Getts D.R.,Northwestern University |
Martin A.J.,Northwestern University |
Mccarthy D.P.,Northwestern University |
Terry R.L.,Robert Bosch GmbH |
And 8 more authors.
Nature Biotechnology | Year: 2012
Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity. © 2012 Nature America, Inc. Source
Reich D.S.,U.S. National Institutes of Health |
White R.,University of British Columbia |
Cortese I.C.M.,U.S. National Institutes of Health |
Vuolo L.,U.S. National Institutes of Health |
And 3 more authors.
Multiple Sclerosis | Year: 2015
Background: New multiple sclerosis (MS) lesion activity on magnetic resonance imaging (MRI) can test immunomodulatory therapies in proof-of-concept trials. Comparably powerful endpoints to assess tissue protection or repair are lacking. Objective: The objective of this paper is to report sample-size calculations for assessment of new lesion recovery. Methods: In two sets of six active MS cases, new lesions were observed by monthly MRI for approximately 12 months. Averages and quartiles of normalized (proton density/T1/T2 weighted) and quantitative (T1/T2 and mean diffusivity maps for dataset 1, T2 and magnetization transfer ratio maps for dataset 2) measures were used to compare the lesion area before lesion appearance to afterward. A linear mixed-effects model incorporating lesion- and participant-specific random effects estimated average levels and variance components for sample-size calculations. Results: In both datasets, greatest statistical sensitivity was observed for the 25th percentile of normalized proton density-weighted signal. At 3T, using new lesions 3/415 mm3, as few as nine participants/arm may be required for a six-month placebo-controlled add-on trial postulating a therapeutic effect size of 20% and statistical power of 90%. Conclusion: Lesion recovery is a powerful outcome measure for proof-of-concept clinical trials of tissue protection and repair in MS. The trial design requires active cases and is therefore best implemented near disease onset. © SAGE Publications. Source
Emery B.,University of Melbourne |
Dugas J.C.,Myelin Repair Foundation |
Dugas J.C.,Stanford University
Cold Spring Harbor Protocols | Year: 2013
Oligodendrocytes are the myelinating cells of the vertebrate central nervous system, responsible for generating the myelin sheath necessary for saltatory conduction. The use of increasingly sophisticated genetic tools, particularly in mice, has vastly increased our understanding of the molecular mechanisms that regulate development of the oligodendrocyte lineage. This increased reliance on the mouse as a genetic model has led to a need for the development of culture methods to allow the use of mouse cells in vitro as well as in vivo. Here, we present a protocol for the isolation of different stages of the oligodendrocyte lineage, oligodendrocyte precursor cells (OPCs) and/or postmitotic oligodendrocytes, from the postnatal mouse cortex using immunopanning. This protocol allows for the subsequent culture or biochemical analysis of these cells. © 2013 Cold Spring Harbor Laboratory Press. Source
Way S.W.,University of Chicago |
Podojil J.R.,Northwestern University |
Clayton B.L.,University of Chicago |
Zaremba A.,Case Western Reserve University |
And 7 more authors.
