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J Antel

Publications and source records attributed to J Antel.

At least 19 recordsLinked to original sources
PubMed2006

Proinflammatory cytokine gene induction by human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 Tax in primary human glial cells.

Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a chronic inflammatory disease of the central nervous system (CNS). HTLV-2 is highly related to HTLV-1 at the genetic level and shares a high degree of sequence homology, but infection with HTLV-2 is relatively nonpathogenic compared to HTLV-1. Although the pathogenesis of HAM/TSP remains to be fully elucidated, previous evidence suggests that elevated levels of the proinflammatory cytokines in the CNS are associated with neuropathogenesis. We demonstrate that HTLV-1 infection in astrogliomas results in a robust induction of interleukin-1beta (IL-1beta), IL-1alpha, tumor necrosis factor alpha (TNF-alpha), TNF-beta, and IL-6 expression. HTLV encodes for a viral transcriptional transactivator protein named Tax that also induces the transcription of cellular genes. To investigate and compare the effects of Tax1 and Tax2 expression on the dysregulation of proinflammatory cytokines, lentivirus vectors were used to transduce primary human astrocytomas and oligodendrogliomas. The expression of Tax1 in primary human astrocytomas and oligodendrogliomas resulted in significantly higher levels of proinflammatory cytokine gene expression compared to Tax2. Notably, Tax1 expression uniquely sensitized primary human astrocytomas to apoptosis. A Tax2/Tax1 chimera encoding the C-terminal 53 amino acids of the Tax1 fused to the Tax2 gene (Tax(221)) demonstrated a phenotype that resembled Tax1, with respect to proinflammatory cytokine gene expression and sensitization to apoptosis. The patterns of differential cytokine induction and sensitization to apoptosis displayed by Tax1 and Tax2 may reflect differences relating to the heightened neuropathogenicity associated with HTLV-1 infection and the development of HAM/TSP.

Apoptosis↗
PubMed2006

No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation.

The underlying mechanisms of antipsychotic (AP)-induced weight gain are unknown, but both central and peripheral AP target receptors could potentially be involved. This study used radioligand binding assays to compare the binding affinities of clozapine, olanzapine and haloperidol for candidate receptors potentially involved in AP-induced weight gain. Selected candidates derived from known pathways involved in body weight regulation included receptors classified as anorexigenic (bombesin receptor subtype 3, calcitonin gene-related peptide receptor, cholecystokinin receptor, melanocortin-4 receptor, neurotensin receptor 1) or orexigenic (cannabinoid receptor 1, galanin 1 receptor, melanin-concentrating hormone receptor (MCHR), neuropeptide Y1 receptor) as well as receptors involved in physiological actions related to digestion and fluid homeostasis (angiotensin II type 1 receptor, bradykinin B2 receptor, endothelin receptor, neurokinin 1 receptor, vasoactive intestinal polypeptide receptor 1). Clozapine, olanzapine and haloperidol exhibited negligible affinities to all of these receptors except for the MCHR (Ki=501 nM; haloperidol). With respect to other candidates from (neuro)transmitter systems already suggested to be involved in AP-induced weight gain, the binding profile of olanzapine resembled that of clozapine, with high affinity (Ki<10 nM) for serotonin (5-HT) 5-HT2A, 5-HT2C and 5-HT6, muscarinic M1 and histamine H1 receptors. In contrast, the binding profile of haloperidol was substantially different (high affinity only for the dopamine D1 receptor). In conclusion, we have not identified a novel binding site of the two investigated atypical AP that could contribute to the induced weight gain.

Animals↗
PubMed2006

Altered naive CD4 and CD8 T cell homeostasis in patients with relapsing-remitting multiple sclerosis: thymic versus peripheral (non-thymic) mechanisms.

We have reported previously that naive T cells from relapsing-remitting multiple sclerosis (RRMS) patients have T cell receptor (TCR) repertoire shifts, but the basis of these TCR repertoire shifts was uncertain. Here, we questioned whether RRMS patients have altered naive CD4 and CD8 T cell homeostasis by studying homeostatic proliferation and thymic production in RRMS patients and healthy controls. We measured thymic production by quantifying signal joint T cell receptor excision circles (sjTRECs). Both naive T subsets from controls showed an age-associated decrease in sjTRECs, i.e. evidence of progressive thymic involution, but we detected no age-associated decrease in sjTRECs in RRMS patients. Instead, naive CD8 T cells from patients had lower sjTRECs (P = 0.012) and higher Ki-67 proliferation levels (P = 0.04) than controls. Naive CD4 T cell sjTRECs did not differ between patients and controls. However, in RRMS these sjTRECs correlated strongly with CD31, a marker expressed by newly generated CD4 T cells but not by naive CD4 T cells that have undergone homeostatic proliferation. HLA-DR2 positivity correlated negatively with naive CD4 T cell CD31 expression in RRMS (P = 0.002). We conclude in RRMS that naive T subsets have homeostatic abnormalities due probably to peripheral (non-thymic) mechanisms. These abnormalities could have relevance for MS pathogenesis, as naive T cell changes may precede MS onset.

