Multiple Sclerosis: Rivera VM

Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, Frank JA, Galetta SL, Grossman RI, Hawker K, Kachuck NJ, Levin MC, Phillips JT, Racke MK, Rivera VM, Stuart WH, Anonymous00118. · University of Texas Southwestern Medical Center at Dallas, USA. · Neurology. · Pubmed #12963748 No free full text.

Abstract: Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Rivera VM. · Department of Neurology, Baylor College of Medicine, 6560 Fannin, Suite 1224, Houston, Texas 77030, USA. · Rev Neurol. · Pubmed #11310288 No free full text.

Abstract: INTRODUCTION: Multiple sclerosis (MS) is probably caused by many pathological factors, both intrinsic and extrinsic. DEVELOPMENT: When we consider the aetiology of MS, we have to take three basic factors into account: 1. Immunological factors: evidence of involvement of the immune system has been found in plasma, tissues and CSF; 2. Viral factors: epidemiological studies suggest that MS may be a result of contact with environmental factors during childhood or adolescence, and 3. Genetic factors although there is no evidence that MS is inherited directly, there is between 12 and 15 times more involvement of persons from affected families than from the general population. Regarding treatment, since this is a polysymptomatic disorder, the specialist should choose the most suitable drug or intervention in each case, according to the alterations which affect quality of life or the severity of the presenting symptom. Three pharmacological treatments are emphasized: steroids, immunomodulation and immunosuppression. CONCLUSION: In this article we review the aetiology of MS and its pharmacological treatment.

Rivera VM. · Department of Neurology, Baylor College of Medicine, 6560 Fannin, Suite 1224, Houston, Texas 77030, USA. · Rev Neurol. · Pubmed #11310287 No free full text.

Abstract: INTRODUCTION: Multiple sclerosis is currently considered to be a destructive disorder, and a certain degree of alteration in immunity is considered to occur in genetically susceptible persons. DEVELOPMENT: Magnetic resonance (MR) has become the basic technique for diagnosis and evaluation of the response to treatment. The key factor in the information obtained form MR images is the water content. There are several technical situations to be taken into account when using MR in multiple sclerosis: phase T1, phase T2, FLAIR, phase T1 with gadolinium, MR with spectroscopy, cerebral parenchymatous fraction and magnetization transfer MR. Apart from magnetic resonance, immunological changes of multiple sclerosis are seen in the CSF in over 50% of the patients with the disorder. Use of evoked potentials, with the important advantage of detecting lesions not visible on MR and asymptomatic lesions, may also be useful for establishment of the diagnosis. CONCLUSION: In this article we describe the use of neuroimaging in the diagnosis of multiple sclerosis.

Zhang JZ, Rivera VM, Tejada-Simon MV, Yang D, Hong J, Li S, Haykal H, Killian J, Zang YC. · Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA. · J Neurol. · Pubmed #11985389 No free full text.

Abstract: Myelin basic protein (MBP)-reactive T cells are potentially involved in the pathogenesis of multiple sclerosis (MS), and can be depleted by subcutaneous inoculations with irradiated autologous MBP-reactive T cells (T cell vaccination). This preliminary open label study was undertaken to evaluate whether depletion of MBP-reactive T cells would be clinically beneficial to patients with MS. Fifty-four patients with relapsing-remitting (RR) MS (n=28) or secondary progressive (SP) MS (n=26) were immunized with irradiated autologous MBP-reactive T cells and monitored for changes in rate of relapse, expanded disability scale score (EDSS) and MRI lesion activity over a period of 24 months. Depletion of MBP-reactive T cells correlated with a reduction (40%) in rate of relapse in RR-MS patients as compared with the pre-treatment rate in the same cohort. However, the reduction in EDSS was minimal in RR-MS patients while the EDSS was slightly increased in SP-MS patients over a period of 24 months. Serial semi-quantitative MRI examinations suggest stabilization in lesion activity as compared with baseline MRI. The findings suggest some potential clinical benefit of T cell vaccination in MS and encourage further investigations to evaluate the treatment efficacy of T cell vaccination in controlled trials.

