Biomedical subjects

Samia J Khoury

Publications and source records attributed to Samia J Khoury.

At least 19 recordsLinked to original sources

PubMed2004

Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway.

Migration toward pathology is the first critical step in stem cell engagement during regeneration. Neural stem cells (NSCs) migrate through the parenchyma along nonstereotypical routes in a precise directed manner across great distances to injury sites in the CNS, where they might engage niches harboring local transiently expressed reparative signals. The molecular mechanisms for NSC mobilization have not been identified. Because NSCs seem to home similarly to pathologic sites derived from disparate etiologies, we hypothesized that the inflammatory response itself, a characteristic common to all, guides the behavior of potentially reparative cells. As proof of concept, we show that human NSCs migrate in vivo (including from the contralateral hemisphere) toward an infarcted area (a representative CNS injury), where local astrocytes and endothelium up-regulate the inflammatory chemoattractant stromal cell-derived factor 1alpha (SDF-1alpha). NSCs express CXC chemokine receptor 4 (CXCR4), the cognate receptor for SDF-1alpha. Exposure of SDF-1alpha to quiescent NSCs enhances proliferation, promotes chain migration and transmigration, and activates intracellular molecular pathways mediating engagement. CXCR4 blockade abrogates their pathology-directed chain migration, a developmentally relevant mode of tangential migration that, if recapitulated, could explain homing along nonstereotypical paths. Our data implicate SDF-1alpha/CXCR4, representative of the inflammatory milieu characterizing many pathologies, as a pathway that activates NSC molecular programs during injury and suggest that inflammation may be viewed not simply as playing an adverse role but also as providing stimuli that recruit cells with a regenerative homeostasis-promoting capacity. CXCR4 expression within germinal zones suggests that NSC homing after injury and migration during development may invoke similar mechanisms.

Animals↗

PubMed2004

Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II-IV of the cerebral cortex.

Little is known about how neurons in the different layers of the mammalian cerebral cortex are specified at the molecular level. Expression of two homologues of the Drosophila homeobox Cut gene, Cux-1 and Cux-2, is strikingly specific to the pyramidal neurons of the upper layers (II-IV) of the murine cortex, suggesting that they may define the molecular identity of these neurons. An antibody against Cux-1 labels the nucleus of most of the postmitotic upper layer neurons but does not label parvoalbumin-positive cortical interneurons that derive from the medial ganglionic eminence. Cux-1 and Cux-2 represent early markers of neuronal differentiation; both genes are expressed in postmitotic cortical neurons from embryonic stages to adulthood and in the proliferative regions of the developing cortex. In precursors cells, Cux-1 immunoreactivity is weak and diffuse in the cytoplasm and nucleus of ventricular zone (VZ) cells, whereas it is nuclear in the majority of bromodeoxyuridine (BrdU)-positive subventricular zone (SVZ) dividing cells, suggesting that Cux-1 function is first activated in SVZ cells. Cux-2 mRNA expression is also found in the embryonic SVZ, overlapping with BrdU-positive dividing precursors, but it is not expressed in the VZ. A null mutation in Pax-6 disrupts Cux-2 expression in the SVZ and Cux-1 and Cux-2 expression in the postmigratory cortical neurons. Thus, these data support the existence of an intermediate neuronal precursor in the SVZ dedicated to the generation of upper layer neurons, marked specifically by Cux-2. The patterns of expression of Cux genes suggest potential roles as determinants of the neuronal fate of the upper cortical layer neurons.

Animals↗

PubMed2004

Stem cells: cross-talk and developmental programs.

The thesis advanced in this essay is that stem cells-particularly those in the nervous system-are components in a series of inborn 'programs' that not only ensure normal development, but persist throughout life so as to maintain homeostasis in the face of perturbations-both small and great. These programs encode what has come to be called 'plasticity'. The stem cell is one of the repositories of this plasticity. This review examines the evidence that interaction between the neural stem cell (as a prototypical somatic stem cell) and the developing or injured brain is a dynamic, complex, ongoing reciprocal set of interactions where both entities are constantly in flux. We suggest that this interaction can be viewed almost from a 'systems biology' vantage point. We further advance the notion that clones of exogenous stem cells in transplantation paradigms may not only be viewed for their therapeutic potential, but also as biological tools for 'interrogating' the normal or abnormal central nervous system environment, indicating what salient cues (among the many present) are actually guiding the expression of these 'programs'; in other words, using the stem cell as a 'reporter cell'. Based on this type of analysis, we suggest some of the relevant molecular pathways responsible for this 'cross-talk' which, in turn, lead to proliferation, migration, cell genesis, trophic support, protection, guidance, detoxification, rescue, etc. This type of developmental insight, we propose, is required for the development of therapeutic strategies for neurodegenerative disease and other nervous system afflictions in humans. Understanding the relevant molecular pathways of stem cell repair phenotype should be a priority, in our view, for the entire stem cell field.

