Biomedical subjects

Samia J Khoury

Publications and source records attributed to Samia J Khoury.

32 records · Page 2Linked to original sources

PubMed2004

Assessment by flow cytometry of intracellular cytokine production in the peripheral blood cells of renal transplant recipients.

INTRODUCTION: There is accumulating evidence that non-invasive immune monitoring may be useful in the early period after renal transplant, particularly with regard to predicting the presence of acute rejection. It is less clear whether chronic allograft nephropathy (CAN) is also associated with consistent changes in peripheral blood or urine cells. We hypothesized that patients with CAN would manifest different patterns of cytokine production (compared with non-CAN controls), detectable in peripheral blood mononuclear cells (PBMCs). METHODS: Flow cytometry was used to quantify production within PBMCs of multiple cytokines. RESULTS: A pilot study showed significant differences in cytokine production between healthy controls and transplanted subjects. However, differences between transplanted patients with and without CAN were small and non-significant. DISCUSSION: Flow cytometry is a potentially useful method for quantifying cytokine production by PBMCs of renal transplant recipients. The technique is sensitive enough to detect differences between distinct test groups but could not find differences between recipients with and without CAN. This probably reflects the lack of a true difference because pathological changes within the long-term allograft may simply not be reflected or detected in the total population of PBMCs. Further studies should explore the usefulness of this technique in assaying more defined populations of PBMCs (such as those activated by donor allopeptides) and in serial monitoring of individual patients.

Adult↗

PubMed2004

Magnetic resonance imaging surrogates of multiple sclerosis pathology and their relationship to central nervous system atrophy.

This article focuses on the various magnetic resonance imaging metrics currently used in multiple sclerosis and discusses how they relate to central nervous system atrophy. The authors discuss the significance of T2 lesion burden, gray matter damage, T1 hypointense lesions (black holes), contrast-enhanced lesions, magnetization transfer imaging, diffusion imaging, and magnetic resonance spectroscopy. These magnetic resonance imaging surrogates exhibit different sensitivities for each of the underlying pathogenic processes of multiple sclerosis. By exploiting the complementary nature and varying sensitivities of these magnetic resonance imaging surrogates, it is possible to create a more comprehensive picture of the degenerative process of multiple sclerosis.

Atrophy↗

PubMed2003

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.

Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS). ARFGEF2 encodes the large (>200 kDa) brefeldin A (BFA)-inhibited GEF2 protein (BIG2), which is required for vesicle and membrane trafficking from the trans-Golgi network (TGN). Inhibition of BIG2 by BFA, or by a dominant negative ARFGEF2 cDNA, decreases cell proliferation in vitro, suggesting a cell-autonomous regulation of neural expansion. Inhibition of BIG2 also disturbed the intracellular localization of such molecules as E-cadherin and beta-catenin by preventing their transport from the Golgi apparatus to the cell surface. Our findings show that vesicle trafficking is an important regulator of proliferation and migration during human cerebral cortical development.

ADP-Ribosylation Factors↗

PubMed2003

Genetic programs and responses of neural stem/progenitor cells during demyelination: potential insights into repair mechanisms in multiple sclerosis.

In recent years, it has become evident that the adult mammalian CNS contains a population of neural stem cells (NSCs) described as immature, undifferentiated, multipotent cells, that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells. This article reviews recent progress in elucidating the genetic programs and dynamics of NSC and OPC proliferation, differentiation, and apoptosis, including the response to demyelination. Emerging knowledge of the molecules that may be involved in such responses may help in the design of future stem cell-based treatment of demyelinating diseases such as multiple sclerosis.

Animals↗

PubMed2003

Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

Animals↗

PubMed2003

The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Animals↗

PubMed2003

Role of costimulatory pathways in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis.

