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Amit Bar-Or

Publications and source records attributed to Amit Bar-Or.

29 records · Page 2Linked to original sources
PubMed2004

Inflammatory potential and migratory capacities across human brain endothelial cells of distinct glatiramer acetate-reactive T cells generated in treated multiple sclerosis patients.

We asked whether GA-reactive T cells with distinct cytokine profiles (Th2 versus Th1/Th0), induced during GA therapy of multiple sclerosis (MS) patients, have different migratory capacities across human brain endothelial cells (HBECs), and distinct effects on inflammatory responses at the level of the blood-brain barrier (BBB). We confirmed that GA therapy induces a range of GA-reactive T cells defined by distinct profiles of cytokine expression. Supernatants from Th0/Th1 GA-reactive cells significantly upregulated pro-inflammatory chemokine and adhesion molecule expression in HBECs. Post-treatment Th2-polarized GA-reactive cells were significantly less pro-inflammatory but did not suppress the effects induced by Th1 cells. All lines migrated across a HBEC/fibronectin-based model of the BBB with similar efficiencies. We conclude that the spectrum of GA-reactive T cells induced in treated MS patients may differentially impact inflammatory responses at the BBB level. Future studies will determine whether this could contribute to variable clinical response to GA therapy.

Adult↗
PubMed2003

Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis.

Matrix metalloproteinases (MMPs) are implicated in multiple sclerosis where one of their roles may be to facilitate the transmigration of circulating leukocytes into the CNS. Studies have focused on only a few MMPs, and much remains unknown of which of the 23 MMP family members is/are critical to the multiple sclerosis disease process. Using quantitative real time polymerase chain reactions, we have systematically analysed the expression of all 23 MMP members in subsets of leukocytes isolated from the blood of normal individuals. We found a distinctive pattern of MMP expression in different cellular populations: MMP-11, MMP-26 and MMP-27 were enriched in B cells, while MMP-15, MMP-16, MMP-24 and MMP-28 were prominent in T lymphocytes. Of interest is the enrichment of a majority of MMP members in monocytes: MMP-1, MMP-3, MMP-9, MMP-10, MMP-14, MMP-19 and MMP-25. MMP-2 and MMP-17 were also significantly represented in monocytes, although B cells had significant amounts of these MMPs. In correspondence with their strong expression of many MMP members, monocytes migrated more rapidly across a model of the blood-brain barrier in culture than T or B lymphocytes. Finally, we found higher levels of two of the monocyte-expressed MMPs in multiple sclerosis patients compared with normal individuals: MMP-2 and MMP-14. Tissue inhibitor of metalloproteinases (TIMP)-2 was also elevated in monocytes from multiple sclerosis patients, providing a mechanism for the reported activation of MMP-2 by MMP-14 and TIMP-2. These results emphasize that monocytes are prominent contributors of the neuroinflammation in multiple sclerosis through a mechanism that involves their high MMP expression and that they identify specific MMP members as targets for novel therapeutics in the disease.

Adult↗
PubMed2003

Determinants of human B cell migration across brain endothelial cells.

Circulating B cells enter the CNS as part of normal immune surveillance and in pathologic states, including the common and disabling illness multiple sclerosis. However, little is known about the molecular mechanisms that mediate human B cell interaction with the specialized brain endothelial cells comprising the blood-brain barrier (BBB). We studied the molecular mechanisms that regulate the migration of normal human B cells purified ex vivo, across human adult brain-derived endothelial cells (HBECs). We found that B cells migrated across HBECs more efficiently than T cells from the same individuals. B cell migration was significantly inhibited by blocking Abs to the adhesion molecules ICAM-1 and VLA-4, but not VCAM-1, similar to the results previously reported for T cells. Blockade of the chemokines monocyte chemoattractant protein-1 and IL-8, but not RANTES or IFN-gamma-inducible protein-10, significantly inhibited B cell migration, and these results were correlated with the chemokine receptor expression of B cells measured by flow cytometry and by RNase protection assay. Tissue inhibitor of metalloproteinase-1, a natural inhibitor of matrix metalloproteinases, significantly decreased B cell migration across the HBECs. A comprehensive RT-PCR comparative analysis of all known matrix metalloproteinases and tissue inhibitors of metalloproteinases in human B and T cells revealed distinct profiles of expression of these molecules in the different cell subsets. Our results provide insights into the molecular mechanisms that underlie human B cell migration across the BBB. Furthermore, they identify potential common, and unique, therapeutic targets for limiting CNS B cell infiltration and predict how therapies currently developed to target T cell migration, such as anti-VLA-4 Abs, may impact on B cell trafficking.