Rivera VM. · Baylor College of Medicine, Houston, Tex., USA. · Neuroepidemiology. · Pubmed #19246934 links to  free full text

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Ordonez L, Skromne E, Ontaneda D, Rivera VM. · Maxine Mesinger MS Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · Clin Neurol Neurosurg. · Pubmed #16624483 No free full text.

Abstract: We report a case of multiphasic disseminated encephalomyelitis (MDEM) associated with systemic lupus erythematosus (SLE) and antiphospholipid syndrome. The initial presentation was suggestive of multiple sclerosis. Further clinical attacks, MRI imaging, and CSF findings led to a diagnosis of disseminated encephalomyelitis (DEM). Multiple episodes of neurological dysfunction, which differed in clinical presentation, further categorized the diagnosis as multiphasic DEM. The co-occurrence SLE and antiphospholipid syndrome is unusual and provided an additional diagnostic challenge.

Zang YC, Skinner SM, Robinson RR, Li S, Rivera VM, Hutton GJ, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · Mult Scler. · Pubmed #15471364 No free full text.

Abstract: Interferon beta (IFN beta) has complex immune regulatory properties that contribute to its treatment effect on multiple sclerosis (MS). In this study, we investigated the role of IFN beta in differentiation and functional properties of monocytes and monocyte-derived dendritic cells that are critical to the inflammatory process in MS. The results revealed that IFN beta inhibited intracellular production of interleukin (IL)-1b (P<0.01) in both monocytes exposed to in vitro treatment of IFN beta and monocytes analysed ex vivo from MS patients treated with IFN beta. IFN beta was shown to modulate differentiation of monocytes into dendritic cells in the presence of IL-4 and GM-CSF, which resulted in a delayed differentiation process. Furthermore, it characteristically altered the phenotypic features of differentiated dendritic cells by inhibiting the expression of CD1a, CD11b, CD11c, CD123 and CD209 while upregulating costimulatory molecules, such as CD86. The selective regulatory properties of IFN beta appeared to render the function of differentiated dendritic cells to produce an increased amount (P<0.01) while their ability to secrete proinflammatory IL-12 and TGF beta was significantly reduced. The observed collective effects of IFN beta seemed to correlate with Th2 immune deviation. The study has provided new insights into the regulatory mechanisms of IFN beta in the treatment of MS.

Hong J, Zang YC, Hutton G, Rivera VM, Zhang JZ. · Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · J Neuroimmunol. · Pubmed #15223245 No free full text.

Abstract: Multiple sclerosis (MS) is thought to correlate with an array of clinically relevant biomarkers produced during inflammatory process. In this study, a novel gene expression profiling technology was developed and characterized to quantitatively measure the expression profiles of 34 genes selected based on their role in inflammation and their susceptibility to regulation by current MS treatment agents, beta-interferon (IFN) and glatiramer acetate (GA). Potential clinical applications of the technology were evaluated by in vitro and ex vivo analyses in peripheral blood mononuclear cells (PBMC) obtained from MS patients and controls. Interferon-inducible genes were universally up-regulated after in vitro treatment with beta-IFN while the expression of other selected genes encoding cytokines and molecules related to T cell trafficking, activation and apoptosis was variably affected. Beta-IFN and GA exhibited distinctive and characteristic regulatory effects on the expression of the selected genes. Similar regulatory properties of beta-IFN and GA were seen by ex vivo analysis of PBMC specimens in a self-paired study by comparing specific changes induced by beta-IFN or GA treatment in the same patients as well as in a group study by measuring specific profiles in treatment groups compared with an untreated group. Furthermore, the technology served as a simple and sensitive assay for detection of beta-IFN neutralizing antibody based on the blocking effect of serum antibodies on the known regulatory properties of beta-IFN on PBMC. The findings provide important information on the immunoregulatory properties of beta-IFN and GA and support potential clinical applications of this technology in detection of neutralizing antibody (NAB) and evaluation of treatment responses in MS patients.

