title: Retroviral transfer of donor MHC class I or MHC class II genes into recipient bone marrow cells can induce operational tolerance to alloantigens in vivo.
abstract: Infusion of allogeneic, donor bone marrow (BM) can induce specific immunological unresponsiveness in vivo resulting in long-term acceptance of subsequent fully allogeneic, donor-type solid organ grafts, but this may be associated with graft-versus-host disease. We hypothesize that transfer of donor MHC gene(s) to recipient-type BM or hematopoietic stem cells would enable delivery of donor alloantigens to the recipient without the risk of graft-versus-host disease. This strategy could also potentially take advantage of linked suppression to induce specific unresponsiveness to additional alloantigens expressed by the solid organ graft. We found that infusion of 5 x 10(6) CBA (H-2(k)) recipient mouse BM cells transduced with a recombinant replication-defective retrovirus encoding either a single donor MHC class I or class II gene (H-2K(b) or H-2IA(b)) in combination with anti-CD4 monoclonal antibody resulted in long-term survival of C57BL/10 (H-2(b)) but not third-party NZW (H-2(z)) heart grafts. BM cells (3 x 10(3)) enriched for hematopoietic stem cells by sorting for c-Kit(+), lineage-negative cells, were able to induce long-term allograft survival in 50% of recipients after transduction with the vector encoding a single donor MHC class I gene. These results have important implications for future strategies to enhance clinical allograft survival by delivery of donor alloantigens.
authors.affiliation: Department of Nephrology and Transplantation, Guy's Hospital, London SE1 9RT, United Kingdom.
authors.forename: Wilson
authors.initials: W
authors.lastname: Wong
authors.forename: J Stephen
authors.initials: JS
authors.lastname: Billing
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Stranford
authors.forename: Karen
authors.initials: K
authors.lastname: Hyde
authors.forename: Jeremy
authors.initials: J
authors.lastname: Fry
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morris
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wood
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D016026:Bone Marrow Transplantation; D003673:Defective Viruses / Q000235:genetics; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D005822:Genetic Vectors; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000737:chemistry; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008814:Mice, Inbred NZB; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D012190:Retroviridae / Q000235:genetics*; D014019:Tissue Donors; D014161:Transduction, Genetic; D023001:Transplantation Tolerance
chemical_list: D007519:Isoantigens; D019009:Proto-Oncogene Proteins c-kit