T-cell design: optimizing the therapeutic potential of autoreactive T cells by genetic modification

Autoreactive CD4+ Th2 cells have been shown to be therapeutic in the treatment of EAE. However, their full therapeutic potential has yet to be realized. Genetic modification of autoreactive Th2 T cells may provide the means for delivering therapeutic transgene factors to autoimmune inflammatory lesions. Optimum therapeutic effects may be achieved by designing Th2 T cells in such a way that expression of transgene factors is regulated by antigen-inducible IL4, IL5 or IL10 transgene promoters. The innate antiinflammatory effects of the native autoreactive Th2 T cell may be enhanced by incorporating transgene regenerative growth factors in the T-cell design. Such factors may include remyelination growth factors (PDGF-A, bFGF, and IGF-I) that complement each other by acting predominantly at different stages in the development of mature myelinating oligodendrocytes. Moreover, in light of recent findings indicating extensive axonal damage during MS, neuroprotective transgene factors may prove to be therapeutic when delivered to EAE lesions by autoreactive Th2 T cells. Thus, optimum therapeutic effects may require multiple transfers of autoreactive Th2 T cells producing several distinct complementary transgene factors. In addition, the pathogenicity of epitope spreading and the inherent instability of self recognition during EAE may require serial transfer of genetically modified T cells reacting to multiple self determinants.