Response In Multiple Sclerosis Patients Research Articles

Up-regulation of inducible heat shock protein-70 expression in multiple sclerosis patients

Inducible heat shock protein (HSP)70 (HSP70-1A and HSP70-1B proteins) is a chaperone responsible for assisting proper protein folding. Following stress conditions, HSP70 is highly up-regulated to mediate cytoprotective functions. In addition, HSP70 is able to trigger innate and adaptive immune responses that promote the immune recognition of antigens and to act as a cytokine when it is released. The data in the literature are controversial with regard to expression studies in peripheral blood mononuclear cells (PBMCs). In the present study, we aimed to examine if alterations of HSP70-1A/B expression are involved in the autoimmune pathogenesis of multiple sclerosis (MS). We determined both mRNA and protein expression in PBMCs of MS patients and healthy donors (HDs). We found a baseline increased expression of the HSPA1A gene in PBMCs from MS patients compared with HDs. Gene expression findings were associated with an increased protein expression of HSP70-1A/B in T lymphocytes (CD4+ and CD8+) and monocytes from MS patients under basal conditions that may reflect the immunological activation occurring in MS patients. We also provided evidence that heat shock (HS) stimulus induced HSP70-1A/B protein expression in HDs and MS patients, and that HS-induced HSP70-1A/B protein expression in monocytes correlated with the number of T2 lesions at baseline in MS patients. However, after lipopolysaccharide inflammatory stimulus, monocytes from MS patients failed to induce HSP70-1A/B protein expression. Our data hint at altered immune responses in MS and may indicate either a state of chronic stress or increased vulnerability to physiological immune responses in MS patients.

Vitamin D Immunomodulatory Potential in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology whose treatment is of limited efficiency and therefore has a high social burden. As it has been suggested that myelin destruction model, the clinical manifestation and the potential of therapeutic response in MS are correlated, it is quite justifiable that we study various factors (genetic, hormonal, environmental) that take part in the autoimmune process in order to improve the control over the disrupted immune regulation. Results from epidemiological and clinical studies clearly suggest that changes in vitamin D serum concentrations are correlated with the magnitude of the risk of developing MS, the phases of relapse and remittance and with gender differences in vitamin D metabolism. Experimental and clinical studies also have established that 25-hydroxy vitamin D (25(OH)D) and 1,25-dihydroxy vitamin D (1,25(OH)2D) exert an immunomodulatory effect in the central nervous system and peripheral organs of the immune system. The standard reference range of vitamin D concentration in serum is 50-80 nmol/l--it provides normal calcium metabolism. Issues that are discussed include the vitamin D serum concentration needed to suppress the aberrant immune response in MS patients; a subgroup of MS patients suitable for vitamin D treatment, the vitamin D being applied in optimally effective and safe dosage. MS prevalence rate in Bulgaria has increased two-fold in 17 years but this is a rather short interval to be able to assume that the gene pool of the population changes. Thus further studies on possible interactions between different environmental factors and these factors' role in the disease pathogenesis are justified and necessary.

Cellular immune responses in multiple sclerosis patients treated with interferon-beta

We investigated cellular immune responses at baseline in peripheral blood mononuclear cells (PBMC) of patients with multiple sclerosis (MS) treated with interferon (IFN)-β and classified into responders and non-responders according to clinical response criteria. Levels for IFN-γ, interleukin (IL)-17A, IL-17F, IL-10 and IL-4 were determined in activated PBMC of 10 responders, 10 non-responders and 10 healthy controls by cytometric bead arrays. Cytokine levels in cell culture supernatants were similar between responders and non-responders, and comparable to those obtained in healthy controls. These findings do not support differential cellular immune responses in PBMC at baseline between IFN-β responders and non-responders.

Does helminth activation of toll-like receptors modulate immune response in multiple sclerosis patients?

