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Blood, 15 February 2001, Vol. 97, No. 4, pp. 886-894
GENE THERAPY
A gene therapy approach for treating T-cell-mediated
autoimmune diseases
Chiann-Chyi Chen,
Amariliz Rivera,
Naomi Ron,
Joseph P. Dougherty, and
Yacov Ron
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.
Experimental 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.
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