Evaluation of engraftment and immunological tolerance after reduced intensity conditioning in a rhesus hematopoietic stem cell gene therapy model
| Autor: | M M Hsieh, Allen E. Krouse, Mark E. Metzger, Molly E. Evans, John F. Tisdale, R P Weitzel, Naoya Uchida, R Green, Robert E. Donahue, Aylin C. Bonifacino |
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| Rok vydání: | 2013 |
| Předmět: |
Transplantation Conditioning
medicine.medical_treatment Transgene Genetic enhancement Genetic Vectors Antigens CD34 Hematopoietic stem cell transplantation Biology Article Transduction (genetics) Antigen Transduction Genetic Genetics medicine Animals Transgenes Molecular Biology Cells Cultured Graft Survival Lentivirus Hematopoietic Stem Cell Transplantation Hematopoietic stem cell Dose-Response Relationship Radiation Genetic Therapy Hematopoietic Stem Cells biology.organism_classification Combined Modality Therapy Macaca mulatta medicine.anatomical_structure Models Animal Immunology Molecular Medicine Whole-Body Irradiation |
| Zdroj: | Gene Therapy. 21:148-157 |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2013.67 |
| Popis: | Reduced intensity conditioning (RIC) is desirable for hematopoietic stem cell (HSC) targeted gene therapy; however, RIC may be insufficient for efficient engraftment and inducing immunological tolerance to transgenes. We previously established long-term gene marking in our rhesus macaque autologous HSC transplantation model following 10 Gy total body irradiation (TBI). In this study, we evaluated RIC transplantation with 4 Gy TBI in two rhesus macaques that received equal parts of CD34(+) cells transduced with green fluorescent protein (GFP)-expressing lentiviral vector and empty vector not expressing transgenes. In both animals, equivalently low gene marking between GFP and empty vectors was observed 6 months post-transplantation, even with efficient transduction of CD34(+) cells in vitro. Autologous lymphocyte infusion with GFP marking resulted in an increase of gene marking in lymphocytes in a control animal with GFP tolerance, but not in the two RIC-transplanted animals. In vitro assays revealed strong cellular and humoral immune responses to GFP protein in the two RIC-transplanted animals, but this was not observed in controls. In summary, 4 Gy TBI is insufficient to permit engraftment of genetically modified HSCs and induce immunological tolerance to transgenes. Our findings should help in the design of conditioning regimens in gene therapy trials. |
| Databáze: | OpenAIRE |
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