Adult↗
PubMed2003

Differential effects of Th1 and Th2 lymphocyte supernatants on human microglia.

We assessed the effects of soluble molecules (supernatants) produced by pro- (Th1) and anti- (Th2) inflammatory T-cell lines on the capacity of adult human CNS-derived microglia to express or produce selected cell surface and soluble molecules that regulate immune reactivity or impact on tissue protection/repair within the CNS. Treatment of microglia with supernatants from allo-antigen and myelin basic protein-specific Th1 cell lines augmented expression of cell surface molecules MHC class II, CD80, CD86, CD40, and CD54, enhanced the functional antigen-presenting cell capacity of microglia in a mixed lymphocyte reaction, and increased cytokine/chemokine secretion (TNFalpha, IL-6, and CXCL10/IP-10). These Th1-induced effects were not reproduced by interferon-gamma (IFNgamma) alone and were only incompletely blocked by anti-IFNgamma antibody. Th2 cell supernatant treatments did not alter costimulatory/adhesion molecule expression or induce cytokine/chemokine production by microglia. Th2 treatment, furthermore, failed to reduce the induction observed in response to Th1 supernatants. Neither Th1 nor Th2 supernatants induced production of the neurotrophin molecules, nerve growth factor, or brain-derived neurotrophic factor. Our results suggest that soluble molecules released by Th1 and not Th2 cells that infiltrate the CNS can stimulate resident microglia to acquire enhanced effector and accessory cell functions; the Th1-induced effects were not downregulated by Th2 supernatant-mediated bystander suppression.

Cell-Free System↗
PubMed2003

Myelin basic protein-reactive autoantibodies in the serum and cerebrospinal fluid of multiple sclerosis patients are characterized by low-affinity interactions.

The presence of autoantibodies to the immunodominant antigen, myelin basic protein (MBP), in the serum and cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) has been poorly characterized. Many studies report detectable levels of autoantibodies to myelin basic protein though other studies, using similar techniques, report their absence. We compared a solution-phase assay that has detected clinically relevant autoantibodies in diabetes and other autoimmune diseases to solid phase assays similar to those used in previous reports. The solution-phase assay consistently measured autoantibodies to MBP in serum from human subjects with Semple rabies vaccine (SRV)-induced demyelinating disease and from MBP-immunized animals. A solid phase assay detected MBP autoantibodies in the serum of a fraction of patients with MS. Autoantibodies capable of binding to MBP in the solution-phase were not detected in the CSF or serum of patients with MS. Additional solution-phase measurements revealed that anti-MBP antibodies from individuals with SRV-induced demyelinating disease demonstrated a binding affinity profile consistent with that of polyclonal antibodies with a range of affinities from low to high. In contrast, antibodies to MBP in the serum of MS patients detected by ELISA did not bind soluble MBP in the same assay. These results indicate that the humoral response in patients with MS does not include moderate- or high-affinity autoantibodies to MBP.

Antibody Affinity↗
PubMed2003

CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, thought to be mediated in part by an autoimmune response of T cells to protein components of the myelin sheath. The reaction of naïve T cells against these antigens requires co-stimulation through CD28. However, the proliferative response of peripheral blood mononuclear cells isolated from patients with MS and stimulated with myelin basic protein (MBP) has been shown to be relatively independent of B7-CD28 co-stimulation, suggesting that dysregulation of co-stimulatory pathways may be involved in the pathogenesis of MS. Here, the role of CTLA-4 engagement was investigated. As expected, blocking CTLA-4-mediated signaling during stimulation of MBP-reactive T cells from healthy controls enhanced the proliferative and cytokine responses. In contrast, CTLA-4 blockade had less effect in patients with MS, suggesting that at least two regulatory mechanisms may be impaired in these individuals. Understanding how co-stimulatory signals may be dysregulated in patients with MS is important at a time when targeting of these pathways is being developed.

Adult↗
PubMed2003

Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease.

Alzheimer disease (AD) is characterized by the progressive deposition of the 42-residue amyloid beta protein (Abeta) in brain regions serving memory and cognition. In animal models of AD, immunization with Abeta results in the clearance of Abeta deposits from the brain. However, a trial of vaccination with synthetic human Abeta1-42 in AD resulted in the development of meningoencephalitis in some patients. We measured cellular immune responses to Abeta in middle-aged and elderly healthy subjects and in patients with AD. A significantly higher proportion of healthy elderly subjects and patients with AD had strong Abeta-reactive T cell responses than occurred in middle-aged adults. The immunodominant Abeta epitopes in humans resided in amino acids 16-33. Epitope mapping enabled the identification of MHC/T cell receptor (TCR) contact residues. The occurrence of intrinsic T cell reactivity to the self-antigen Abeta in humans has implications for the design of Abeta vaccines, may itself be linked to AD susceptibility and course, and appears to be associated with the aging process.

