Blood, 15 February
2001, Vol. 97, No. 4, pp. 886-894
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.
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.
© 2001 by The
American Society of Hematology.