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disease affecting the Central Nervous System (CNS), in which Th1 and Th17 cells appear to recognize and react against certain myelin sheath components. Epidemiological evidence has accumulated indicating steady increase in autoimmune disease incidence in developed countries. Reduced infectious disease prevalence in particular has been proposed as the cause. In agreement with this hypothesis, we recently demonstrated significantly better clinical and radiological outcome in helminth-infected MS patients, compared to uninfected ones. Parasite-driven protection was associated with regulatory T cell induction and anti-inflammatory cytokine secretion, including increased TGF-β and IL-10 levels. Interestingly, surface expression of TLR2, on both B cells and dendritic cells (DC) was significantly higher in infected MS patients. Moreover, stimulation of myelin-specific T cell lines with a TLR2 agonist induced inhibition of T cell proliferation, suppression of IFN-γ, IL-12, and IL-17 secretion, as well as increase in IL-10 production, suggesting the functional responses observed correlate with TLR2 expression patterns. Furthermore, parasite antigens were able to induce TLR2 expression on both B cells and DCs. All functional effects mediated by TLR2 were abrogated when MyD88 gene expression was silenced; indicating helminth-mediated signaling induced changes in cytokine secretion in a MyD88-dependent manner. In addition, helminth antigens significantly enhanced co-stimulatory molecule expression, effects not mediated by MyD88. Parasite antigens acting on MyD88 induced significant ERK kinase phosphorylation in DC. Addition of the ERK inhibitor U0126 was associated with dose-dependent IL-10 inhibition and reciprocal enhancement in IL-12, both correlating with ERK inhibition. Finally, cytokine effects and changes observed in co-stimulatory DC molecules after helminth antigen exposure were lost when TLR2 was silenced. Overall, the data described indicate that helminth molecules exert potent regulatory effects on both DCs and B cells from MS patients through TLR2 regulation.

Prognostic Prediction through Biclustering-Based Classification of Clinical Gene Expression Time Series

Summary The constant drive towards a more personalized medicine led to an increasing interest in temporal gene expression analyzes. It is now broadly accepted that considering a temporal perspective represents a great advantage to better understand disease progression and treatment results at a molecular level. In this context, biclustering algorithms emerged as an important tool to discover local expression patterns in biomedical applications, and CCC-Biclustering arose as an efficient algorithm relying on the temporal nature of data to identify all maximal temporal patterns in gene expression time series. In this work, CCC-Biclustering was integrated in new biclustering-based classifiers for prognostic prediction. As case study we analyzed multiple gene expression time series in order to classify the response of Multiple Sclerosis patients to the standard treatment with Interferon-β, to which nearly half of the patients reveal a negative response. In this scenario, using an effective predictive model of a patient’s response would avoid useless and possibly harmful therapies for the non-responder group. The results revealed interesting potentialities to be further explored in classification problems involving other (clinical) time series.

Prognostic prediction through biclustering-based classification of clinical gene expression time series.

The constant drive towards a more personalized medicine led to an increasing interest in temporal gene expression analyzes. It is now broadly accepted that considering a temporal perpective represents a great advantage to better understand disease progression and treatment results at a molecular level. In this context, biclustering algorithms emerged as an important tool to discover local expression patterns in biomedical applications, and CCC-Biclustering arose as an efficient algorithm relying on the temporal nature of data to identify all maximal temporal patterns in gene expression time series. In this work, CCC-Biclustering was integrated in new biclustering-based classifiers for prognostic prediction. As case study we analyzed multiple gene expression time series in order to classify the response of Multiple Sclerosis patients to the standard treatment with Interferon-β, to which nearly half of the patients reveal a negative response. In this scenario, using an effective predictive model of a patient's response would avoid useless and possibly harmful therapies for the non-responder group. The results revealed interesting potentialities to be further explored in classification problems involving other (clinical) time series.

Genetic polymorphisms associated with the development and clinical course of multiple sclerosis (Review)

Multiple sclerosis (MS) is an autoimmune disease characterized by areas of inflammation, demyelination and axonal damage. The etiology of MS is multifactorial with an interaction between genetic, environmental and geographical factors. The objective of this study was to review the physiopathology and the genetic polymorphisms associated with the development and clinical course of MS. Studies carried out in populations worldwide showed that polymorphisms in the genes of the major histocompatibility complex (MHC) class II and class III have been associated with susceptibility, resistance and clinical forms of MS. Considerable attention has been focused on studies evaluating disease-modifying effects in MS that identified seven genes of probable importance such as the HLA class II, ApoE, IL-1ra, IL-1β, TNF-α, TNF-β and CCR5 genes. However, the results described in the literature about genetic biomarkers in MS are not consistent in the worldwide population. The detection of a single nucleotide polymorphism involved in the etiology and physiopathology of MS is very difficult and, it is likely that, several genetic polymorphisms are involved, each with a small contribution to the susceptibility or resistance to MS. Taken together the results show the need for continued research in genetically heterogeneous populations to identify new biomarkers associated with MS that could be used as prognostic markers or as therapeutic targets to modulate the autoimmune response in MS patients. This information may contribute to a better understanding of the physiopathology and treatment of MS, with the possibility of developing different therapeutic strategies according to the genetic profile of each individual.

