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

Kristen M. Drescher, Loc T. Nguyen, Veena Taneja, Michael J. Coenen, Julian L. Leibowitz, Gundrun Strauss, Gunter J. Hammerling, Chella S. David, Moses Rodriguez

Research output: Contribution to journalArticle

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Abstract

The role of various MHC genes in determining the progression of multiple sclerosis (MS) remains controversial. The HLA-DR3 gene has been associated with benign relapsing MS in some genetic epidemiologic studies, but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRBl*0301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV). DR3+ mice experienced a dramatic reduction in the extent and severity of demyelination compared with DR3- littermate controls, whereas anti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups. To address a possible mechanism of how the human transgene is reducing virus-induced demyelination, we analyzed cytokine expression in the lesions and also determined whether B10.M mice can respond to peptides derived from the DR3 molecule. Intense staining for IFN- γ and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, was found in the lesions of TMEV-infected DR3- mice but not in the DR3+ transgenic mice at day 21 after infection. DR3 peptides elicited strong proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II DR gene can alter the severity of demyelination in an animal model of MS without influencing vital load. These experiments are consistent with a mechanism by which DR3 reduces demyelination by altering the cytokine expression in the lesions, possibly by deleting T cells involved in virus-induced pathology.

Original languageEnglish
Pages (from-to)1765-1774
Number of pages10
JournalJournal of Clinical Investigation
Volume101
Issue number8
StatePublished - Apr 15 1998
Externally publishedYes

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Histocompatibility Antigens
Demyelinating Diseases
HLA Antigens
Transgenes
Multiple Sclerosis
Theilovirus
HLA-DR3 Antigen
Viruses
Cytokines
MHC Class II Genes
Peptides
RNA Viruses
Delayed Hypersensitivity
Viral Load
Interleukin-4
Transgenic Mice
Genes
Disease Progression
Epidemiologic Studies
Animal Models

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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, Loc T.; Taneja, Veena; Coenen, Michael J.; Leibowitz, Julian L.; Strauss, Gundrun; Hammerling, Gunter J.; David, Chella S.; Rodriguez, Moses.

In: Journal of Clinical Investigation, Vol. 101, No. 8, 15.04.1998, p. 1765-1774.

Research output: Contribution to journalArticle

Drescher, KM, Nguyen, LT, Taneja, V, Coenen, MJ, Leibowitz, JL, Strauss, G, Hammerling, GJ, David, CS & Rodriguez, M 1998, 'Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis', Journal of Clinical Investigation, vol. 101, no. 8, pp. 1765-1774.
Drescher, Kristen M. ; Nguyen, Loc T. ; Taneja, Veena ; Coenen, Michael J. ; Leibowitz, Julian L. ; Strauss, Gundrun ; Hammerling, Gunter J. ; David, Chella S. ; Rodriguez, Moses. / Expression of the human histocompatibility leukocyte antigen DR3 transgene reduces the severity of demyelination in a murine model of multiple sclerosis. In: Journal of Clinical Investigation. 1998 ; Vol. 101, No. 8. pp. 1765-1774.
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abstract = "The role of various MHC genes in determining the progression of multiple sclerosis (MS) remains controversial. The HLA-DR3 gene has been associated with benign relapsing MS in some genetic epidemiologic studies, but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRBl*0301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV). DR3+ mice experienced a dramatic reduction in the extent and severity of demyelination compared with DR3- littermate controls, whereas anti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups. To address a possible mechanism of how the human transgene is reducing virus-induced demyelination, we analyzed cytokine expression in the lesions and also determined whether B10.M mice can respond to peptides derived from the DR3 molecule. Intense staining for IFN- γ and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, was found in the lesions of TMEV-infected DR3- mice but not in the DR3+ transgenic mice at day 21 after infection. DR3 peptides elicited strong proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II DR gene can alter the severity of demyelination in an animal model of MS without influencing vital load. These experiments are consistent with a mechanism by which DR3 reduces demyelination by altering the cytokine expression in the lesions, possibly by deleting T cells involved in virus-induced pathology.",
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AU - Coenen, Michael J.

AU - Leibowitz, Julian L.

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