Zang YC, Li S, Rivera VM, Hong J, Robinson RR, Breitbach WT, Killian J, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · J Immunol. · Pubmed #15067096 links to  free full text

Abstract: Autoreactive T cells of CD4 and CD8 subsets recognizing myelin basic protein (MBP), a candidate myelin autoantigen, are thought to contribute to and play distinct roles in the pathogenesis of multiple sclerosis (MS). In this study we identified four MBP-derived peptides that had high binding affinity to HLA-A2 and HLA-A24 and characterized the CD8(+) T cell responses and their functional properties in patients with MS. There were significantly increased CD8(+) T cell responses to 9-mer MBP peptides, in particular MBP(111-119) and MBP(87-95) peptides that had high binding affinity to HLA-A2, in patients with MS compared with healthy individuals. The resulting CD8(+) T cell lines were of the Th1 phenotype, producing TNF-alpha and IFN-gamma and belonged to a CD45RA(-)/CD45RO(+) memory T cell subset. Further characterization indicated that the CD8(+) T cell lines obtained were stained with MHC class I tetramer (HLA-A2/MBP(111-119)) and exhibited specific cytotoxicity toward autologous target cells pulsed with MBP-derived peptides in the context of MHC class I molecules. These cytotoxic CD8(+) T cell lines derived from MS patients recognized endogenously processed MBP and lysed COS cells transfected with genes encoding MBP and HLA-A2. These findings support the potential role of CD8(+) CTLs recognizing MBP in the injury of oligodendrocytes expressing both MHC class I molecules and MBP.

Hong J, Zang YC, Li S, Rivera VM, Zhang JZ. · Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · Eur J Immunol. · Pubmed #14991617 No free full text.

Abstract: T cell reactivity to candidate myelin autoantigens, such as myelin basic protein (MBP), may play an important role in the pathogenesis of multiple sclerosis (MS). Although MBP-reactive T cells have been found to undergo in vivo activation in patients with MS, their true precursor frequency in MS is unknown as current frequency analysis is commonly based on the T cell functional responses to MBP. In this study, we developed a TCR sequence-based ex vivo detection system using colony hybridization with oligonucleotide probes specific for CDR3 of selected T cell clones for the analysis of true T cell precursor frequency in PBMC. The results revealed that the precursor frequency of five independent T cell clones recognizing the immunodominant MBP(83-99) region was found to be in the range of 1.6 x 10(-4) in total T cells in three HLA-DR2 patients with MS compared to that of 0.25 x 10(-4) in HLA-DR2 healthy individuals. The observed frequency of MBP(83-99)-reactive T cells in MS patients was considerably higher than those measured in parallel by cell culture-based analysis (2.3 x 10(-6)) or by enzyme-linked immunospot assay (3.9 x 10(-5)) in the same peripheral blood mononuclear cell specimens. Furthermore, the study showed that MBP(83-99)-reactive T cells detected ex vivo belonged to CD45RA+, CD25+ and CD95- T cell subsets as evidenced by preferential expression of specific TCR transcripts in these cell fractions.

Frohman TC, Frohman EM, O'Suilleabhain P, Salter A, Dewey RB, Hogan N, Galetta S, Lee AG, Straumann D, Noseworthy J, Zee D, Corbett J, Corboy J, Rivera VM, Kramer PD. · Department of Neurology, University of Texas Southwestern Medical Center at Dallas, TX 75235, USA. · Neurology. · Pubmed #14504338 No free full text.

Abstract: The authors compared the accuracy of clinical detection (by 279 physician observers) of internuclear ophthalmoparesis (INO) with that of quantitative infrared oculography. For the patients with mild adduction slowing, INO was not identified by 71%. Intermediate dysconjugacy was not detected by 25% of the evaluators. In the most severe cases, INO was not identified by only 6%. Oculographic techniques significantly enhance the precision of INO detection compared to the clinical exam.

