A gene therapy approach for treating T-cell–mediated autoimmune diseases

Author:

Chen Chiann-Chyi1,Rivera Amariliz1,Ron Naomi1,Dougherty Joseph P.1,Ron Yacov1

Affiliation:

1. From the Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ; and the Graduate Program in Microbiology and Molecular Genetics, Rutgers University, Piscataway, NJ.

Abstract

AbstractExperimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that serves as a model for multiple sclerosis (MS) in humans. In mice, EAE is mediated by Th1 type CD4+ T cells specific for various myelin proteins which migrate from the periphery to the CNS. Removal or blocking of CD4+ cells before or shortly after disease induction was shown to prevent disease onset and/or disease progression but also results in general immune suppression. Most treatment regimens for autoimmune diseases currently rely on general suppression of the T-cell compartment most commonly by steroids. In this paper, an experimental, gene therapy-based model is presented in which susceptible mice are made resistant to EAE induction by specifically down-regulating an autoreactive T-cell population. By using a retroviral gene transfer protocol, normal B cells were genetically modified to constitutively express the SJL-specific proteolipid (PLP) encephalitogenic determinant and then adoptively transferred into syngeneic hosts. To ensure appropriate presentation of the exogenous encephalitogenic peptide in association with MHC class II, the encephalitogenic sequence was fused to a lysosomal targeting sequence. Adoptive transfer of syngeneic B cells expressing the PLP encephalitogenic determinant into normal, naive, genetically susceptible mice induced PLP-specific unresponsiveness and completely protected the majority (62% and 83% using an intermediate and a high titer retroviral vector, respectively) of the animals from EAE induction. The remaining animals had a delayed disease onset and/or lower disease severity. All protected mice expressed the exogenous gene in the spleen as detected by reverse transcriptase-polymerase chain reaction.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference63 articles.

1. Immunological aspects of demyelinating diseases.;Martin;Annu Rev Immunol.,1992

2. The T lymphocyte in experimental allergic encephalomyelitis.;Zamvil;Annu Rev Immunol.,1990

3. T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis.;Zamvil;Nature.,1986

4. Myelin proteolipid protein-induced experimental allergic encephalomyelitis: variations of disease expression in different strains of mice.;Tuohy;J Immunol.,1988

5. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells.;Mendel;Eur J Immunol.,1995

Cited by 52 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3