Biomedical subjects

Paulo Fontoura

Publications and source records attributed to Paulo Fontoura.

11 recordsLinked to original sources

PubMed2006

Nogo in multiple sclerosis: growing roles of a growth inhibitor.

In recent years, knowledge about the physiological functions of the Nogo-A protein has grown considerably, and this molecule has evolved from being one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin, to several other potentially important roles in different areas such as nervous system development, epilepsy, vascular physiology, muscle pathology and CNS tumors. Therapeutically, targeting the Nogo-A protein by means of the immune response has been tried in an attempt to block neurite growth inhibition and promote regeneration in spinal cord injury models; the immune response to Nogo-A, however, has not been extensively studied. We propose to review recent evidence that Nogo-A may also play an important role in autoimmune demyelinating diseases such as experimental autoimmune encephalomyelitis and multiple sclerosis, including that Nogo-66 derived epitopes are encephalitogenic antigens in susceptible mouse strains, and that the immune response to Nogo-66 antigens includes both strong T cell and B cell activation, with epitope spreading of the antibody response to other myelin molecules. In CNS immunotherapy, careful targeting of neural self-antigens is a prerequisite in order to avoid unexpected deleterious effects, and increasing knowledge about the immune response to Nogo-A may provide a safe basis for the development of relevant therapeutic alternatives for several neurological conditions.

Animals↗

PubMed2006

Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review.

OBJECTIVE: To identify clinical and demographic factors associated with long-term disability in patients with relapsing-remitting multiple sclerosis. DATA SOURCES: We searched the MEDLINE (1966-May 2005), EMBASE, CINAHL, Cochrane, and PsycINFO computerized databases, and reviewed reference lists of retrieved articles. STUDY SELECTION: We included studies that examined predictors of long-term disability in patients with relapsing-remitting multiple sclerosis. We excluded studies that did not distinguish relapsing-remitting multiple sclerosis from primary progressive multiple sclerosis, enrolled fewer than 40 subjects, observed subjects for less than 5 years, or collected follow-up information in less than 80% of the inception cohort. DATA EXTRACTION: Two reviewers assessed study quality in 4 domains: cohort assembly, definitions and assessments of prognostic factors and outcomes, and statistical methods. One reviewer extracted data on the direction, magnitude, precision, and statistical significance of the effect of each predictor on prognosis. DATA SYNTHESIS: Heterogeneity of study designs precluded us from pooling the results of 27 eligible studies. Study quality was limited by cross-sectional design, enrollment of prevalent cases from referral centers, and lack of multivariate adjustment. Sphincter symptoms at onset (hazard ratio, 1.1-3.1), incomplete recovery from the first attack (hazard ratio, 1.3-3.3), and a short interval between the first and second attack (hazard ratio, 1.6-1.9) were most strongly and consistently associated with poor prognosis. Other factors widely believed to be of prognostic importance, including sex and age at onset, demonstrated inconsistent or weak effects on prognosis. CONCLUSIONS: The most robust predictors of long-term physical disability in relapsing-remitting multiple sclerosis are sphincter symptoms at onset and early disease course outcomes. These factors can be used to guide treatment decisions for drugs with significant toxicities.

Adult↗

PubMed2006

Emerging therapeutic targets in multiple sclerosis.

PURPOSE OF REVIEW: The aim of this review is to describe the recent findings regarding the pathogenesis of multiple sclerosis and their translation to new therapies. RECENT FINDINGS: Basic research is providing new insights into the immune elements involved in the pathogenesis of multiple sclerosis, both in the periphery as well as in the central nervous system. Unveiling the complex interplay of the molecules involved in the immunological cascade of the disease supplies new targets for the development of new immunotherapeutic strategies. Similarly, clinical studies and identification of distinct subgroups of patients based on their responsiveness to immunotherapies provides support for the existence of immunopathological disease subtypes that seem to require different therapeutic approaches. These studies extend the theoretical basis that facilitates development of neuroprotective and repair-promoting therapeutic strategies. SUMMARY: The application of novel and cutting-edge technologies in the fields of genomics and proteomics is providing a better understanding of the genetic and environmental factors involved in multiple sclerosis susceptibility and progression, as well as the detection of biomarkers for disease activity and response to therapy. Implementation of these facilitates identification of new targets for therapy towards tailoring treatment to the individual patient with multiple sclerosis.

