Adenoviral transfer of a single donor-specific MHC class I gene to recipient bone marrow cells can induce specific immunological unresponsiveness in vivo.
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.
Fry
J W
JW
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Morris
P J
PJ
Wood
K J
KJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001854:Bone Marrow Cells / Q000276:immunology*; D016026:Bone Marrow Transplantation; D015704:CD4 Antigens / Q000276:immunology; D005805:Genes, MHC Class I; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006086:Graft vs Host Disease / Q000517:prevention & control*; D016027:Heart Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens