IMMUNE RESPONSE TO TRANSGENE FOLLOWING LENTIVIRAL VECTOR GENE DELIVERY: MECHANISM AND MODULATION BY CELLULAR THERAPY

One of the major impediments to the success of gene therapy is the immune response towards genetically modified cells, which is primarily mediated by a class of white blood cells known as T lymphocytes. To limit this immune response that ultimately results in the eradication of the genetically modified cells, several approaches have been described. However, to date none of the proposed strategies allows for sufficient down-regulation of the immune response to maintain long-term expression of the transgene. A novel approach to prevent clearance of genetically modified cells resides in the induction of transgene-specific tolerance. To achieve this, a subset of T cells, known as regulatory T cells, has been described to suppress immune responses. In addition, a second cell subset, known as APCs, which normally present antigens to effector T cells, can be manipulated to induce regulatory T cells. This proposal will evaluate novel strategies for rendering APCs able to induce transgene-specific regulatory T cells. In particular, a specific type of vectors, known as lentiviral vectors, will be introduced into APCs in order to investigate the tolerogenic potential of lentiviral vector expressing APCs. In addition, different subsets of regulatory T cells induced by the tolerogenic APCs will be characterized in detail. The results from these studies will allow us to design new approaches for controlling immune responses to therapeutic transgenes used in gene therapy for the cure of variety of genetic diseases, thus improving the therapeutic efficacy of this treatment.