Antigens↗

PubMed2005

Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite.

Local catabolism of the amino acid tryptophan (Trp) by indoleamine 2,3-dioxygenase (IDO) is considered an important mechanism of regulating T cell immunity. We show that IDO transcription was increased when myelin-specific T cells were stimulated with tolerogenic altered self-peptides. Catabolites of Trp suppressed proliferation of myelin-specific T cells and inhibited production of proinflammatory T helper-1 (T(H)1) cytokines. N-(3,4,-Dimethoxycinnamoyl) anthranilic acid (3,4-DAA), an orally active synthetic derivative of the Trp metabolite anthranilic acid, reversed paralysis in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS). Trp catabolites and their derivatives offer a new strategy for treating T(H)1-mediated autoimmune diseases such as MS.

Adoptive Transfer↗

PubMed2005

A suppressive oligodeoxynucleotide enhances the efficacy of myelin cocktail/IL-4-tolerizing DNA vaccination and treats autoimmune disease.

Targeting pathogenic T cells with Ag-specific tolerizing DNA vaccines encoding autoantigens is a powerful and feasible therapeutic strategy for Th1-mediated autoimmune diseases. However, plasmid DNA contains abundant unmethylated CpG motifs, which induce a strong Th1 immune response. We describe here a novel approach to counteract this undesired side effect of plasmid DNA used for vaccination in Th1-mediated autoimmune diseases. In chronic relapsing experimental autoimmune encephalomyelitis (EAE), combining a myelin cocktail plus IL-4-tolerizing DNA vaccine with a suppressive GpG oligodeoxynucleotide (GpG-ODN) induced a shift of the autoreactive T cell response toward a protective Th2 cytokine pattern. Myelin microarrays demonstrate that tolerizing DNA vaccination plus GpG-ODN further decreased anti-myelin autoantibody epitope spreading and shifted the autoreactive B cell response to a protective IgG1 isotype. Moreover, the addition of GpG-ODN to tolerizing DNA vaccination therapy effectively reduced overall mean disease severity in both the chronic relapsing EAE and chronic progressive EAE mouse models. In conclusion, suppressive GpG-ODN effectively counteracted the undesired CpG-induced inflammatory effect of a tolerizing DNA vaccine in a Th1-mediated autoimmune disease by skewing both the autoaggressive T cell and B cell responses toward a protective Th2 phenotype. These results demonstrate that suppressive GpG-ODN is a simple and highly effective novel therapeutic adjuvant that will boost the efficacy of Ag-specific tolerizing DNA vaccines used for treating Th1-mediated autoimmune diseases.

Amino Acid Sequence↗

PubMed2005

Bone marrow metastases from glioblastoma multiforme--A case report and review of the literature.

Clinically detected extra-cranial metastases from glioblastoma multiforme (GBM) are quite rare, with an incidence of <2% reported in the published literature. Among the various reported sites of systemic metastases from GBM, there are few cases of clinically symptomatic bone marrow metastasis. The case of a patient developing systemic dissemination of a GBM is described. A 60-year-old man with GBM who developed back pain, thrombocytopenia and subsequently neurological deficits was found to have extensive bony and bone marrow metastases. Previously reported cases of extra-cranial systemic spread of GBM and attempts made in the literature to explain the possible routes of extra-neural dissemination are reviewed.

Bone Marrow Neoplasms↗

PubMed2004

Immunity to the extracellular domain of Nogo-A modulates experimental autoimmune encephalomyelitis.

