interferon-gamma production of CD4(+)CD25(-) responder T cells was found in RR-MS patients, SP-MS patients showed a normal Treg function. The suppressive capacity of MS-derived CD4(+)CD25(+) T cells was correlated with disease duration but not with age, indicating that Treg function is more affected in the early phase of the disease process. Consistently with the suppressive capacity, CD4(+)CD25(+) T cells from SP-MS patients showed normal levels of FOXP3 mRNA in contrast to RR-MS patients that had a reduced FOXP3 expression. These data are the first to demonstrate differences in function and FOXP3 expression of CD4(+)CD25(+) T cells from patients with RR- and SP-MS.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterised by focal areas of demyelination in the CNS (Ffrench-Constant 1994). Autoimmune processes involving myelin-reactive T cells are considered to play an essential role in the pathogenesis of MS (for a review, see Stinissen et al. 1997). In vivo activated T cells reactive to myelin basic protein (MBP) are clonally expanded in the blood of MS patients and may persist for many years in some patients (Goebels et al. 2000). The activation of MBP-reactive T cells via molecular mimicry could be a common process, as suggested by the high level of cross-reactivity of MBP-reactive T cells to various microbial ligands, even in the absence of any sequence homology (Wucherpfennig et al. 1995,Hemmer et al. 1998). Accidentally stimulated autoreactive T cells however may not automatically lead to autoimmunity. Indeed, several observations support the existence of a peripheral regulatory network that prevents activation or expansion of pathogenic T cells (Cohen et al. 1992). However, an imbalanced regulatory network may lead to sub-optimal suppression of activated pathogenic T cells and give rise to autoimmunity. Administration of attenuated autoreactive T cells as a vaccine (T cell vaccination, TCV) may enhance the regulatory networks to specifically suppress the eliciting autoreactive T cells as shown in experimental autoimmune encephalomyelitis (EAE), an animal model of MS (Ben-Nun et al. 1981,Lider et al. 1988). We have performed a pilot study of TCV with MBP-reactive T cells in a small number of MS patients (Zhang et al. 1993,Medaer et al. 1995). The patients were immunised three times with autologous irradiated MBP-reactive T cell clones (see Figure 1).

In multiple sclerosis (MS), T-cells are considered to be critical in coordinating an immunopathological cascade that results in myelin damage. We investigated whether clinical disease activity or brain inflammatory activity as measured by magnetic resonance imaging (MRI) was associated with changes in autoreactive T-cell reactivities in MS patients. To this end, a longitudinal study was performed in which T-cell-related immune parameters and clinical parameters (including MRI) were monitored in seven relapsing-remitting (RR) MS patients and two healthy controls with bimonthly intervals over a period of 18 months. The serial evaluation of antimyelin (MBP, PLP, MOG) T-cell responses revealed highly dynamic shifts and fluctuations from one pattern to another in a patient-dependent manner. In some of the patients, changes in T-cell-related immune variables were found to concur with MRI activity and generally preceded clinical relapses. These alterations include: increased number of myelin-reactive IFN-gamma secreting T-cells, detection of clonally expanded myelin-reactive T-cells, elevated proinflammatory and decreased antiinflammatory cytokine production, upregulation of ICAM-1 membrane expression and highly increased serum levels of soluble VCAM-1. However, not all exacerbations and MRI changes were associated with changes in antimyelin reactivity. Some of the observed immune alterations were also detected in the healthy controls, indicating that additional regulatory mechanisms-which may be defective in MS-play a role in the downregulation of potentially pathological T-cell responses. In conclusion, this study provides further support for an important role of myelin-reactive T-cells in the pathogenesis of MS. In addition, the observed dynamic changes in the antimyelin T-cell reactivity pattern may be a major obstacle for the development of antigen-specific immunotherapies.

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.

T cell responses to myelin basic protein (MBP) are implicated to play an important role in the pathogenesis of multiple sclerosis (MS). These MBP autoreactive T cells are found to undergo in vivo activation and clonal expansion in patients with MS. They accumulate in the brain compartment and may reside in the brain lesions of patients with MS. As MBP-reactive T cells potentially hold a central position in initiation and perpetuation of the brain inflammation, specific immune therapies designed to deplete them may improve the clinical course of the disease. We review here the recent application of T cell vaccination in patients with MS to deplete circulating MBP-reactive T cells. The results of our phase I clinical trial indicate that T cell vaccination with inactivated MBP autoreactive T cells induces specific regulatory T cell network of the host immune system to deplete circulating MBP-reactive T cells in a clonotype-specific fashion. The immunity induced by T cell vaccination is clonotype specific and long-lasting. Our longitudinal clinical evaluation further suggests a moderately lower rate of clinical exacerbation, disability score, and brain lesions (measured by magnetic resonance imaging) in vaccinated patients than in matched controls. Our study should encourage further investigation on the treatment efficacy of T cell vaccination and further improvement for its clinical administration in other human autoimmune diseases. This review discusses the immune regulation and therapeutic administration of T cell vaccination in human autoimmune diseases, exemplified by our recent T cell vaccination trial in MS.

Although the etiology and pathogenesis of Multiple Sclerosis (MS) remain elusive, accumulating evidence indicates that MS is a chronic inflammatory disease with an autoimmune component, mediated by autoreactive T lymphocytes specific for myelin antigens. The triggering T cell autoantigen has not been identified yet, but recent immunological studies in MS and parallel experiments in experimental allergic encephalomyelitis (EAE), the animal model of MS, have indicated that myelin basic protein (MBP) can be considered as one of the major candidate autoantigens in the pathogenesis of the disease. Based on these observations, several therapeutic strategies have been developed aimed at the specific elimination or inactivation of MBP reactive T cells in MS. One of these approaches involves the immunization of MS patients with autologous attenuated autoreactive T cells to induce an immune response specifically targeted at these autoreactive T cells. This method, termed T cell vaccination, has been shown to prevent and treat EAE. We have recently conducted a pilot trial of T cell vaccination in a limited group of MS patients to evaluate the immunological responses to the injected cells. The data obtained indicate that this type of vaccination induces an effective anti-clonotypic T cell response leading to a specific depletion of circulating MBP reactive T cells. Preliminary data on the clinical effects are promising, encouraging further clinical trials.

A panel of 90 myelin basic protein (MBP)-specific T-cell lines were derived from peripheral blood of eight patients with multiple sclerosis and four normal subjects. The precursor frequency of MBP-reactive T cells in peripheral blood mononuclear cells ranged from 10(-7) to 9 x 10(-7) (mean, 6.7 x 10(-7)) in the group of patients with multiple sclerosis and from 0.5 x 10(-7) to 9.8 x 10(-7) (mean, 5.6 x 10(-7)) in the control subjects. This difference between the two groups was not statistically significant (p greater than 0.1). These T-cell lines expressed exclusively CD3+CD4+CD8- phenotypes and were restricted predominantly by HLA-DR molecules. When tested with fragments and synthetic peptides of human MBP, these MBP-specific T-cell lines (45 lines for each group) displayed a limited heterogeneous pattern with a biased recognition to peptide 84-102 and the C-terminal peptide 149-171. The reactivity to the 84-102 region of MBP was associated with the HLA-DR2, DRw15 (DRw15,2) haplotype, whereas the recognition to peptide 149-171 did not correlate with a particular HLA-DR allele(s). Furthermore, the majority of T-cell lines (greater than 75%) were found to exhibit substantial cytotoxic activity against MBP-coated target cells, but showing no significant difference between these two groups. This MBP-dependent cytotoxicity was not associated with epitope specificities of the T-cell lines tested.