Innate and adaptive anti-viral immune responses in MS patients treated with interferon-beta

Background Interferon-beta (IFN-b) has both immuno-modulating and anti-viral effects. In a longitudinal study of multiple sclerosis (MS) patients undergoing interferon-beta therapy, we have performed a comprehensive study of factors in the innate and adaptive immune response to the two types of virus associated with MS: human endogenous retroviruses (HERVs), and herpesviruses. Materials and methods Anti-viral antibodies towards HERVs and herpesviruses were assayed using TRIFMA or ELISA. Cytokine profiling was performed using the Luminex-system. Factors in the lectin complement activation pathway were assayed using TRIFMA. Results We demonstrate significant decreases in anti-Envelope antibody reactivity for the two closely related Gammaretroviral HERVs, HERV-H and HERV-W, as a consequence of IFN-b therapy, closely linked to efficacy of therapy/low disease activity. We also found strong indications of a protective effect of high levels of two components in the innate pathogen-associated molecular pattern recognition: mannan-binding lectin (MBL), and MASP-3. Serum levels of typical Th1- and Th2- related, MSrelevant cytokines were also monitored. We found no overall changes in Th1/Th2 ratios. Conclusions Our results support that IFN-b exerts effects on immune response to HERV-H/HERV-W, and that this antiviral response may play a role in MS development. Components in the immune response to HERVs have potential as biomarkers for disease activity.

Patterns of Th1/Th2 Cytokines Predict Clinical Response in Multiple Sclerosis Patients Treated with Glatiramer Acetate

The patterns of Th1/Th2 cytokines in relapsing-remitting multiple sclerosis were analyzed to evaluate their relevance as biomarkers of therapy response to glatiramer acetate (GA). Serum interferon-γ (IFN-γ), osteopontin and interleukin (IL)-2, IL-4, and IL-10 were measured in 19 relapsing-remitting multiple sclerosis patients treated with GA in a prospective study over 3 years. The quotient (IL-2 + IFN-γ)/(IL-4 + IL-10) was elevated in patients with relapses as compared to relapse-free patients after 12 (p = 0.04), 24 (p = 0.02) and 36 months (p = 0.04). Our study indicates that specific patterns of Th1/Th2 cytokines predict the response to GA therapy.

Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS-specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25− T-cells when stimulated by their cognate antigen. While CD8+ T-cell-mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naïve MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology.

Commentary on Immune System Associated Diseases Caused by Viruses: The Role of EBV

In her review using the human Epstein–Barr virus (EBV) as an example, Dr. Chen intends to illustrate how host immune systems have evolved in response to pathogens or in many cases co-evolved with pathogens. She discusses why EBV in most people causes what appears to be a self-limiting lymphoproliferative disease (or is it? See her discussion of autoimmune diseases and EBV), but in a very small proportion of individuals the virus causes malignant diseases of severe consequence. She reviews some of the plausible explanations that may include interactions of environmental and host genetic factors resulting in EBV associated malignancies. She points out that EBV may not merely transform B cells, but it could also impact the host immune system on a much more global basis than previously realized. She also suggests that EBV associated diseases, in lieu of reflecting the pathogenic potential of the virus, are actually a reflection of the genetic predisposition of certain populations to the modulate immune system inappropriately in response to the virus infection. She supports this notion by detailing the abnormal modulation of NKT cells when the host is infected with EBV. For example, she cites a study that shows that the frequencies of regulatory CD8 + NKT, but not CD4 + NKT cells, in EBV associated Burkitt's lymphoma (BL) and nasopharyngeal carcinoma (NPC) patients are much lower than CD8 + NKT levels in healthy EBV carriers (Yuling et al., 2009), concluding that a skewed NKT cell response might modify the pathogenesis caused by the virus. She also supports her supposition that EBV pathogenesis is likely due to improper immune modulation in response to the infection by reviewing the data associating autoimmune diseases with EBV infections, especially focusing on multiple sclerosis (MS). She cites a study by Serafini et al. (2007) in which it was found that that almost 100% of the early onset MS cases with the secondary progressive phase contain dysregulated EBV infected plasma cells in MS brains. She also reviews other studies that describe atypical responses of MS patients who have been exposed to EBV. Nevertheless, the cause and effect link, EBV to MS, is still tenuous, yet intriguing. She concludes that the malignancies associated with EBV infection and especially the autoimmune diseases associated with EBV infection may result from human genetic variations that cause the host to differentially modulate the immune response to EBV infection to the detriment of the host.

