Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis.

Drescher, Kristen M.; Nguyen, Huu Lam; Taneja, Veena; Coenen, Michael J.; Leibowitz, Julian L.; Strauss, G.; Hämmerling, Günter J.; David, Chella S.; Rodriguez, Moses

doi:10.1172/jci167

Cited by 16 publications

(10 citation statements)

References 44 publications

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“…Transgenic expression of DR3 molecules in mice of a susceptible B10.M (H-2 f ) haplotype developed less demyelination than littermate controls without the DR3 transgene (5). These experiments differed from the present experiments in that the parental mice were immune competent and of a haplotype that develops demyelination.…”

Section: The Humoral Immune Response To Virus Antigens Does Not Explacontrasting

confidence: 86%

“…We then substituted the human class II gene (DR2 or DR3) for the mouse class II response. These mice mount normal class II-restricted CD4 T-cell-mediated immune responses to a number of antigens and infectious agents, (5,14,23,34) and have an intact mouse CD8 ϩ T-cell-restricted endogenous class I major histocompatibility complex (MHC) immune response. Therefore, we could not exclude the contribution of the endogenous mouse MHC class I response to antigen challenge.…”

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confidence: 99%

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Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

Rodriguez

Zoecklein²,

Kerkvliet³

et al. 2008

J Virol

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We evaluated the participatory role of human HLA-DR molecules in control of virus from the central nervous system and in the development of subsequent spinal cord demyelination. The experiments utilized intracranial infection with Theiler's murine encephalomyelitis virus (TMEV), a picornavirus that, in some strains of mice, results in primary demyelination. We studied DR2 and DR3 transgenic mice that were bred onto a combined class I-deficient mouse (beta-2 microglobulin deficient; ␤2m

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Section: The Humoral Immune Response To Virus Antigens Does Not Explacontrasting

confidence: 86%

mentioning

confidence: 99%

Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

Rodriguez

Zoecklein²,

Kerkvliet³

et al. 2008

J Virol

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“…Intracerebral (i.c.) inoculation of mice with Theiler's murine encephalomyelitis virus (TMEV), is commonly used to study viral demyelination and remyelination of the central nervous system (CNS) (Drescher, Nguyen et al, 1998;Drescher, Zoecklein et al, 2000;Dal Canto & Lipton, 1975;Lipton, 1975;Rodriguez, 1993;Pena Rossi, Delcroix et al, 1997;Rodriguez, Pavelko et al, 1995;Rodriguez, Nabozny et al, 1994;Rodriguez & David, 1985). Because the pathologic changes and subsequent clinical signs of the disease in mice are similar to those observed in humans with multiple sclerosis (MS) TMEV infection of mice is also used to model a hypothetical viral etiology of MS (Dal Canto & Lipton, 1975;Lipton, 1975).…”

Section: Introductionmentioning

confidence: 99%

Injection of the sciatic nerve with TMEV: A new model for peripheral nerve demyelination

Drescher

Tracy

2007

Virology

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Demyelination of the human peripheral nervous system (PNS) can be caused by diverse mechanisms including viral infection. Despite association of several viruses with the development of peripheral demyelination, animal models of the condition have been limited to disease that is either autoimmune or genetic in origin. We describe here a model of PNS demyelination based on direct injection of sciatic nerves of mice with the cardiovirus, Theiler's murine encephalomyelitis virus (TMEV). Sciatic nerves of FVB mice develop inflammatory cell infiltration following TMEV injection. Schwann cells and macrophages are infected with TMEV. Viral replication is observed initially in the sciatic nerves and subsequently the spinal cord. Sciatic nerves are demyelinated by day 5 post-inoculation (p.i.). Injecting sciatic nerves of scid mice resulted in increased levels of virus recovered from the sciatic nerve and spinal cord relative to FVB mice. Demyelination also occurred in scid mice and by 12 days p.i., hindlimbs were paralyzed. This new model of virus-induced peripheral demyelination may be used to dissect processes involved in protection of the PNS from viral insult and to study the early phases of lesion development.

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“…In a previous study we demonstrated that expression of HLA-DR3 in transgenic mice reduced the severity of TMEV-induced demyelination (Drescher et al, 1998). To understand the role of HLA-DQ polymorphisms in de-myelination and neurologic deficits, in this study we generated mice lacking expression of murine class I and class II molecules that were reconstituted with a single human class II DQ gene and examined the role of HLA-DQ polymorphisms in the TMEV model of MS. We first assessed the contribution of these genes to protection from neuronal disease and then investigated subsequent development of demyelination and progressive neurologic deficits.…”

Section: Introductionmentioning

confidence: 99%

HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

Pavelko

Drescher

McGavern

et al. 2000

Molecular and Cellular Neuroscience

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The importance of genetic susceptibility in determining the progression of demyelination and neurologic deficits is a major focus in neuroscience. We studied the influence of human leukocyte antigen (HLA)-DQ polymorphisms on disease course and neurologic impairment in virus-induced demyelination. HLA-DQ6 or DQ8 was inserted as a transgene into mice lacking endogenous expression of MHC class I (β 2 m) and class II (H2-A β ) molecules. Following Theiler's murine encephalomyelitis virus (TMEV) infection, we assessed survival, virus persistence, demyelination, and clinical disease. Mice lacking expression of endogenous class I and class II molecules (β 2 m°A β°mice) died 3 to 4 weeks postinfection (p.i.) due to overwhelming virus replication in neurons. β 2 m°Aβ°DQ6 and β 2 m°Aβ°DQ8 mice had increased survival and decreased gray matter disease and virus replication compared to nontransgenic littermate controls. Both β 2 m°Aβ°DQ6 and β 2 m°A β°DQ8 mice developed chronic virus persistence in glial cells of the white matter of the spinal cord, with greater numbers of virus antigen-positive cells in β 2 m°Aβ°DQ8 than in β 2 m°Aβ°DQ6 mice. At day 45 p.i., the demyelinating lesions in the spinal cord of β 2 m°Aβ°DQ8 were larger than those in the β 2 m°Aβ°DQ6 mice. Earlier and more profound neurologic deficits were observed in β 2 m°Aβ°DQ8 mice compared to β 2 m°Aβ°DQ6 mice, although by 120 days p.i. both strains of mice showed similar extent of demyelination and neurologic deficits. Delayed-type hypersensitivity and antibody responses to TMEV demonstrated that the mice mounted class IImediated cellular and humoral immune responses. The results are consistent with the hypothesis that rates of progression of demyelination and neurologic deficits are related to the differential ability of DQ6 and DQ8 transgenes to modulate the immune response and control virus.

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Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis.

Cited by 16 publications

References 44 publications

Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

Human HLA-DR Transgenes Protect Mice from Fatal Virus-Induced Encephalomyelitis and Chronic Demyelination

Injection of the sciatic nerve with TMEV: A new model for peripheral nerve demyelination

HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

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