Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: the future for therapy of autoimmune disease?

Based on the principle that immune ablation followed by HSC-mediated recovery purges disease-causing leukocytes to interrupt autoimmune disease progression, hematopoietic stem cell transplantation (HSCT) has been increasingly used as a treatment for severe autoimmune diseases. Despite clinically-relevant outcomes, HSCT is associated with serious iatrogenic risks and is suitable only for the most serious and intractable diseases. A further limitation of autologous HSCT is that relapse rates can be high, suggesting disease-causing leukocytes are incompletely purged or the environmental and genetic determinants that drive disease remain active. Incorporation of antigen-specific tolerance approaches that synergise with autologous HSCT could reduce or prevent relapse. Further, by reducing the requirement for highly toxic immune-ablation and instead relying on antigen-specific tolerance, the clinical utility of HSCT could be significantly diversified. Substantial progress has been made exploring HSCT-mediated induction of antigen-specific tolerance in animal models but studies have focussed on primarily on prevention of autoimmune diseases. However, as diagnosis of autoimmune disease is often not made until autoimmune disease is well developed and populations of autoantigen-specific pathogenic effector and memory T cells have become well established, immunotherapies must be developed to address effector and memory T-cell responses which have traditionally been considered the key impediment to immunotherapy. Here, focusing on T-cell mediated autoimmune diseases we review progress made in antigen-specific immunotherapy using HSCT-mediated approaches, induction of tolerance in effector and memory T cells and the challenges for progression and clinical application of antigen-specific ‘tolerogenic’ HSCT therapy

Leukotriene modifiers for asthma treatment

Leukotrienes (LTs), including cysteinyl LTs (CysLTs) and LTB 4 , are potent lipid mediators that have a role in the pathophysiology of asthma. At least two receptor subtypes for CysLTs, CysLT 1 and CysLT 2 , have been identified. The activation of the CysLT 1 receptor is responsible for most of the pathophysiological effects of CysLTs in asthma, including increased airway smooth muscle activity, microvascular permeability, and airway mucus secretion. LTB 4 might have a role in severe asthma, asthma exacerbations, and the development of airway hyperresponsiveness. CysLT 1 receptor antagonists can be given orally as monotherapy in patients with mild persistent asthma, but these drugs are generally less effective than inhaled glucocorticoids. Combination of CysLT 1 receptor antagonists and inhaled glucocorticoids in patients with more severe asthma may improve asthma control and enable the dose of inhaled glucocorticoids to be reduced while maintaining similar efficacy. The identification of subgroups of asthmatic patients who respond to CysLT 1 receptor antagonists is relevant for asthma management as the response to these drugs is variable. CysLT 1 receptor antagonists have a potential anti-remodelling effect that might be important for preventing or reversing airway structural changes in patients with asthma. This review discusses the role of LTs in asthma and the role of LT modifiers in asthma treatment.Cite this as: P. Montuschi and M. L. Peters-Golden, Clinical & Experimental Allergy , 2010 (40) 1732–1741.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79154/1/j.1365-2222.2010.03630.x.pd

Membrane Potential Controls Adipogenic and Osteogenic Differentiation of Mesenchymal Stem Cells

Background: Control of stem cell behavior is a crucial aspect of developmental biology and regenerative medicine. While the functional role of electrophysiology in stem cell biology is poorly understood, it has become clear that endogenous ion flows represent a powerful set of signals by means of which cell proliferation, differentiation, and migration can be controlled in regeneration and embryonic morphogenesis. Methodology/Principal Findings: We examined the membrane potential (Vmem) changes exhibited by human mesenchymal stem cells (hMSCs) undergoing adipogenic (AD) and osteogenic (OS) differentiation, and uncovered a characteristic hyperpolarization of differentiated cells versus undifferentiated cells. Reversal of the progressive polarization via pharmacological modulation of transmembrane potential revealed that depolarization of hMSCs prevents differentiation. In contrast, treatment with hyperpolarizing reagents upregulated osteogenic markers. Conclusions/Significance: Taken together, these data suggest that the endogenous hyperpolarization is a functiona

The nature of the body in sport and physical culture: from bodies and environments to ecological embodiment

This article raises the ecological substance and relational co-constitution of bodies as a generative question for sociologists of sport and physical culture. It proceeds from our observation that recent research on the materiality of athletic bodies, and on the environmental issues in which sport is implicated, tends to run on parallel tracks. By exploring how biological, environmental, and social natures cohere in the making and unmaking of healthy bodies, our aim is to connect and extend these vibrant areas of research. We do so by developing the concept of “ecological embodiment,” a descriptor for a fluid state of becoming and a sensibility for thinking about hierarchical socioecological entanglements. To illustrate this concept, we draw on a study of whey protein powder, a key ingredient in contemporary fitness cultures

