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We investigated the delivery of a donor-specific MHC class I gene, H-2K(b), using a newly constructed replication-defective recombinant adenovirus (AdSV40K(b)) to recipient tissue before transplantation as a means of inducing donor-specific immunological unresponsiveness. AdSV40K(b) was able to transduce both a fibroblast cell line and freshly isolated bone marrow cells (BMCs) resulting in cell surface expression of H2-K(b) protein. Intravenous infusion of AdSV40K(b)-transduced syngeneic CBA/Ca (H-2(k)) BMCs into CBA recipient mice treated with an anti-CD4 monoclonal antibody 27 days before transplantation of a fully MHC-mismatched, C57BL/10 (H-2K(b+)), cardiac allograft resulted in significant long-term graft survival when compared with mice receiving the same dose of syngeneic BMCs transduced with a control adenovirus, AdRSVbetagal. Despite the induction of H-2K(b)-specific hyporesponsiveness following pretreatment with AdSV40K(b)-transduced CBA BMCs, persistence of H-2K(b) mRNA in central or peripheral tissues could not be demonstrated by RT-PCR. This result was in contrast to the observed persistence of K(b) mRNA both in the periphery and thymus following the infusion of transgenic CBK (H-2(k) + K(b)) BMCs. We conclude that ex vivo adenoviral gene transfer of a single donor MHC class I gene to recipient BMCs in combination with transient depletion of CD4(+) cells is sufficient to induce long-term graft survival of a fully allogeneic cardiac graft. In addition, detectable microchimerism is not a prerequisite for graft survival.

Original publication

DOI

10.1038/sj.gt.3301648

Type

Journal article

Journal

Gene Ther

Publication Date

02/2002

Volume

9

Pages

220 - 226

Keywords

Adenoviridae, Animals, Antibodies, Monoclonal, Antigens, CD4, Bone Marrow Cells, Bone Marrow Transplantation, Genes, MHC Class I, Genetic Therapy, Genetic Vectors, Graft vs Host Disease, Heart Transplantation, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Transplantation Immunology, Transplantation, Homologous