Gene therapy for T cell-mediated autoimmunity: teaching the immune system how to restrain its own harmful activities by targeted DNA vaccines.

We recently used a modification of gene therapy (naked DNA vaccination) to induce immunological memory against self-pro-inflammatory chemokines such as macrophage inflammatory protein-1 alpha or monocyte chemoattractant protein-1, and against the pro-inflammatory cytokine tumor necrosis factor-alpha. First, DNA constructs encoding each of the different pro-inflammatory mediators together with a repeated immunostimulatory sequence were prepared. Then, experiment animals were subjected to a repeated administration of each construct. Under these conditions, tolerance to the product of each insert was broken, and immunological memory established. Upon induction of experimental autoimmune encephalomyelitis, a T cell-mediated autoimmune disease of the central nervous system that serves as a model for multiple sclerosis or adjuvant induced arthritis, this memory was "turned on" to provide DNA-vaccinated animals a high state of disease resistance. Antibodies to the product of each inserted gene were isolated form these animals. Each antibody was found capable of neutralizing in vitro the chemoattractive properties of each relevant chemokine, thereby transferring disease resistance. Interestingly, the level of their production was dependent on disease severity, that is, each titer was accelerated in accordance with disease progression. Thus, by using a simple gene therapy technique the immune system could be "re-educated" to restrain its own harmful activities.