Nature Communications | Year: 2015
Oligodendrocyte death contributes to the pathogenesis of the inflammatory demyelinating disease multiple sclerosis (MS). Nevertheless, current MS therapies are mainly immunomodulatory and have demonstrated limited ability to inhibit MS progression. Protection of oligodendrocytes is therefore a desirable strategy for alleviating disease. Here we demonstrate that enhancement of the integrated stress response using the FDA-approved drug guanabenz increases oligodendrocyte survival in culture and prevents hypomyelination in cerebellar explants in the presence of interferon-γ, a pro-inflammatory cytokine implicated in MS pathogenesis. In vivo, guanabenz treatment protects against oligodendrocyte loss caused by CNS-specific expression of interferon-γ. In a mouse model of MS, experimental autoimmune encephalomyelitis, guanabenz alleviates clinical symptoms, which correlates with increased oligodendrocyte survival and diminished CNS CD4+ T cell accumulation. Moreover, guanabenz ameliorates relapse in relapsing-remitting experimental autoimmune encephalomyelitis. Our results provide support for a MS therapy that enhances the integrated stress response to protect oligodendrocytes against the inflammatory CNS environment. © 2015 Macmillan Publishers Limited. All rights reserved. Source
Multiple sclerosis (MS) may be triggered by the death of brain cells that make the insulation around nerve fibers, a surprising new view of the disease reported in a study from Northwestern Medicine and The University of Chicago. And a specially developed nanoparticle prevented MS even after the death of those brain cells, an experiment in the study showed. The nanoparticles are being developed for clinical trials that could lead to new treatments -- without the side effects of current therapies -- in adults. MS can be initiated when damage to the brain destroys the cells that make myelin, the scientists showed. Myelin is the insulating sheath around nerve fibers that enables nerve impulses to be transmitted. The death of these cells, oligodendrocytes, can activate the autoimmune response against myelin, which is the main feature of MS. Oligodendrocytes can possibly be destroyed by developmental abnormalities, viruses, bacterial toxins or environmental pollutants. The scientists also developed the first mouse model of the progressive form of the autoimmune disease, which will enable the testing of new drugs against progressive MS. In the study, nanoparticles creating tolerance to the myelin antigen were administered and prevented progressive MS from developing. The study was published in Nature Neuroscience December 14. The lead investigators are Stephen Miller, Judy Gugenheim Research Professor of Microbiology-Immunology at Northwestern University Feinberg School of Medicine, and Brian Popko, the Jack Miller Professor of Neurological Disorders at the University of Chicago. The nanoparticle technology was developed in Miller’s lab and has been licensed to Cour Pharmaceutical Development Company, which is developing the technology for human trials in autoimmune disease. “We’re encouraged that immune tolerance induced with nanoparticles could stop disease progression in a model of chronic MS as efficiently as it can in progressive-remitting models of MS,” Miller said. The timing of therapy is important, Popko pointed out. “Protecting oligodendrocytes in susceptible individuals might help delay or prevent MS from initiating,” Popko said. “It’s likely that therapeutic strategies that intervene early in the disease process will have greater impact.” In the experiment, scientists developed a genetically engineered mouse model in which the oligodendrocytes died, affecting the animals’ ability to walk. The central nervous system regenerated the myelin-producing cells, enabling the mice to walk again. But about six months later, the MS-like disease came barreling back. This demonstrated the scientists’ theory that the death of oligodendrocytes can initiate MS. In humans, the scientists posit, the disease develops years after the initial injury to the brain. The current prevailing theory is that an event outside of the nervous system triggers MS in susceptible individuals who may have a genetic predisposition to the disease. In these individuals, the immune cells that normally fight infections confuse a component of the myelin sheath as foreign. These confused immune cells enter the brain and begin their mistaken attack on myelin, thus initiating MS. But the new study demonstrates the possibility that MS can begin from the inside out, in which damage to oligodendrocytes in the central nervous system can trigger an immune response directly. Oligodendrocytes are responsible for the maintenance of myelin. If they die, the myelin sheath falls apart. The inside-out hypothesis suggests that when myelin falls apart, the products of its degradation are presented to the immune system as foreign bodies or antigens. The immune system then erroneously views them as invaders and begins a full-scale attack on myelin, initiating MS. An estimated 400,000 people in the U.S. and 2.5 million worldwide have MS. Of those with long-standing disease, 50 to 60 percent have progressive MS. The other authors on the paper are Maria Traka of U of C, and Joseph Podojil and Derrick McCarthy of Northwestern. Miller, a founder and chief of the scientific advisory board of Cour Pharmaceutical, does not receive financial compensation from the company. The research was supported by grants from the Myelin Repair Foundation and the National Multiple Sclerosis Society.