Nogo-66, the extracellular 66 aa loop of the Nogo-A protein found in CNS myelin, interacts with the Nogo receptor and has been proposed to mediate inhibition of axonal regrowth. It has been shown that immunization with Nogo-A promotes recovery in animal models of spinal cord injury through induction of Ab production. In this report, studies were performed to characterize the immune response to Nogo-66 and to determine the role of Nogo in experimental autoimmune encephalomyelitis (EAE). Immunization of EAE-susceptible mouse strains with peptides derived from Nogo-66 induced a CNS immune response with clinical and pathological similarities to EAE. The Nogo-66 peptides elicited strong T cell responses that were not cross-reactive to other encephalitogenic myelin Ags. Using a large scale spotted microarray containing proteins and peptides derived from a wide spectrum of myelin components, we demonstrated that Nogo-66 peptides also generated a specific Ab response that spreads to several other encephalitogenic myelin Ags following immunization. Nogo-66-specific T cell lines ameliorated established EAE, via Nogo-66-specific Th2 cells that entered the CNS. These results indicate that some T cell and B cell immune responses to Nogo-66 are associated with suppression of ongoing EAE, whereas other Nogo-66 epitopes can be encephalitogenic.

Adoptive Transfer↗

PubMed2003

An immunomodulatory GpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immune systems.

Bacterial DNA and immunostimulatory CpG oligodeoxynucleotides (ODNs) activate the innate immune system to produce proinflammatory cytokines. Shown to be potent Th1-like adjuvants, stimulatory CpG motifs are currently used as effective therapeutic vaccines for various animal models of infectious diseases, tumors, allergies, and autoimmune diseases. In this study, we show that the application of an immunomodulatory GpG ODN, with a single base switch from CpG to GpG, can effectively inhibit the activation of Th1 T cells associated with autoimmune disease. Moreover, this immunomodulatory GpG ODN suppresses the severity of experimental autoimmune encephalomyelitis in mice, a prototypic Th1-mediated animal disease model for multiple sclerosis.

Adjuvants, Immunologic↗

PubMed2003

Protein microarrays guide tolerizing DNA vaccine treatment of autoimmune encephalomyelitis.

The diversity of autoimmune responses poses a formidable challenge to the development of antigen-specific tolerizing therapy. We developed 'myelin proteome' microarrays to profile the evolution of autoantibody responses in experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). Increased diversity of autoantibody responses in acute EAE predicted a more severe clinical course. Chronic EAE was associated with previously undescribed extensive intra- and intermolecular epitope spreading of autoreactive B-cell responses. Array analysis of autoantigens targeted in acute EAE was used to guide the choice of autoantigen cDNAs to be incorporated into expression plasmids so as to generate tolerizing vaccines. Tolerizing DNA vaccines encoding a greater number of array-determined myelin targets proved superior in treating established EAE and reduced epitope spreading of autoreactive B-cell responses. Proteomic monitoring of autoantibody responses provides a useful approach to monitor autoimmune disease and to develop and tailor disease- and patient-specific tolerizing DNA vaccines.

Animals↗

PubMed2003

Multiple elements of the allergic arm of the immune response modulate autoimmune demyelination.

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.

Animals↗

PubMedDate not supplied

Antigen-specific therapies in multiple sclerosis: going beyond proteins and peptides.

Multiple sclerosis (MS) is a complex immune-mediated disease resulting largely from an autoimmune attack against components of central nervous system myelin, including several proteins and lipids. Knowledge about the details of this anomalous immune response has come mostly from studies in the animal model experimental autoimmune encephalomyelitis (EAE). In this model, it has been possible to prevent and effectively treat established disease through several antigen-specific therapeutic strategies, which have included administration of whole myelin or myelin proteins by various routes, random copolymers consisting of the main major histocompatability complex (MHC) and T-cell receptor (TCR) contact amino acid residues, altered peptide ligands of dominant myelin epitopes in which one or more residues are selectively substituted, and lately DNA vaccination encoding self-myelin antigens. However, there have been difficulties in making successful transitions from animal models to human clinical trials, due either to lack of efficacy or unforeseen complications. Despite these problems, antigen-specific therapies have retained their attraction for clinicians and scientists alike, and hopefully the upcoming generation of agents--including altered peptide ligands and DNA vaccines--will benefit from the increasing knowledge about this disease and surmount existing difficulties to make an impact in the treatment of multiple sclerosis.

Animals↗