Zang YC, Hong J, Rivera VM, Killian J, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · Int Immunol. · Pubmed #12917259 links to  free full text

Abstract: T cells recognizing myelin basic protein (MBP) are potentially involved in the pathogenesis of multiple sclerosis (MS). In vivo clonal expansion of MBP-reactive T cells in MS may relate in part to dysfunction of peripheral regulatory mechanisms, including the anti-idiotypic immune network. In this study, we examined anti-idiotypic immune responses and the functional properties of anti-idiotypic T cells in patients with MS and healthy controls using TCR peptides corresponding to a CDR3 sequence motif preferentially expressed among T cells recognizing the 83-99 immunodominant peptide of MBP in some patients with MS. The study demonstrated that anti-idiotypic T cells could be induced in vitro by 8mer and 15mer peptides containing the CDR3 motif in MS patients and healthy controls respectively. The estimated precursor frequency of the anti-idiotypic T cells was slightly reduced in MS patients compared to control subjects. The obtained anti-idiotypic T cells recognizing the 15mer TCR peptide were found to express the CD4 phenotype, produce predominantly IL-10 and inhibit the proliferation of autologous T cells recognizing the immunodominant peptide of MBP. Anti-idiotypic T cells induced by the 8mer TCR peptide were predominantly CD8+ cytotoxic T cells and exhibited cytotoxic activity against autologous MBP-specific T cells expressing the CDR3 sequence. When added in primary culture, both TCR peptides had a significant inhibitory effect on the T cell responses to the immunodominant peptide of MBP. The findings suggest that anti-idiotypic immune responses can be activated by selected TCR peptides and may play an important role in the in vivo regulation of MBP-reactive T cells.

Zang Y, Hong J, Robinson R, Li S, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, 6501 Fannin Street, NB302, Houston, TX 77030, USA. · J Neuroimmunol. · Pubmed #12667659 No free full text.

Abstract: The treatment efficacy of beta-interferon (beta-IFN) and Copolymer-1 (COP-1) for multiple sclerosis (MS) is potentially attributable to the immune regulatory properties of the drugs. In this study, we compared the regulatory effects of beta-IFN-1a and COP-1 used individually and in combination on the function of T cells derived from MS patients and healthy controls. The results revealed that the two drugs regulated predominantly CD4+ T cells with distinct properties. COP-1 activated both Th1 and Th2 cells while beta-IFN-1a was generally suppressive for Th1 cells and up-regulated IL-10 production. Furthermore, both drugs seemed to alter the T cell responses to myelin basic protein (MBP), a candidate myelin autoantigen for MS. The most significant finding is that COP-1 and beta-IFN-1a act individually through distinct regulatory properties and interact antagonistically when they are combined. The study has important clinical implications in the planned clinical trials to test treatment efficacy of combination therapy.

Rivera VM. · Department of Neurology Baylor College of Medicine. 6560 Fannin, Suite 1224, Houston, Texas, 77030, USA. · Rev Neurol. · Pubmed #12577220 links to  free full text

Abstract: The modern history of the treatment of multiple sclerosis is reflected during the last years with the advent of controlled clinical trials design to produce measurable outcomes utilizing MRI techniques and statistical analysis. Addressing in this form the use of disease modifying medications: immunomodulation with interferons and glatiramer acetate in the relapsing/remitting type, and combination therapies or immunosuppression in the progressive forms, these studies based on evidence provide to the clinician direction in the process to decide the most appropriate treatment for the individual patient.

Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor Multiple Sclerosis Center, Baylor College of Medicine, Houston, TX 77030, USA. · Ann Neurol. · Pubmed #12557285 No free full text.

Abstract: Viral infections are though to play an important role in the pathogenesis of multiple sclerosis (MS) potentially through molecular mimicry. An identical sequence was found in both myelin basic protein (MBP, residues 96-102), a candidate autoantigen for MS, and human herpesvirus-6 (HHV-6 U24, residues 4-10) that is a suspected viral agent associated with MS. In this study, we showed that greater than 50% of T cells recognizing MBP(93-105) cross-reacted with and could be activated by a synthetic peptide corresponding to residues 1 to 13 of HHV-6 U24 in MS patients. The estimated precursor frequency of these cross-reactive T cells recognizing both peptides, MBP(93-105) and HHV-6 (U24)(1-13), was significantly elevated in MS patients compared with that in healthy controls. These cross-reactive CD4+ T cells represented the same Th1 phenotype as that of monospecific T cells recognizing MBP(93-105). There were increased antibody titers for both peptide HHV-6 (U24)(1-13) and peptide MBP(93-105) in the same patients with MS compared with those in healthy controls, suggesting B-cell sensitization to the antigens in MS patients. The study provides important evidence in the understanding of the potential role of HHV-6 infection/reactivation in the activation of autoimmune reactivity to MBP and its implication in the pathogenesis of MS.

Tejada-Simon MV, Hong J, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Unit, Baylor-Methodist Multiple Sclerosis Center and Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. · Immunology. · Pubmed #12460184 links to  free full text

Abstract: Myelin oligodendrocyte glycoprotein (MOG) is found to induce both autoreactive T-cell and antibody responses associated with demyelinating pathology and is implicated in the pathogenesis of multiple sclerosis (MS). In this study, we addressed the potential association of anti-MOG immune responses with MS by examining, comparatively, both the T-cell and antibody responses to recombinant MOG fragments in MS patients and healthy subjects. T cells recognizing MOG were detected in MS patients as well as in healthy subjects, and their precursor frequency in the blood was not increased in patients with MS. MOG-reactive T cells isolated from both MS patients and healthy subjects exhibited a similar cytokine profile, producing interleukin (IL)-4, IL-10 and tumour necrosis factor (TNF), but not interferon-gamma (IFN-gamma), and recognized predominantly the extracellular (residues 1-60) and the transmembrane/cytoplasmic (residues 154-218) domains of MOG. In contrast, anti-MOG antibodies derived from MS patients displayed a skewed reactivity pattern, even though the occurrence and titres of serum anti-MOG antibodies were only slightly elevated in MS patients. MS-derived autoantibodies were predominantly directed at the 1-60 region of MOG, while naturally occurring anti-MOG antibodies derived from healthy individuals reacted selectively to the 154-218 domain. These differences were statistically significant. The findings of this study are consistent with the presence of anti-MOG antibodies within demyelinating lesions of MS and their role in the induction of demyelinating pathology in animal models. The study has important implications in the understanding of the autoimmune processes in MS.

Hong J, Tejada-Simon MV, Rivera VM, Zang YC, Zhang JZ. · Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, Houston, Texas, USA. · Mult Scler. · Pubmed #12120696 No free full text.

Abstract: Viral infections are potentially associated with the etiology and pathogenesis of multiple sclerosis (MS). It has been speculated that the treatment efficacy of interferon beta (IFN beta) in MS may relate to its anti-viral properties. The study was undertaken to evaluate the in vivo anti-viral effects of IFN beta-1a in patients with MS. Human herpesvirus-6 (HHV-6) was studied as an example for being a latent neurotropic virus. IFN beta used at concentrations of approximately 0.5 microg/ml was shown to significantly reduce in vitro HHV-6 replication in a susceptible T-cell line. Sera derived from 23 MS patients treated with IFN beta-1a were examined for serum cell-free DNA of HHV-6 as an indicator for viral replication and the reactivity of IgM antibodies to a recombinant HHV-6 virion protein containing a known immunoreactive region. The results were compared with those of control sera obtained from untreated MS (n=29) and healthy individuals (n=21). The findings indicated that IFN beta treatment significantly reduced HHV-6 replication as evident by decreased cell-free DNA in treated MS specimens. The results correlated with decreased IgM reactivity to the HHV-6 antigen in treated MS patients compared to untreated controls, suggesting reduced exposure to HHV-6. The findings were confirmed in paired sera obtained from seven MS patients before and after the treatment The study provides new evidence indicating that IFN beta has potent in vivo anti-viral effects that may contribute to the treatment efficacy in MS.

Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Killian JM, Zhang JZ. · Multiple Sclerosis Research Unit, Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, Baylor College of Medicine, Houston, Texas 77030, USA. · J Virol. · Pubmed #12021348 links to  free full text

Abstract: Human herpesvirus 6 (HHV-6), a latent lymphotropic and neurotropic virus, has been suspected as an etiologic agent in multiple sclerosis (MS). The study was undertaken to correlate virologic evidence for HHV-6 activity with the state of host immunity to HHV-6 in MS patients and control subjects. The study revealed that cell-free DNA of HHV-6 was detected more frequently in both serum and cerebrospinal fluid of MS patients than in those of control subjects. T cells recognizing the recombinant 101-kDa protein (101K) corresponding to the major immunoreactive region unique to HHV-6 occurred at significantly lower precursor frequency in MS patients than in control subjects. The resulting HHV-6-specific T-cell lines obtained from MS patients exhibited skewed cytokine profiles characterized by the inability to produce interleukin-4 (IL-4) and IL-10. The decreased T-cell responses to HHV-6 and the altered cytokine profile were consistent with significantly declined serum immunoglobulin G (IgG) titers for HHV-6 of MS patients compared to those of control subjects. In contrast, elevated serum IgM titers for HHV-6 were detected in the majority of MS patients, which may reflect frequent exposure of B cells to HHV-6. The findings suggest that the decreased immune responses to HHV-6 may be responsible for ineffective clearance of HHV-6 in MS patients.

Zang YC, Halder JB, Hong J, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Unit, Baylor-Methodist Multiple Sclerosis Center and Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. · J Neuroimmunol. · Pubmed #11958828 No free full text.

Abstract: The protective role of pregnancy in autoimmune conditions, such as multiple sclerosis (MS), is potentially associated with immune regulation by sex hormones produced during pregnancy. This study was undertaken to examine the regulatory effects of estriol on the T cell functions, including transmigration and the cytokine production. The results revealed for the first time that estriol significantly inhibited T cell transmigration at a concentration range typical of pregnancy, which correlated with decreased T cell expression of matrix metalloproteinase-9. Estriol was also found to alter the cytokine profile of T cells toward Th2 phenotype by up-regulating the production of IL-10 and inhibiting TNFalpha secretion of T cells. However, the inhibitory effects of estriol on T cells were not antigen-dependent. Further characterization indicated that estriol inhibited nuclear transcription factor kappa B (NF-kappa B), which controls a variety of immune-related genes. This study provides new evidence that estriol is a potent regulator for the T cell functions potentially through its interaction with the NF-kappa B signaling pathway.

Tejada-Simon MV, Hong J, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Laboratory, Baylor-Methodist Multiple Sclerosis Center and Department of Neurology, Baylor College of Medicine, Houston, USA. · Eur J Immunol. · Pubmed #11241296 No free full text.

Abstract: Autoreactive T cells specific for candidate myelin antigens, including myelin basic protein (MBP) and proteolipid protein (PLP), are thought to play an important role in the pathogenesis of multiple sclerosis (MS). Myelin-reactive T cells primed in vivo by myelin breakdown products or microbial cross-reactive antigens during the disease processes may exhibit a reactivity pattern and cytokine profile different from those in the normal T cell repertoire. In this study, we examined the precursor frequency, the reactivity pattern and cytokine profile of myelin-reactive T cells that were primed in vitro with overlapping peptides of MBP and PLP in patients with MS and healthy individuals. The results revealed that T cells specific for peptides of MBP and PLP occurred at a relatively higher precursor frequency in patients with MS than that in healthy individuals. We identified a number of dominant T cell epitopes within MBP and PLP, some of which were not previously detected using whole myelin antigens as the primary stimuli. Some residues represented common immunodominant regions that were detected in both MS patients and healthy controls while others were associated only with MS. MBP-reactive T cell lines generally exhibited a Th0-like cytokine profile. There was significantly increased Th1 cytokine production (i. e. TNF and IFN-gamma) among MS-derived T cell lines. PLP-reactive T cell lines had a distinct cytokine profile, producing predominantly TNF-alpha and little or not IFN-gamma and IL-4. The findings have important implications in the understanding of the role of myelin-reactive T cells in MS.

