Gene Therapy for the Induction of Chimerism and Transplant Tolerance

Abstract

Technical advances in transplant surgery and the development of powerful and effective immunosuppressive drugs have contributed to the success of organ transplantation as a medical treatment for patients with end-stage diseases. Associated with this procedure, however, is a dependence on life-long immunosuppressive drugs, which are required to prevent graft rejection. These agents render the patient susceptible to infections, tumors and various side affects. The ability to achieve tolerance to organ grafts would free transplant patients from lifelong dependency on pharmacological agents with harmful side effects. Several laboratories have shown that tolerance can be achieved by the induction of mixed cell chimerism and/or by molecular chimerism achieved by gene transfer techniques prior to graft placement. Molecular chimerism, induced by transplantation of autologous bone marrow expressing either allo- or xenoantigens has the potential to induce tolerance without the development of graft vs. host disease. The application of gene transfer techniques to induce chimerism has been shown to reshape the immune repertoire by mechanisms that include clonal deletion, the induction of central tolerance or generation of regulatory T cells that would eliminate the need for immunosuppressive drugs. Optimization of this methodology for clinical use could therefore revolutionize the field of transplantation. This review summarizes the recent studies which have compared the efficacy of different vectors, conditioning regimens, and transduction conditions leading to new and improved techniques for the application of gene therapy to induce chimerism and transplant tolerance to both allografts and xenografts.

Partial phenotypic correction and immune tolerance induction to enzyme replacement therapy after hematopoietic stem cell gene transfer of α‐glucosidase in Pompe disease

“…However, in the present study, we show that as low as 20% transduction efficiency of HSC allows a complete tolerance to ERT. Moreover, several studies have demonstrated that a partial hematopoietic chimerism obtained with low preconditioning regimen leads to a complete tolerance induction to alloantigens 38, 59.…”

Development of gene transfer for induction of antigen-specific tolerance

“… 101–106 Gene transfer to HSC has successfully induced tolerance for tissue transplantation, desensitized allergic responses, protected against autoimmune diseases, and provided tolerance and therapeutic protein expression in a variety of disease models. 102 , 107–110 …”

“…Efficient engraftment in early HSC transplantations often required complete myeloablation of the host bone marrow compartment by total body irradiation. Milder nonmyeloablation conditioning regimens using chemicals or low-dose radiation often failed to promote sufficient levels of engraftment to induce tolerance but instead were hyporesponsive, 102 , 107 with the level of antigen expression determining hyporesponsiveness or tolerance. Newly developed nonmyeloablative regimens and gene transfer platforms can now provide sufficient engraftment and transgene expression for successful tolerance induction from gene-modified HSC following transplantation.…”