Role of Differential Expression of Interferon Receptor Isoforms on the Response of Multiple Sclerosis Patients to Therapy with Interferon Beta

The cytokine interferon (IFN)-β is successfully used in the treatment of multiple sclerosis. However, some patients fail to respond to therapy, probably due to different biological patterns that are of importance in influencing clinical response. A common mechanism involved in the modulation of responsiveness to cytokine is represented by regulation of their receptor expression through autocrine-ligand-mediated loops. Mechanistically, IFN-β exerts its biological effects through interaction with the IFN-α/-β-receptor (IFNAR), which then activates several transcription factors. IFNAR is composed of 2 chains, IFNAR-1 and IFNAR-2, which associate with IFN-β to form a ternary complex. The major ligand-binding subunit is IFNAR-2 and it exists in 3 mRNA splice variants, resulting in 2 transmembrane (IFNAR-2b and IFNAR-2c) isoforms and a soluble (IFNAR-2a) one. On the contrary, from normal cells only one IFNAR-1 isoform, with transcriptional capacity, was identified. In the past decades, considerable information has accumulated pertaining to the downregulation of the IFNAR complex in IFN-treated patients, but only a few studies have investigated the molecular events involved in this phenomenon. The intent of the present review is to place this receptor downregulation in the context of IFN-β therapy and of its clinical and biological outcomes in IFN-β-treated patients.

Epstein-Barr virus and multiple sclerosis: Cellular immune response and cross-reactivity

We investigated T cell immunity to Epstein-Barr virus (EBV) in multiple sclerosis (MS) and assessed cross-reactivity of the anti-EBV cellular response with brain antigens. We measured the proliferation, cytotoxicity, and number of interferon-γ secreting cells following stimulation with autologous EBV-infected lymphoblastoid cell lines (LCL) in MS patients and matched controls. There were no statistically significant differences for any of the measured responses, but there was a trend towards decreased proliferative responses in MS patients. There was no measured cross-reactivity between LCL and brain antigens. We conclude that the cellular immune response against EBV-infected cells is neither increased nor decreased in MS.

Thermoregulation in multiple sclerosis

Multiple sclerosis (MS) is a progressive neurological disorder that disrupts axonal myelin in the central nervous system. Demyelination produces alterations in saltatory conduction, slowed conduction velocity, and a predisposition to conduction block. An estimated 60-80% of MS patients experience temporary worsening of clinical signs and neurological symptoms with heat exposure. Additionally, MS may produce impaired neural control of autonomic and endocrine functions. This review focuses on five main themes regarding the current understanding of thermoregulatory dysfunction in MS: 1) heat sensitivity; 2) central regulation of body temperature; 3) thermoregulatory effector responses; 4) heat-induced fatigue; and 5) countermeasures to improve or maintain function during thermal stress. Heat sensitivity in MS is related to the detrimental effects of increased temperature on action potential propagation in demyelinated axons, resulting in conduction slowing and/or block, which can be quantitatively characterized using precise measurements of ocular movements. MS lesions can also occur in areas of the brain responsible for the control and regulation of body temperature and thermoregulatory effector responses, resulting in impaired neural control of sudomotor pathways or neural-induced changes in eccrine sweat glands, as evidenced by observations of reduced sweating responses in MS patients. Fatigue during thermal stress is common in MS and results in decreased motor function and increased symptomatology likely due to impairments in central conduction. Although not comprehensive, some evidence exists concerning treatments (cooling, precooling, and pharmacological) for the MS patient to preserve function and decrease symptom worsening during heat stress.

Abnormal B‐cell cytokine responses a trigger of T‐cell–mediated disease in MS?

