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Jack Antel

Publications and source records attributed to Jack Antel.

9 recordsLinked to original sources
PubMed2006

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

BACKGROUND: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis. METHODS: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses. RESULTS: A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second. CONCLUSIONS: In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].).

Adolescent↗
PubMed2006

Roles of immunoglobulins and B cells in multiple sclerosis: from pathogenesis to treatment.

Immunoglobulins (Igs) have long been implicated in contributing to the disease course of multiple sclerosis (MS). The earliest and perhaps still most consistent abnormal immunologic laboratory finding in MS is the increased concentration of Ig in the CSF, representing intrathecal antibody synthesis. Analysis of CSF Ig in terms of rate of production and restricted diversity (oligoclonal bands) remains a supportive diagnostic criteria for MS. Despite large-scale studies such as the analysis of 1000 cases reported by Ebers and Paty [Ebers, G.C., Paty, D.W., 1980. CSF electrophoresis in one thousand patients. Can. J. Neurol. Sci. 7 (4) 275-280], the challenge of correlating CSF Ig profiles and specific disease phenotypes remains. More recently, evidence from animal models and several human studies suggests that antibody-independent functions of B cells may also be implicated in the pathogenesis of MS. This presentation considers what roles Ig and/or B cells can play in mediating or regulating disease-relevant immune responses in MS. A timely corollary is whether B cell/Ig-directed therapeutic strategies can be effective in MS.

Animals↗
PubMed2005

Oligodendrocyte/myelin injury and repair as a function of the central nervous system environment.

Multiple sclerosis is a chronic neurologic disorder considered to result from relatively selective immune mediated injury of central nervous system (CNS) myelin and/or its cell of origin, the oligodendrocyte (OGC). Constituents of both the innate and adaptive immune systems are potential contributors to this process. Endogenous (microglia) and infiltrating (macrophages, dendritic cells) constituents of the innate immune system serve as sensors of events occurring within the CNS; their response to such events underlies the extent of their interaction (chemoattraction, antigen presentation) with the components of the adaptive immune system (alphabeta T cells, B cells) and ultimately the extent of the resultant inflammatory response. Constituents of both the innate and adaptive immune system can serve as effectors of tissue injury. The susceptibility of specific types of neural cells to injury further reflects the extent to which immune mediators modulate expression of crucial molecules (adhesion molecules, receptors) involved in effector-target interactions. Ongoing interactions between the constituents of the immune system themselves and between these constituents and neural cells are important determinants of disease recurrence and/or progression. Conversely, these interactions also impact on the mechanisms involved in target protection and repair.

Central Nervous System↗
PubMed2005

Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity.

HLA-G is a non-classical major histocompatibility complex (MHC) class I antigen with highly limited tissue distribution under non-pathological conditions. Although capable of acting as a peptide-presenting molecule, its strong immune-inhibitory properties identify HLA-G as a mediator of immune tolerance with specific relevance at immune-privileged sites such as trophoblast or thymus. To assess the role of HLA-G in CNS immunity, we investigated its expression in brain specimens from patients with multiple sclerosis (n = 11), meningitis (n = 2) and Alzheimer's disease (n = 2) and non-pathological CNS controls (n = 6). Furthermore, cultured human microglial cells and CSF of patients with multiple sclerosis and controls were assessed. Furthermore, CSF from MS patients and controls, as well as cultured human microglial cells were assessed. Using several HLA-G specific mAb and immunohistochemistry, HLA-G protein was found strongly expressed in brain specimens from patients with multiple sclerosis while it was rarely detectable in the non-pathological control specimens. In multiple sclerosis brain specimens, HLA-G immunoreactivity was observed in acute plaques, in chronic active plaques, in perilesional areas as well as in normal appearing white matter. In all areas microglial cells, macrophages, and in part endothelial cells were identified as the primary cellular source of expression. HLA-G was also found in other disease entities (meningitis, Alzheimer's specimens) where expression correlated to activation and MHC class II expression on microglial cells. Importantly, ILT2, a receptor for HLA-G, was also found in multiple sclerosis brain specimens thus emphasizing the relevance of this inhibitory pathway in vivo. HLA-G mRNA and protein expression and regulation could also be corroborated on cultured human microglial cells in vitro. Further, expression of HLA-G in the CSF of multiple sclerosis patients and controls was analysed by flow cytometry and ELISA. Monocytes represented the main source of cellular HLA-G expression in the CSF. Corresponding to the observations with the tissue specimens, CSF mean levels of soluble HLA-G were significantly higher in multiple sclerosis than in non-inflammatory controls (171 +/- 31 versus 39 +/- 10 U/ml; P = 0.0001). The demonstration of HLA-G and its receptor ILT2 on CNS cells and in areas of microglia activation implicate HLA-G as a contributor to the fundamental mechanisms regulating immune reactivity in the CNS. This pathway may act as an inhibitory feedback aimed to downregulate the deleterious effects of T-cell infiltration in neuroinflammation.

Adult↗
PubMed2005

Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS.

