Immune Tolerance Induced by a Mixture of Cytokines and Dendritic Cells Enhances Gene Therapy

A study carried out in mice has demonstrated the potential for using primed immune dendritic cells to induce immune tolerance and reduce the possibility of rejection of therapeutic proteins administered by gene therapy.

A major obstacle to the application of genetic therapy to inherited metabolic disease is the development of host immune responses to the therapeutic protein. Investigators at the Baylor College of Medicine (Houston, TX, USA) have been evaluating the potential use of tolerogenic dendritic cells (DCtols) alone or in combination with cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-beta1 - known to induce tolerance - to prevent rejection of therapeutic proteins by the recipient.

In their study, which was published in the July 23, 2012, online edition of the journal Human Gene Therapy, the investigators used the protein ovalbumin as antigen in BALB/c mice and their transgenic derivative, DO11.10 mice. They showed that adoptive transfer of antigen-pulsed dendritic cells treated with a combination of IL-10 and TGF-beta1 could suppress the antibody response in these animals.

Adoptive transfer of cytokine-conditioned dendritic cells in preimmunized mice resulted in reduction of antibody response in the mice. The effect was antigen specific, as the recipient mice were able to mount a potent antibody response to a control antigen. TGF-beta1 and IL-10-conditioned dendritic cells were able to inhibit anti-FVIII antibody responses in mice that had been genetically engineered to lack the gene for FVIII.

Analysis of the contribution of IL-10 and TGF-beta1 to the action of the dendritic cells showed that IL-10 treatment of was sufficient for inducing ovalbumin-specific tolerance in BALB/c mice. However, but both human TGF-beta1 and human IL-10 were required to significantly inhibit anti-FVIII antibody responses in FVIII knockout mice.

The approach described in this paper to induce partial or full tolerance to proteins replaced via gene therapy may someday replace today's expensive techniques that are unsuccessful in as many as 40% of cases.

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