CD4-Positive T-Lymphocytes↗
PubMed2002

The role of MRI as a surrogate outcome measure in multiple sclerosis.

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.

Central Nervous System↗
PubMed2001

NG2 immunoreactivity on human brain endothelial cells.

In this study, we evaluated the expression of NG2 on human brain endothelial cells derived from temporal lobe tissue resected as a treatment for intractable epilepsy. Using dissociated cell cultures, we found expression of NG2 on both proliferating and non-proliferating cells, at the mRNA level by reverse transcription-polymerase chain reaction analyses, and at the protein level by immunocytochemistry and immunoblotting. We further observed that human cerebral microvessels in nonmalignant CNS tissues immunoreacted with NG2. NG2 protein was detected using both a rabbit antibody raised against the rodent NG2 and a monoclonal antibody raised against the human NG2 (9.2.27). Our findings further define the range of resident cells of the CNS that can express NG2 and indicate that expression of NG2 by endothelial cells is not restricted to proliferating CNS endothelial cells or to endothelial cells found in brain tumors.

Adult↗
PubMed2001

Genetic models for CNS inflammation.

The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on the autoimmune disease multiple sclerosis, as well as conditions in which an inflammatory response makes a secondary contribution to tissue injury or repair, such as neurodegeneration, ischemia and trauma.

Animals↗
PubMed2000

HTLV type 1 Tax transduction in microglial cells and astrocytes by lentiviral vectors.

Infection with human T cell leukemia virus type 1 (HTLV-1) can result in the development of HAM/TSP, a nonfatal, chronic inflammatory disease involving neuronal degeneration and demyelination of the central nervous system. Elevated levels of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 observed in the cerebrospinal fluid of HAM-TSP patients suggest that cytokine dysregulation within the CNS is involved in neuropathogenesis. HTLV-1 infection and enhanced expression of TNF-alpha by microglial cells, astrocytes, and macrophages has been hypothesized to lead to the destruction of myelin and oligodendrocytes in the CNS. Although the association of HTLV-2 infection and development of neurological disease is more tenuous, HTLV-2 has also been found to be associated with peripheral neuropathies. To investigate the roles of HTLV Tax(1) and Tax(2) in the induction of cytokine disregulation in these cell types, we are currently developing gene delivery vectors based on human immunodeficiency virus type-1 (HIV-1) capable of stably coexpressing the HTLV-1 or -2 tax and eGFP reporter genes in primary human cells. Transduction frequencies of up to 50%, as assessed by eGFP expression, can be achieved in human monocyte-derived macrophages and in explanted cultures of human microglia. Preliminary data suggest that Tax(1) expression is sufficient to up-regulate the proinflammatory cytokine profile in explanted human microglial cells. Future experiments will compare and evaluate the effect of tax(1) and tax(2) gene expression on the cellular proinflammatory cytokine expression profile, as well as demonstrate the effects of transducing human fetal astrocytes and PBMC-derived macrophages.

Astrocytes↗
PubMed2000

Characterization of T cell lines derived from glatiramer-acetate-treated multiple sclerosis patients.

We analyzed the effects of glatiramer acetate (GA) therapy on in vitro proliferative responses and cytokine production by lymphocytes derived from multiple sclerosis patients receiving this therapy. We confirmed that lymphocytes derived from GA naïve patients show a high frequency of response when initially exposed to GA in vitro; this frequency decreased following GA therapy. The frequency of lymphocytes responding to whole MBP stimulation did not change with GA therapy. GA- and MBP-specific T cell lines generated from these patients by repeated cycles of in vitro stimulation did not cross react. Some (23%) whole MBP-reactive T cell lines did cross react with MBP peptide 83-99. The mean levels of interferon (IFN) gamma secretion and the mean ratio of IFN-gamma/IL-5 were lower for GA-reactive cell lines, derived from patients both prior to and during GA therapy, compared to MBP-reactive T cell lines. The proportion of IFN-gamma(+) cells in unfractionated lymphocyte preparations derived from the GA-treated patients did not differ from that found for healthy controls. Our findings indicate that GA-reactive T cell lines derived from GA-treated MS patients continue to show a relative Th2 cytokine bias consistent with a bystander suppressor function. GA treatment is not associated with a cytokine phenotype shift in the total T cell or MBP-reactive T cell populations.

Adult↗
PubMed2000

Relating axonal injury to functional recovery in MS.

A patient was followed after the new onset of hemiparesis from relapse of MS with serial MR spectroscopy and functional MRI. The association of clinical improvement with recovery of N-acetylaspartate, a marker of neuronal integrity, and progressive reduction of abnormally large functional MRI cortical activation with movement demonstrates that dynamic reorganization of the motor cortex accompanies remission of MS.