Adult↗
PubMed2003

Patient and community preferences for treatments and health states in multiple sclerosis.

OBJECTIVE: To examine preferences for treatments and health states for patients with relapsing-remitting MS and members of the community. METHODS: A survey was developed to evaluate health-related quality-of-life measures (utilities) for three treatments and six MS health states using a utility-elicitation software package, U-Titer II. Sixty-two MS patients at two large teaching hospitals in Boston, MA, and 67 members of the general community in San Diego, CA, completed the health-related quality-of-life survey using a computer. RESULTS: Assessment of quality of life decreased as disability level of MS health states increased for both respondent groups. Respondents rated less-disabled health states relatively highly (> 0.94 for patients and > 0.89 for community respondents). Quality-of-life measures for treatments in mean utilities ranged from 0.80 to 0.96. Patients assigned higher utilities for both MS health states and treatment states than community respondents; the ratings became more disparate as health states worsened. CONCLUSIONS: On average, respondents assigned utilities to currently available treatments for MS that are comparable to those of mild to moderate stages of the disease itself. These results underscore the importance of including preferences for health states and treatment alternatives in the decision to initiate treatment for individual patients or in the evaluation of effectiveness or cost-effectiveness of these treatments in patients with MS.

Adult↗
PubMedDate not supplied

Cost-effectiveness of interferon beta-1a, interferon beta-1b, and glatiramer acetate in newly diagnosed non-primary progressive multiple sclerosis.

OBJECTIVE: To perform a cost-effectiveness analysis of three immunomodulatory treatments for newly diagnosed nonprimary progressive MS: interferon beta-1a, interferon beta-1b, and glatiramer acetate. METHODS: We developed a state-transition model to estimate the health effects and costs associated with interferon beta-1a, interferon beta-1b, glatiramer acetate, and no treatment for hypothetical cohorts of men and women with non-primary progressive MS. We used the Expanded Disability Status Scale as the measure of disability and included both relapses and disease progression in the model. We evaluated treatment strategies assuming a 10-year treatment duration using the societal perspective. We elicited preferences for disability and treatment states using standard-gamble questions and modeled the disutility associated with treatment administration and side effects explicitly. Main outcome measures were net gains in quality-adjusted life expectancy and incremental cost-effectiveness ratios in dollars per quality-adjusted life year (QALY) gained. RESULTS: For treatment duration of 10 years for newly diagnosed non-primary progressive MS, interferon beta-1a yielded the largest gain in quality-adjusted life expectancy with an incremental cost-effectiveness ratio of $2,200,000/QALY for women and $1,800,000/QALY for men, compared with no treatment. For a 5-year treatment duration, a "no treatment" strategy yielded more quality-adjusted life years than any of the treatment strategies. Cost-effectiveness ratios were similar for all three immunomodulatory treatments evaluated. CONCLUSIONS: Cost-effectiveness results for all three immunomodulatory treatments for MS were unfavorable in the simulated study population under a wide range of assumptions. For treatment duration less than or equal to 5 years, expected benefits of treatment may not outweigh disutility associated with side effects and treatment discomfort.

Adjuvants, Immunologic↗
PubMedDate not supplied

The relationship between risk attitude and treatment choice in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: Many patients with multiple sclerosis (MS) eligible for beta-interferons or glatiramer acetate have chosen to forgo or discontinue treatment The objective of this study was to evaluate risk attitude as a patient characteristic related to treatment choice for patients with MS. METHODS: Sixty-two MS patients completed a survey on treatment history, risk preference, and socioeconomic and clinical variables. Multinomial logistic regression was used to assess the relationship between treatment choice and risk attitude. Risk attitude was measured using a standard gamble question on short-term health outcomes. RESULTS: More risk-seeking patients were less likely to choose treatment compared with more risk-averse patients (P < 0.01). Forpatients who discontinued treatment, the explanatory variable of significance was severity of side effects (P < 0.05). CONCLUSIONS: Risk attitude is a patient characteristic related to treatment initiation in patients with MS. This could be an important factor to consider when identifying optimal treatment decisions for individual patients.

Adjuvants, Immunologic↗