title: Tolerance induction with gene-modified stem cells and immune-preserving conditioning in primed mice: restricting antigen to differentiated antigen-presenting cells permits efficacy.
abstract: Bone marrow (BM) or hematopoietic stem cell (HSC) transplantation is used as curative therapy for hematologic malignancies. Incorporation of gene therapy to drive tolerogenic expression of antigens is a promising strategy to overcome the limited long-term efficacy of autologous HSC transplantation for autoimmune diseases. HSC engraftment and tolerance induction is readily achieved after myeloablative or immune-depleting conditioning regardless of the cellular compartment in which antigen is expressed. It is unclear whether the efficiency of engraftment and tolerance induction is influenced by targeting antigen to specific cellular compartments. This is particularly important when using clinically feasible low-intensity conditioning aimed at preserving infectious immunity in individuals where immunologic memory exists to the autoantigen to be expressed. Here we demonstrate that, under immune-preserving conditions, confining expression of a transgenically expressed antigen to dendritic cells permits stable, long-term engraftment of genetically modified BM even when recipients are immune to the expressed antigen. In contrast, broader expression within the hematopoietic compartment leads to graft rejection and therapeutic failure because of antigen expression in HSCs. These findings are relevant to the clinical application of genetically engineered HSCs and provide evidence that careful selection of promoters for HSC-mediated gene therapy is important, particularly where tolerance is sought under immune-preserving conditions.
authors.affiliation: UQ Diamantina Institute, University of Queensland, Brisbane, Australia.
authors.forename: Miranda A
authors.initials: MA
authors.lastname: Coleman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Bridge
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.forename: Chantelle M
authors.initials: CM
authors.lastname: Dixon
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: James W
authors.initials: JW
authors.lastname: Wells
authors.forename: Ranjeny
authors.initials: R
authors.lastname: Thomas
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Steptoe
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013234:Stem Cells / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D039521:CD11c Antigen; D000949:Histocompatibility Antigens Class II; D010047:Ovalbumin