Ciancio SJ, Mutchnik SE, Rivera VM, Boone TB. · Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA. · Urology. · Pubmed #11182328 No free full text.

Abstract: OBJECTIVES: Multiple sclerosis (MS) causes neurologic symptoms to change over time. Voiding dysfunction is common in patients with MS, and few studies have examined the changes in urodynamic patterns in these patients over time. The purpose of this study was to examine the frequency and nature of urodynamic pattern changes in patients with MS who underwent two or more urodynamic studies. METHODS: Twenty-two patients (7 men and 15 women) with well-documented MS were referred to one urologist (T.B.B.) for evaluation of lower urinary tract symptoms. All patients had undergone two or more urodynamic evaluations during a 14-year period for persistent or new symptoms, and a retrospective comparison was made among the urodynamic test results. RESULTS: Overall, 12 (55%) of 22 patients experienced a change in their urodynamic patterns and/or compliance during a mean follow-up interval of 42 +/- 45 months between the urodynamic studies. Most patients initially had urodynamic patterns showing detrusor hyperreflexia, detrusor external sphincter dyssynergia, or detrusor hypocontractility. Fourteen (64%) of the 22 patients studied had the same or worsening of the same symptoms and 8 (36%) of 22 had new urologic symptoms. Six (43%) of 14 patients with no new symptoms and 6 (75%) of 8 with new symptoms had significant changes found with follow-up urodynamic testing. CONCLUSIONS: A significant proportion of patients with MS with and without new urinary symptoms will develop changes in their underlying urodynamic patterns and detrusor compliance. Therefore, urodynamic evaluations should be repeated at regular intervals in symptomatic patients to optimize clinical management, reduce complications, and better enable these patients to manage their neurogenic bladder dysfunction.

Hong J, Zang YC, Tejada-Simon MV, Li S, Rivera VM, Killian J, Zhang JZ. · Multiple Sclerosis Research Laboratory, Department of Neurology, and Baylor-Methodist Multiple Sclerosis Center, Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA. · J Immunol. · Pubmed #11120809 links to  free full text

Abstract: Immunization with irradiated autoreactive T cells (T cell vaccination) induces anti-idiotypic T cell responses that preferentially recognize complementarity-determining region 3 sequences, contributing to clonal depletion of autoreactive T cells. However, it remains unknown whether T cell vaccination elicits anti-idiotypic humoral responses and whether the anti-idiotypic Abs play a similar role in the regulatory mechanism induced by T cell vaccination. In this study we examined the occurrence, the reactivity pattern, and the regulatory role of anti-idiotypic Abs elicited by T cell vaccination in patients with multiple sclerosis. We demonstrated for the first time that B cells producing anti-idiotypic Abs could be isolated from vaccinated patients. These EBV-transformed B cell lines were selected for specific reactivity to a 20-mer TCR peptide incorporating a common complementarity-determining region 3 sequence of the immunizing T cell clones. The resulting anti-idiotypic Abs were found to react with the original immunizing T cell clones and exhibit an inhibitory effect on their proliferation. The findings suggest that anti-idiotypic Ab responses can be induced by T cell vaccination in humans and that their regulatory properties are likely to contribute to the suppression of myelin basic protein-reactive T cells in vaccinated patients. The study has important implications in our understanding of the regulatory role of the anti-idiotypic humoral responses induced by T cell vaccination.

Zang YC, Halder JB, Samanta AK, Hong J, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Laboratory, Department of Neurology and Baylor-Methodist Multiple Sclerosis Center, 6501 Fannin Street, NB302, Houston, TX 77030, USA. · J Neuroimmunol. · Pubmed #11108946 No free full text.

