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Nonmyeloablative conditioning is sufficient to allow engraftment of EGFP-expressing bone marrow and subsequent acceptance of EGFP-transgenic skin grafts in mice

Andersson G, Illigens BMW, Johnson KW, Calderhead D, LeGuern C, Benichou G, White-Scharf ME, Down JD

Sammanfattning

Immunologic reactions against gene therapy products may prove to be a frequent problem in clinical gene therapy protocols. Enhanced green fluorescence protein (EGFP) is commonly used as a marker in gene transfer protocols, and immune responses against EGFP-expressing cells have been documented. The present study was designed to investigate the effect of a pharmacologic, nonmyeloablative, conditioning regimen on the development of EGFP(+) donor/recipient mixed bone marrow chimerism and ensuing tolerance to EGFP-expressing transplants. To this end, C57BL/6J (136) mice were treated with soluble formulations of either busulfan (Busulfex) or the closely related compound treosulfan, followed by transplantation of bone marrow cells from EGFP-transgenic (B6-EGFR.Tg) donor mice. Such conditioning regimens resulted in long-term persistence of donor EGFP(+) cells among various hematopoietic lineages from blood, bone marrow, and thymus. Stable hematopoietic chimeras transplanted at 10 to 17 weeks after bone marrow transplantation (BMT) with B6-EGFP.Tg skin grafts all accepted their transplants, whereas non-EGFP chimeric B6 control animals were able to mount rejection of the EGFP(+) B6 skin grafts. Control third-party grafts from major histocompatibility complex (MHC)-mismatched mice were rejected within 20 days, indicating that acceptance of EGFP-expressing skin grafts was the result of specific immune tolerance induction by the transplantation of EGFP-transgenic bone marrow. Long-term tolerance to EGFP in chimeric recipients was confirmed by the absence of anti-EGFP-reactive T cells and antibodies. These results broaden the therapeutic potential for using hematopoietic molecular chimerism in nonmyeloablated recipients as a means of preventing rejection of genetically modified cells. (C) 2003 by The American Society of Hematology

Publicerad i

Blood
2003, Volym: 101, nummer: 11, sidor: 4305-4312
Utgivare: AMER SOC HEMATOLOGY

    UKÄ forskningsämne

    Husdjursvetenskap
    Veterinärmedicin

    Publikationens identifierare

    DOI: https://doi.org/10.1182/blood-2002-06-1649

    Permanent länk till denna sida (URI)

    https://res.slu.se/id/publ/714