Multiple sclerosis is an immune-mediated disorder of the central nervous system. T lymphocytes are thought to play a central role in the initiation and potentially in the propagation of this disease. Two signals are required for T-cell activation. The first signal consists of the interaction of the T-cell receptor with antigen presented by the MHC molecule on antigen-presenting cells. The second signal requires engagement of costimulatory receptors on T cells with their ligands on antigen-presenting cells. Several costimulatory pathways have been shown to play an important role in T-lymphocyte activation. Here we will review the current literature on the contribution of the B7-1/2-CD28/CTLA-4, inducible costimulatory molecule-B7h, programmed death pathway 1-programmed death pathway ligand 1/ligand 2, CD40-CD154, OX40-OX40 ligand, and CD137-CD137 ligand pathways to the pathogenesis of multiple sclerosis and their potential roles as therapeutic targets.

Animals↗

PubMed2003

20. Immunologic neuromuscular disorders.

Immune-mediated disorders of each of the structural subdivisions of the nervous and neuromuscular system have been described. Despite the immune privilege of the central nervous system, and to a lesser extent the peripheral nervous system, immune dysregulation is not uncommon. Environmental, genetic, and immunologic factors have been postulated to be involved in the development of these disorders. Major immune-mediated neurologic diseases of the central nervous system include multiple sclerosis and acute disseminated encephalomyelitis. Immune-mediated diseases of the peripheral nervous system include myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and inclusion body myositis. Some of these disorders, such as myasthenia gravis and certain forms of acute inflammatory demyelinating polyneuropathy, are clearly autoimmune in nature, whereas the immune system plays an important role in pathogenesis in others. Understanding the immune mechanisms of disease and uncovering potential therapeutic targets are essential for the design of new treatments. The epidemiology, pathogenesis, diagnostic criteria, and current therapeutic approaches to the major neuroimmunologic diseases are reviewed.

Humans↗

PubMed2003

Regulatory functions of CD8+CD28- T cells in an autoimmune disease model.

CD8+ T cell depletion renders CD28-deficient mice susceptible to experimental autoimmune encephalomyelitis (EAE). In addition, CD8-/-CD28-/- double-knockout mice are susceptible to EAE. These findings suggest a role for CD8+ T cells in the resistance of CD28-deficient mice to disease. Adoptive transfer of CD8+CD28- T cells into CD8-/- mice results in significant suppression of disease, while CD8+CD28+ T cells demonstrate no similar effect on the clinical course of EAE in the same recipients. In vitro, CD8+CD28- but not CD8+CD28+ T cells suppress IFN-gamma production of myelin oligodendrocyte glycoprotein-specific CD4+ T cells. This suppression requires cell-to-cell contact and is dependent on the presence of APCs. APCs cocultured with CD8+CD28- T cells become less efficient in inducing a T cell-dependent immune response. Such interaction prevents upregulation of costimulatory molecules by APCs, hence decreasing the delivery of these signals to CD4+ T cells. These are the first data establishing that regulatory CD8+CD28- T cells occur in normal mice and play a critical role in disease resistance in CD28-/- animals.

Amino Acid Sequence↗

PubMed2003

Cytokine shifts and tolerance in experimental autoimmune encephalomyelitis.

Cytokines play an important role in the pathogenesis of both multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Effective treatments for both diseases have been shown to alter cytokines in the central nervous system and in activated mononuclear cells. EAE is an animal model that mimics many aspects of multiple sclerosis, and has been widely used to study the mechanisms of disease and therapeutic approaches to multiple sclerosis. Cytokines play an important role in regulation of disease expression in EAE, and in tolerance to disease induction. In this review, we will summarize the current findings on the role of cytokine shifts in the induction of tolerance in EAE. In addition, we will discuss modulation of EAE by altered expression of members of the cytokineregulated Jak/STAT intracellular signaling pathway.

Animals↗

PubMed2003

T cell costimulatory pathways: blockade for autoimmunity.