Inflammation of the CNS is usually locally limited to avoid devastating consequences. Critical players involved in this immune regulatory process are the resident immune cells of the brain, the microglia. Interactions between the growing family of B7 costimulatory ligands and their receptors are increasingly recognized as important pathways for costimulation and/or inhibition of immune responses. Human and mouse microglial cells constitutively express B7 homolog 1 (B7-H1) in vitro. However, under inflammatory conditions [presence of interferon-gamma (IFN-gamma) or T-helper 1 supernatants], a significant upregulation of B7-H1 was detectable. Expression levels of B7-H1 protein on microglial cells were substantially higher compared with astrocytes or splenocytes. Coculture experiments of major histocompatibility complex class II-positive antigen-presenting cells (APC) with syngeneic T cells in the presence of antigen demonstrated the functional consequences of B7-H1 expression on T-cell activation. In the presence of a neutralizing anti-B7-H1 antibody, both the production of inflammatory cytokines (IFN-gamma and interleukin-2) and the upregulation of activation markers (inducible costimulatory signal) by T cells were markedly enhanced. Interestingly, this effect was clearly more pronounced when microglial cells were used as APC, compared with astrocytes or splenocytes. Furthermore, B7-H1 was highly upregulated during the course of myelin oligodendrocyte glycoprotein-induced and proteolipid protein-induced experimental allergic encephalomyelitis in vivo. Expression was predominantly localized to areas of strongest inflammation and could be colocalized with microglial cells/macrophages as well as T cells. Together, our data propose microglial B7-H1 as an important immune inhibitory molecule capable of downregulating T-cell activation in the CNS and thus confining immunopathological damage.

Animals↗
PubMed2005

Pathogenesis of multiple sclerosis.

PURPOSE OF REVIEW: The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of multiple sclerosis. RECENT FINDINGS: A current debate is where and what initiates the neuroinflammatory reaction that characterizes the acute multiple sclerosis lesion. Immune sensitization to neural antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly viral derived, peptides (molecular mimicry). Although CD4 T cells are considered central to initiating central nervous system inflammation, the actual extent and specificity of tissue injury reflects the array of adaptive (CD8 T cells and antibody) and innate (microglia/macrophages) immune constituents present in the lesions. Neuropathologic studies indicate that lethal changes in neural cells (oligodendrocytes) could also be the initiating event, reflecting as yet unidentified acquired insults (e.g. exogenous virus or reactivated endogenous retrovirus) or intrinsic abnormalities ('neurodegenerative' hypothesis). Recurrence or persistence of the disease process can reflect events occurring at multiple sites including expansion of the immune repertoire in response to neural antigens transported to regional lymph nodes (determinant spreading), especially if immune regulatory mechanisms are defective; alterations in blood-brain barrier properties consequent to initial cellular transmigration; and participation of endogenous (microglia, astrocytes) or long lived infiltrating cells (macrophages, B cells in ectopic germinal centers) in regulating and effecting immune functions within the central nervous system. Accumulating neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (trophic support and clearance of tissue debris) impacted by inflammatory processes. SUMMARY: Understanding the full spectrum of multiple sclerosis presents a continuing challenge for both immunology and neurobiology.

Animals↗
PubMed2003

Oligodendrocyte injury in multiple sclerosis: a role for p53.

Multiple sclerosis (MS) is a neurological disorder characterized by myelin destruction and a variable degree of oligodendrocyte death. We have previously shown that overexpression of the transcription factor p53 can induce oligodendrocyte apoptosis. We investigated the mechanism of p53-induced apoptosis using primary cultures of central nervous system-derived adult human oligodendrocytes. Adenovirus-mediated p53 overexpression resulted in up-regulation of the death receptors Fas, DR4 and DR5 with subsequent caspase-mediated apoptosis of the oligodendrocytes. The oligodendrocytes were protected from p53-induced cell death by blocking signaling through Fas and/or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors. Although lower levels of p53 did not induce apoptosis, the increase in death receptor expression was sufficient to render the oligodendrocytes susceptible to apoptosis in the presence of exogenous Fas ligand and TRAIL. These ligands are present in the inflammatory milieu of active MS lesions. In situ analysis of active MS lesions revealed increased p53 expression in oligodendrocytes in lesions that featured oligodendrocyte apoptosis and cell loss. Our data provide evidence for a novel role for p53 in the pathogenesis of MS.

Adenoviridae↗
PubMed2002

Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes.

Tumors of glial origin such as glioblastoma multiforme (GBM) comprise the majority of human brain tumors. Patients with GBM have a very poor survival rate, with an average life expectancy of <1 year. We asked whether we could identify a survival pathway in high-grade glioma and oligodendroglioma cells that when suppressed, would induce apoptosis of these tumor cells but not of normal human adult astrocytes. To identify these pathways, we selectively suppressed the activity of a number of proteins (Ras, Rac1, Akt1, RhoA, c-jun, and MEK1/2) hypothesized to play roles in cell survival. We found that suppression of Rac1, a small GTP-binding protein, inhibited survival and produced apoptosis in three human glioma cell lines (U87, U343, and U373). Serum induced the activity of Rac1 and the activity or phosphorylation state of p21-activated kinase 1 and c-Jun NH(2)-terminal kinase (JNK), two intracellular targets of Rac1. Suppression of Rac1 also induced apoptosis in 19 of 21 short-term cultures of human primary cells from grades II and III oligodendroglioma and grade IV glioblastoma that varied in p53, epidermal growth factor receptor, epidermal growth factor receptor vIII, MDM2, and p16/p19 mutational or amplification status. In contrast, inhibition of Rac1 activity did not induce apoptosis of normal primary human adult astrocytes. In both established glioma cell lines and primary glioma cells, apoptosis induced by the inhibition of Rac was partially rescued by activated mitogen-activated protein kinase kinase 1, an activator of JNK, suggesting that JNK functions downstream of Rac1 in glioma cells. These results indicate that Rac1 regulates a major survival pathway in most glioma cells, and that suppression of Rac1 activity stimulates the death of virtually all glioma cells, regardless of their mutational status. Agents that suppress Rac1 activity may therefore be useful therapeutic treatments for malignant gliomas.

Adenoviridae↗