Adult↗
PubMed2000

Encephalitogenic potential of the myelin basic protein peptide (amino acids 83-99) in multiple sclerosis: results of a phase II clinical trial with an altered peptide ligand.

Myelin-specific T lymphocytes are considered essential in the pathogenesis of multiple sclerosis. The myelin basic protein peptide (a.a. 83-99) represents one candidate antigen; therefore, it was chosen to design an altered peptide ligand, CGP77116, for specific immunotherapy of multiple sclerosis. A magnetic resonance imaging-controlled phase II clinical trial with this altered peptide ligand documented that it was poorly tolerated at the dose tested, and the trial had therefore to be halted. Improvement or worsening of clinical or magnetic resonance imaging parameters could not be demonstrated in this small group of individuals because of the short treatment duration. Three patients developed exacerbations of multiple sclerosis, and in two this could be linked to altered peptide ligand treatment by immunological studies demonstrating the encephalitogenic potential of the myelin basic protein peptide (a.a. 83-99) in a subgroup of patients. These data raise important considerations for the use of specific immunotherapies in general.

Adolescent↗
PubMed2000

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo-controlled, randomized phase II trial. The Altered Peptide Ligand in Relapsing MS Study Group.

In this 'double-blind', randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing-remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Dose-Response Relationship, Drug↗
PubMed2000

Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis.

Axonal injury occurs even in the earliest stages of multiple sclerosis. Magnetic resonance spectroscopic imaging (MRSI) measurements of brain N:-acetylaspartate (NAA), a marker of axonal integrity, show that this axonal injury can occur even in the absence of clinically evident functional impairments. To test whether cortical adaptive responses contribute to the maintenance of normal motor function in patients with multiple sclerosis, we performed MRSI and functional MRI (fMRI) examinations of nine multiple sclerosis patients who had unimpaired hand function. We found that activation of the ipsilateral sensorimotor cortex with simple hand movements was increased by a mean of fivefold relative to normal controls (n = 8) and that the extent of this increase was strongly correlated (sigma = -0.93, P = 0.001) with decreases in brain NAA. These results suggest that compensatory cortical adaptive responses may help to account for the limited relationship between conventional MRI measures of lesion burden and clinical measures of disability, and that therapies directed towards promoting cortical reorganization in response to brain injury could enhance recovery from relapses of multiple sclerosis.

Aspartic Acid↗
PubMed1999

Monitoring relapsing remitting MS patients.

The availability of safe and partially effective disease modifying therapies necessitates changes in how neurologists monitor patients with relapsing remitting multiple sclerosis (RRMS). Neurologists need to make the diagnosis of MS as soon as possible to be able to initiate therapy early in the course of disease. In deciding whom to treat, neurologists should consider information on disease activity and burden acquired from the neurologic history and examination and magnetic resonance imaging (MRI). Patients not on a disease modifying therapy should undergo yearly clinical assessments and periodic cerebral MRI to monitor for changes in disease activity. Patients on disease modifying therapy should undergo regular clinical assessments to monitor for side-effects and disease activity. Cerebral MRI scanning may also be useful in assessing patients on therapy, particularly when considering changes in therapy.

Brain↗
PubMed1999

Multiple sclerosis--emerging concepts of disease pathogenesis.

Multiple sclerosis has been recognized as a clinical pathologic entity for more than a century. The pioneering microscopic anatomic studies of Charcot illustrate the power of careful observations taking maximal advantage of available technology. Using carmine as 'a precious agent' to stain spinal cord hardened with dilute chromic acid, he described the characteristic myelin loss with relative but not absolute axonal preservation. This presentation summarizes how following the principle of careful application of emerging technologies to MS patients and their tissues, as described in this symposium, as the foundation for our continuing advances regarding the etiology and pathogenesis of MS.

Humans↗
PubMed1998

Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis.

The cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients is characterized by increased concentrations of immunoglobulin (Ig), which on electrophoretic analysis shows restricted heterogeneity (oligoclonal bands). CSF Ig is composed of both serum and intrathecally produced components. To examine the properties of intrathecal antibody-producing B cells, we analyzed Ig heavy-chain variable (V(H)) region genes of B cells recovered from the CSF of 12 MS patients and 15 patients with other neurological diseases (OND). Using a PCR technique, we could detect rearrangements of Ig V(H) genes in all samples. Sequence analysis of complementarity-determining region 3 (CDR3) of rearranged VDJ genes revealed expansion of a dominant clone or clones in 10 of the 12 MS patients. B cell clonal expansion was identified in 3 of 15 OND. The nucleotide sequences of V(H) genes from clonally expanded CSF B cells in MS patients demonstrated the preferential usage of the V(H) IV family. There were numerous somatic mutations, mainly in the CDRs, with a high replacement-to-silent ratio; the mutations were distributed in a way suggesting that these B cells had been positively selected through their antigen receptor. Our results demonstrate that in MS CSF, there is a high frequency of clonally expanded B cells that have properties of postgerminal center memory or antibody-forming lymphocytes.

Adolescent↗