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

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease of the central nervous system (CNS) that serves as a model for multiple scl erosis (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 th e 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 au toimmune diseases currently rely on general suppression of the T-cell compa rtment most commonly by steroids. In this paper, an experimental, gene ther apy-based model is presented in which susceptible mice are made resistant t o EAE induction by specifically down-regulating an autoreactive T-cell popu lation. By using a retroviral gene transfer protocol, normal B cells were g enetically modified to constitutively express the SJL-specific proteolipid (PLP) encephalitogenic determinant and then adoptively transferred into syn geneic hosts. To ensure appropriate presentation of the exogenous encephali togenic peptide in association with MHC class II, the encephalitogenic sequ ence was fused to a lysosomal targeting sequence. Adoptive transfer of syng eneic B cells expressing the PLP encephalitogenic determinant into normal, naive, genetically susceptible mice induced PLP-specific unresponsiveness a nd completely protected the majority (62% and 83% using an intermediate and a high titer retroviral vector, respectively) of the animals from EAE indu ction. The remaining animals had a delayed disease onset and/or lower disea se severity. All protected mice expressed the exogenous gene in the spleen as detected by reverse transcriptase-polymerase chain reaction. (C) 2001 by The American Society of Hematology.