The activation of T lymphocytes is thought to require at least two signals, one delivered by the T cell receptor (TCR) complex after antigen recognition, and one provided on engagement of costimulatory receptors. The B7-1/B7-2-CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4) and CD154-CD40 pathways have been shown to be crucial in regulating T cell activation and tolerance. Novel members of the B7-CD28 superfamily have recently been discovered and they seem to be particularly important for regulating the responses of previously activated T cells. Superimposition of inhibitory signals like those delivered by CTLA-4 and programmed death (PD)-1-PD-1-ligand (PD-L1) pathway leads to a complex network of positive and negative costimulatory signals, the integration of which modulates immune responses. Furthermore, expression of several B7 homologues on cells other than professional antigen-presenting cells (APCs), indicate new mechanisms for regulating T cell responses in peripheral tissues. This review focuses on our current understanding of the members of the B7-CD28 superfamily and discusses their therapeutic potential.

Animals↗

PubMed2002

IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions.

We investigated T cell receptor induced IL-18 secretion, the cellular and molecular mechanisms associated with the induction of IL-18 and the role of IL-18 in IFN-gamma production in the different stages of multiple sclerosis (MS). We found that anti-CD3/CD28 induced IL-18 production by peripheral blood mononuclear cells was increased in both relapsing-remitting and secondary progressive MS. In controls and relapsing-remitting MS neutralizing anti-IL-12 and anti-IL-18 alone equally suppressed IFN-gamma production whereas in progressive MS, maximum suppression of IFN-gamma was only observed when neutralizing anti-IL-12 and anti-IL-18 were given together, suggesting that in progressive MS, IL-12 and IL-18 function in a non-linked manner to induce IFN-gamma. Elevated IL-18 production in MS was dependent on the interaction of antigen presenting cells with activated CD4(+) T cells via CD40-CD40 ligand and the levels of IL-18 correlated with disease duration in secondary progressive MS. These results demonstrated that IL-18 has an important role in augmenting Th-1 type immune responses in MS and may be involved in immune changes that occur when patients enter the progressive stage.

Adult↗

PubMed2002

Interferon-beta treatment alters peripheral blood monocytes chemokine production in MS patients.

Chemokines direct the recruitment of leukocytes to inflammatory sites and may also participate in the regulation of cytokine production by naive T helper cells. Chemokine production by blood monocytes was investigated by intracytoplasmic staining in interferon-beta (IFN-beta)-treated multiple sclerosis (MS) patients, untreated MS patients, and healthy controls. Under unstimulated conditions, no differences in the production of interleukin-8 (IL-8), IFN-inducible protein 10 (IP-10), monokine induced by interferon-gamma (Mig), monocyte chemoattractant protein-1 (MCP-1), and monocyte chemoattractant protein-3 (MCP-3) were seen between untreated MS patients and controls. Chemokine production by monocytes following T cell activation was decreased in MS patients taking IFN-beta compared to controls and untreated MS patients. Unlike other chemokines, macrophage inflammatory protein-1alpha (MIP-1alpha) production by monocytes was significantly decreased in untreated MS patients compared to controls, and IFN-beta treatment increased MIP-1alpha expression to the level seen in controls. In vitro addition of IFN-beta1b to peripheral blood mononuclear cells (PBMC) cultures tended to decrease the production of IL-8, IP-10, Mig, MCP-1, and MCP-3, but not of MIP-1alpha. These findings suggest that IFN-beta treatment may have a differential affect on chemokine production by monocytes. Longitudinal studies must be done to confirm these observations.

Adjuvants, Immunologic↗

PubMed2002

Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol).

The beta2-adrenergic receptor agonist salbutamol (albuterol) has been used for many years in the treatment of bronchospasm in patients with asthma. In this patient group, salbutamol is a relatively safe and inexpensive drug, and is easy to administer. Within the last few years, there has been increasing evidence that salbutamol might have immunomodulatory properties both in vitro and in vivo, in different animal models as well as in humans. This has led researchers to consider salbutamol as a potential therapy for several autoimmune diseases, including multiple sclerosis (MS). In this article, we review the literature presenting such evidence, and discuss the possible mechanisms by which salbutamol influences the immune system. We conclude that salbutamol might be an interesting add-on therapy in patients with MS and that further research is warranted.

Adjuvants, Immunologic↗