Introduction of a xenogeneic gene via hematopoietic stem cells leads to specific tolerance in a rhesus monkey model

Host immune responses against foreign transgenes may be a major obstacle to successful gene therapy. To clarify the impact of an immune response to fo reign transgene products on the survival of genetically modified cells, we! studied the in vivo persistence of cells transduced with a vector expressi ng a foreign transgene compared to cells transduced with a nonexpressing ve ctor in the clinically predictive rhesus macaque model. We constructed retr oviral vectors containing the neomycin phosphotransferase gene (neo) sequen ces modified to prevent protein expression (nonexpressing vectors). Rhesus monkey lymphocytes or hematopoietic stem cells (HSCs) were transduced with nonexpressing and neo-expressing vectors followed by reinfusion, and their in vivo persistence was studied. While lymphocytes transduced with a nonexp ressing vector could be detected for more than 1 year, lymphocytes transduc ed with a neo-expressing vector were no longer detectable within several we eks of infusion. However, five of six animals transplanted with HSCs transd uced with nonexpression or neo-expression vectors, and progeny lymphocytes marked with either vector persisted for more than 2 years. Furthermore, in recipients of transduced HSCs, infusion of mature lymphocytes transduced wi th a second neo-expressing vector did not result in elimination of the tran sduced lymphocytes. Our data show that introduction of a xenogeneic gene vi a HSCs induces tolerance to the foreign gene products. HSC gene therapy is therefore suitable for clinical applications where long-term expression of a therapeutic or foreign gene is required.