To study antibody-independent contributions of B cells to inflammatory disease activity, and the immune consequences of B-cell depletion with rituximab, in patients with multiple sclerosis (MS). B-Cell effector-cytokine responses were compared between MS patients and matched controls using a 3-signal model of activation. The effects of B-cell depletion on Th1/Th17 CD4 and CD8 T-cell responses in MS patients were assessed both ex vivo and in vivo, together with pharmacokinetic/pharmacodynamic studies as part of 2 rituximab clinical trials in relapsing-remitting MS. B Cells of MS patients exhibited aberrant proinflammatory cytokine responses, including increased lymphotoxin (LT):interleukin-10 ratios and exaggerated LT and tumor necrosis factor (TNF)-alpha secretion, when activated in the context of the pathogen-associated TLR9-ligand CpG-DNA, or the Th1 cytokine interferon-gamma, respectively. B-Cell depletion, both ex vivo and in vivo, resulted in significantly diminished proinflammatory (Th1 and Th17) responses of both CD4 and CD8 T cells. Soluble products from activated B cells of untreated MS patients reconstituted the diminished T-cell responses observed following in vivo B-cell depletion in the same patients, and this effect appeared to be largely mediated by B-cell LT and TNFalpha. We propose that episodic triggering of abnormal B-cell cytokine responses mediates 'bystander activation' of disease-relevant proinflammatory T cells, resulting in new relapsing MS disease activity. Our findings point to a plausible mechanism for the long-recognized association between infections and new MS relapses, and provide novel insights into B-cell roles in both health and disease, and into mechanisms contributing to therapeutic effects of B-cell depletion in human autoimmune diseases, including MS.

The antibody response to oligodendrocyte specific protein in multiple sclerosis

The role of autoantibody responses in pathogenesis or progression of multiple sclerosis (MS) remains controversial. This is partly because the methods that can distinctly identify pathogenic antibody reactivities targeting native membrane proteins from the reactivities that originate as an epiphenomenon in such disease are just emerging. Oligodendrocyte specific protein (OSP or claudin-11) is a candidate autoantigen in MS and CSF reactivity towards OSP has been reported in MS patients. We characterized the autoantibody response to OSP using sensitive cell based assays. In line with a previous report, higher antibody response to OSP 114–120 peptide and denatured protein was observed. However applying assays based on native OSP we did not observe any specific OSP response in MS patients. Our results demonstrate that anti-OSP antibodies do not recognise native glial OSP and may therefore rather represent an epiphenomenon in MS.

Methylprednisolone does not restore biological response in multiple sclerosis patients with neutralizing antibodies against interferon‐β

Neutralizing antibodies (NAbs) appearing during treatment with Interferon-beta (IFN-beta) reduce or abolish bioactivity and therapeutic efficacy. Initial combination therapy with methylprednisolone (MP) may reduce the frequency of NAb positive patients. We hypothesized that MP treatment might also reduce NAb levels and re-establish IFN-beta bioactivity in patients already NAb+, who discontinue IFN-beta therapy. In a 6-month open-label trial, we compared monthly high-dose pulsed MP treatment in 38 Nab positive patients with 35 NAb+, MP-untreated control patients discontinuing any therapy or switching to glatiramer acetate. All patients were NAb+ with an absent in vivo response to IFN-beta. NAbs were measured using a cytopathic effect assay and expressed as neutralizing capacity (NC) in percentage of added IFN-beta. Bioactivity was expressed as in vivo Myxovirus Resistance Protein A (MxA) mRNA induction in whole blood using real time PCR. At the end of study, median NAb NC was 92% in both groups. Eight patients (21%) in the MP group and four patients (11%) in the control group had regained an in vivo MxA response to IFN-beta (P = 0.35). Monthly pulsed MP treatment in NAb positive patients has no beneficial effect on NAb status or IFN-beta bioactivity.

Could cytokines levels or adhesion molecules expression be predictor of IFN-β treatment response in multiple sclerosis patients?