Brain↗

PubMed2004

Defining Th1 and Th2 immune responses in a reciprocal cytokine environment in vivo.

The ability of committed Th1 and Th2 cells to function in altered cytokine environments is a central issue in autoimmune and immune-mediated diseases. Therefore, it is of interest to study the ability of Th1 or Th2 cells to expand and produce cytokine reciprocal environments in vivo. Using STAT4- and STAT6-deficient mice, we studied the expansion and cytokine production of Ag-specific Th1 or Th2 cells after transfer into Th1, Th2, or wild-type recipients. Our data show that these Th1 or Th2 cells proliferated and clonally expanded normally, regardless of the in vivo cytokine environment. These data have implications for the treatment of immune-mediated diseases by immunomodulatory agents that alter the cytokine milieu in vivo.

Adoptive Transfer↗

PubMed2004

Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system considered to be mediated by T helper type-1 cells. Several agents have been found to modify the disease course of MS, including interferon-beta1 (IFN-beta1), glatiramer acetate mitoxantrone. We have employed pulse therapy with cyclophosphamide in a selected group of patients with actively progressive disease. Chemokine receptors have been found to differentiate between polarized T helper type-1 (Th1) and type-2 (Th2) lymphocytes. The chemokine receptors CCR5 and CXCR3 are expressed primarily on Th1 cells and CCR3, CCR4 and CCR8 on Th2 cells. Previous studies of the expression of chemokine receptors in MS have shown that active MS plaques are infiltrated by CCR5(+) and CXCR3(+) T cells. Some of these T cells may express both CCR5 and CXCR3. These T cells are major producers of IFN-gamma, which worsens the clinical condition of patients with MS. We previously found that patients with MS had a high proportion of CXCR3(+) T cells and that those with chronic progressive MS had a high proportion of CCR5(+) T cells in their peripheral blood. We report here that in patients with secondary progressive MS, cyclophosphamide induces a marked increase in the percentage of CCR4(+) T cells that produce high levels of IL-4 and reverses the increase in the percentages of IFN-gamma-producing CCR5(+) and CXCR3(+) CD8(+) T cells. Furthermore, therapy with cyclophosphamide increases IL-4-producing CD4(+) T cells and reverses the increase in IFN-gamma-producing CD8(+) T cells. Our study shows that cyclophosphamide has immunomodulatory properties besides its suppressive effects, and that chemokine receptors can be important tools both for understanding the immune dysregulation in MS and for monitoring response to therapy.

Adjuvants, Immunologic↗

PubMed2004

Neural stem/progenitor cells express costimulatory molecules that are differentially regulated by inflammatory and apoptotic stimuli.

Increased expression of the costimulatory molecule CD80 (B7-1) was noted in the subventricular zone of the brain during the course of experimental autoimmune encephalomyelitis (EAE). This area of the brain is a neural stem cell (NSC) niche in the adult. We show that isolated NSCs from adult brain express CD80 and CD86 (B7-2) and this expression is increased after exposure to IFN-gamma or TNF-alpha, the prototypical Th1 cytokines expressed during EAE. CD80 and CD86 expressed by NSCs are functional and can costimulate allogeneic cells in a mixed lymphocyte reaction. Furthermore, cross-linking of CD80 on the surface of NSCs results in apoptosis of NSCs. In vitro, we show that T cells can interact with NSCs and form conjugates with redistribution of CD3 on the surface of T cells to the area of contact. These data raise the possibility that during CNS inflammatory diseases such as EAE, NSCs may express immune molecules and interact with the inflammatory environment potentially resulting in injury to the NSCs, which may have implications for repair mechanisms in the central nervous system.

Animals↗

PubMed2004

The roles of the new negative T cell costimulatory pathways in regulating autoimmunity.

The B7 family of T cell costimulatory molecules has recently acquired several new members. Some of these are activating while others are inhibitory. In this review, we will focus on the novel inhibitory pathways with particular emphasis on the PD-1:PD-L pathway. Understanding the mechanisms of these pathways has implications for development of novel treatment strategies for autoimmune disease, transplantation, tumor immunotherapy, and vaccine development.

Animals↗

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↗