T cells mediate resistance to genetically modified bone marrow in lethally irradiated recipients |
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Authors: | Bagley Jessamyn Tian Chaorui Sachs David H Iacomini John |
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Affiliation: | Transplantation Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. |
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Abstract: | BACKGROUND: In order for gene therapy to attain clinical relevance, efficient engraftment and long-term survival of cells that express transduced genes of interest must be achieved. In this study, we examined the extent to which host T cells affect engraftment of syngeneic bone marrow cells engineered to express a retrovirally transduced allogeneic major histocompatibility complex class-I gene. METHODS: B10.AKM mice were preconditioned with lethal irradiation or lethal irradiation plus transient CD4 and CD8 T-cell depletion in addition to CD40-CD154 costimulatory blockade and were then reconstituted with syngeneic bone marrow cells transduced with retroviruses that carried the gene that encoded H-2K(b) (K(b)). Expression of K(b) on bone marrow-derived cells was then analyzed, and induction of tolerance to K was evaluated. RESULTS: Mice conditioned using CD4 and CD8 T-cell depletion in addition to CD40-CD154 costimulatory blockade and lethal irradiation showed a significant increase in the frequency of bone marrow-derived cells that expressed K(b) when compared to animals that received lethal irradiation alone. Survival of allogeneic skin grafts that expressed K(b) was significantly prolonged in animals conditioned with anti-CD4, anti-CD8, and co-stimulatory blockade in addition to lethal irradiation (median survival time, 81 days) when compared to mice that received irradiation alone (mean survival time, 31 days; P=0.001). CONCLUSIONS: Radioresistant host T cells significantly affect the ability to induce tolerance by gene therapy by affecting engraftment of transduced cells that expressed allogeneic major histocompatibility complex class-I genes in the absence of host T-cell depletion and costimulatory blockade, even after lethal irradiation. Thus, radioresistant host T cells are a significant barrier to engraftment of transduced bone marrow progenitors and to the induction of tolerance by gene therapy. |
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