Abstract: Trafficking of inflammatory T cells into the brain is associated with interactions of certain chemokines with their receptors, which plays an important role in the pathogenesis of multiple sclerosis (MS). We examined whether interferon-beta (IFN-beta) had the ability to regulate the production of chemokines and the expression of their receptors in T cells derived from patients with MS. It was demonstrated for the first time that in vitro exposure of T cells to IFN-beta-1a selectively inhibited mRNA expression for RANTES and MIP-1alpha and their receptor CCR5. T cell surface expression of CCR5 was significantly reduced in MS patients treated with IFN-beta, correlating with decreased T cell transmigration toward RANTES and MIP-1alpha. The study provides new evidence suggesting that IFN-beta treatment impairs chemokine-induced T cell trafficking by reducing the production of RANTES and MIP-1alpha and the expression of their receptors CCR5.

Tejada-Simon MV, Zang YC, Yang D, Hong J, Li S, Singh RA, Van den Berg-Loonen E, Killian JM, Rivera VM, Zhang JZ. · Multiple Sclerosis Research Laboratory, Baylor-Methodist Multiple Sclerosis Center and Department of Neurology, Houston, TX 77030, USA. · Int Immunol. · Pubmed #11099303 links to  free full text

Abstract: Multiple sclerosis (MS) is a demyelinating disease of presumed T cell autoimmunity against self myelin. We hypothesized that if myelin-reactive T cells are associated with the disease processes, they may undergo activation and expansion during acute exacerbation. In this study, we examined the precursor frequency, epitope recognition and cytokine profile of myelin-reactive T cells in 14 relapsing/remitting MS patients during exacerbation and remission. The study revealed that T cells recognizing the immunodominant peptides of candidate myelin antigens, including myelin basic protein (MBP), proteolipid protein and myelin oligodendrocyte glycoprotein, occurred at increased precursor frequency during acute exacerbation. The T cell responses to MBP focused on the immunodominant regions (residues 83-99 and 151-170) during exacerbation and shifted toward other epitopes of MBP at the time of remission. Furthermore, there was a marked increase in the production of T(h)1 cytokines among T cell lines obtained during exacerbation compared to those obtained during remission. The study demonstrated that myelin-reactive T cells underwent selective activation and expansion during acute MS exacerbation. In contrast, myelin-reactive T cells found during remission in the same patients generally resembled those identified in healthy controls with some discrepancies. The findings suggest potential association of aberrant myelin-reactive T cell responses with acute exacerbation in MS, which may reflect transient activation of myelin-reactive T cell populations of pathogenic potential.

Rivera VM. · Dpto. de Neurología, Baylor College of Medicine, Houston, Texas 77030, USA. · Rev Neurol. · Pubmed #11027100 No free full text.

Abstract: INTRODUCTION AND OBJECTIVE: Preliminary studies (phase III) have shown that treatment with beta-interferon 1a (avonex) is effective in diverse aspects of relapsing/remitting multiple sclerosis (RRMS). The present study discusses results of an opened prolonged (phase IV) trial at the Baylor/Methodist International Multiple Sclerosis Center using 6 MIU by intramuscular injection once a week. PATIENTS AND METHODS: Clinical measurements: EDSS and Patient's Subjective Self-Evaluation (PSSE) and magnetic resonance (MR) were utilized every three months in 300 patients studied between 1996-1999. Patients with RRMS (71.8%) and secondarily progressive multiple sclerosis (SPMS) (28.2%) were included. RESULTS: Global clinical improvement parameter integration was 22.7% and clinical stabilization 39.4%. MR did not show quantitative alterations for either group. Sixteen patients abandoned treatment and 16 (5.3%) had relapses correlated by MR activity; 34.9% remained stable by EDSS and magnetic resonance findings but deteriorated subjectively by PSSE (62% has SPMS). CONCLUSION: This phase IV study indicates that prolonged treatment of RRMS and SPMS with avonex maintains a positive effect in 62.1% of patients.