Objective Some patients with relapsing-remitting multiple sclerosis (RRMS) do not respond to treatment with interferon-β and continue to have relapses and new enhancing lesions on MRI. The markers which would predict the treatment response are still not known. The objectives of the study were to compare cytokines levels (IFN-γ, IL-4, IL-6, IL-10) and expression of adhesion molecules before and during treatment in responders and nonresponders to IFN-β treatment. Methods Twenty-nine patients with RRMS were enrolled in the study. Cytokine levels were evaluated by ELISA in supernatants of IONO/PMA activated PBMC cultures (IFN-γ, IL-4, IL-6, IL-10), and by flow cytometry (intracellular IFN-γ, IL-4 and IL-2R expression) before and during treatment. Expression of adhesion molecules (VLA-4, ICAM-1) was evaluated by flow cytometry (CD49+ and CD54+) before and during treatment. Results Only 9 of 29 patients were responders to treatment according to definition (no relapse in the first 2 years of treatment). We found significant differences in the expression of IL-2R after 1 month of treatment, intracellular IFN-γ after 6 months of treatment and IL-10 level in nonactivated PBMC cultures after 1 week of treatment. Conclusion We concluded that the differences we had found between responders and nonresponders are most probably incidental and not predictive of treatment response. Our study shows that cytokines levels and expression of adhesion molecules cannot be used as markers for treatment response.

Vaccines for multiple sclerosis: progress to date.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS, characterized pathologically by a perivascular infiltrate consisting predominantly of T cells and macrophages. Although its aetiology remains unknown, several lines of evidence support the hypothesis that autoimmune mechanisms play a major role in the development of the disease. Several widely used disease-modifying agents are approved for the treatment of MS. However, these agents are only partially effective and their ability to attenuate the more progressive phases of the disease is not clear at this time. Therefore, there is a need to develop improved treatment options for MS. This article reviews the role of several novel, selective vaccine strategies that are currently under investigation, including: (i) T-cell vaccination (TCV); (ii) T-cell receptor (TCR) peptide vaccination; (iii) DNA vaccination; and (iv) altered peptide ligand (APL) vaccination. The administration of attenuated autoreactive T cells induces regulatory networks to specifically suppress pathogenic T cells in MS, a strategy named TCV. The concept of TCV was based on the experience of vaccination against aetiological agents of infectious diseases in which individuals are purposely exposed to an attenuated microbial pathogen, which then instructs the immune system to recognize and neutralize it in its virulent form. In regard to TCV, attenuated, pathogenic T cells are similarly used to instruct the immune system to recognize and neutralize disease-inducing T cells. In experimental allergic encephalomyelitis (EAE), an animal model for MS, pathogenic T cells use a strikingly limited number of variable-region elements (V region) to form TCR specific for defined autoantigens. Thus, vaccination with peptides directed against these TCR structures may induce immunoregulatory mechanisms, thereby preventing EAE. However, unlike EAE, myelin-reactive T cells derived from MS patients utilize a broad range of different V regions, challenging the clinical utility of this approach. Subsequently, the demonstration that injection of plasmid DNA encoding a reporter gene into skeletal muscle results in expression of the encoded proteins, as well as in the induction of immune responses in animal models of autoimmunity, was explored as another strategy to re-establish self-tolerance. This approach has promise for the treatment of MS and, therefore, warrants further investigation. APLs are molecules in which the native encephalitogenic peptides are modified by substitution(s) of one or a few amino acids critical for contact with the TCR. Depending on the substitution(s) at the TCR contact residues of the cognate peptide, an APL can induce immune responses that can protect against or reverse EAE. However, the heterogeneity of the immune response in MS patients requires further study to determine which patients are most likely to benefit from APL therapy. Other potential approaches for vaccines in MS include vaccination against axonal growth inhibitors associated with myelin, use of dendritic cells pulsed with specific antigens, and active vaccination against proinflammatory cytokines. Overall, vaccines for MS represent promising approaches for the treatment of this devastating disease, as well as other autoimmune diseases.

JC virus induces a vigorous CD8 + cytotoxic T cell response in multiple sclerosis patients

We sought to compare the ongoing CD8 + cytotoxic T lymphocytes (CTL) immune response of MS patients to self and viral antigens. Using 51Cr release and tetramer staining assays, we found that the CTL response against VP1, the major capsid protein of the polyomavirus JC (JCV), was significantly higher than the one against epitopes of MBP and PLP. The JCV-specific CTL response was also significantly stronger in MS patients than healthy control subjects. These findings may shed a new light on the recent events related to the development of progressive multifocal leukoencephalopathy in three natalizumab-treated patients.