Role of nicotinic acetylcholine receptors at the vertebrate myotendinous junction: a hypothesis

It has long been known that nicotinic acetycholine receptors (nAChRs) are present in muscle fibres not only at the end plate region but also at the myotendinous junction (MTJ). Their function at the MTJ, however, is yet unknown. Recent experiments in our laboratory lead us to suggest that nAChRs at this site might be involved in muscle repair. MTJ is subject to high mechanical stress and therefore is easily damaged. We found in pure cultures of human myogenic cells that (1) the density of nAChRs in myoblasts increases markedly just before cell fusion, (2) the fusion of human myoblasts is accelerated by the presence of a cholinergic agonist acting on nAChRs and (3) human myoblasts and myotubes spontaneously release an ACh-like compound. Based on these observations we propose that in damaged muscles the nAChRs at the MTJ and those of myogenic cells are activated by the ACh-like compound these cells release. This leads to fusion of myogenic cells with damaged muscle fibres and hence promotes repair

Mibefradil (Ro 40-5967) inhibits several Ca2+ and K+ currents in human fusion-competent myoblasts

1. The effect of mibefradil (Ro 40-5967), an inhibitor of T-type Ca2+ current (I(Ca)(T)), on myoblast fusion and on several voltage-gated currents expressed by fusion-competent myoblasts was examined. 2. At a concentration of 5 microM, mibefradil decreases myoblast fusion by 57%. At this concentration, the peak amplitudes of I(Ca)(T) and L-type Ca2+ current (I(Ca)(L)) measured in fusion-competent myoblasts are reduced by 95 and 80%, respectively. The IC50 of mibefradil for I(Ca)(T) and I(Ca)(L) are 0.7 and 2 microM, respectively. 3. At low concentrations, mibefradil increased the amplitude of I(Ca)(L) with respect to control. 4. Mibefradil blocked three voltage-gated K+ currents expressed by human fusion-competent myoblasts: a delayed rectifier K+ current, an ether-a-go-go K+ current, and an inward rectifier K+ current, with a respective IC50 of 0.3, 0.7 and 5.6 microM. 5. It is concluded that mibefradil can interfere with myoblast fusion, a mechanism fundamental to muscle growth and repair, and that the interpretation of the effect of mibefradil in a given system should take into account the action of this drug on ionic currents other than Ca2+ currents

Contribution of a non-inactivating potassium current to the resting membrane potential of fusion-competent human myoblasts

1. Using the patch-clamp technique, a new non-inactivating voltage-gated potassium current, IK(ni), was studied in cultured fusion-competent human myoblasts. 2. IK(ni) is activated at voltages above -50 mV and its conductance reaches its maximum around +50 mV. Once activated, the current remains at a steady level for minutes. 3. Reversal potential measurements at various extracellular potassium concentrations indicate that potassium ions are the major charge carriers of IK(ni). 4. IK(ni) is insensitive to potassium channel blockers such as charybdotoxin, dendrotoxins, mast cell degranulating (MCD) peptide, 4-aminopyridine (4-AP), 3,4-diaminopyridine (3,4-DAP) and apamin, but can be blocked by high concentrations of TEA and by Ba2+. 5. A potassium channel of small conductance (8.4 pS at +40 mV) with potential dependence and pharmacological properties corresponding to those of IK(ni) in whole-cell recording is described. 6. IK(ni) participates in the control of the resting potential of fusion-competent myoblasts, suggesting that it may play a key role in the process of myoblast fusion

Acceleration of human myoblast fusion by depolarization: graded Ca2+ signals involved

We have previously shown that human myoblasts do not fuse when their voltage fails to reach the domain of a window T-type Ca(2+) current. We demonstrate, by changing the voltage in the window domain, that the Ca(2+) signal initiating fusion is not of the all-or-none type, but can be graded and is interpreted as such by the differentiation program. This was carried out by exploiting the properties of human ether-a-go-go related gene K(+) channels that we found to be expressed in human myoblasts. Methanesulfonanilide class III antiarrhythmic agents or antisense-RNA vectors were used to suppress completely ether-a-go-go related gene current. Both procedures induced a reproducible depolarization from -74 to -64 mV, precisely in the window domain where the T-type Ca(2+) current increases with voltage. This 10 mV depolarization raised the cytoplasmic free Ca(2+) concentration, and triggered a tenfold acceleration of myoblast fusion. Our results suggest that any mechanism able to modulate intracellular Ca(2+) concentration could affect the rate of myoblast fusion