Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells.
Genetic modification of hematopoietic stem cells (HSCs) resulting in a state of molecular chimerism can be used to induce donor-specific tolerance to allografts. However, the requirements for maintaining tolerance in molecular chimeras remain unknown. Here, we examined whether long-term expression of a retrovirally encoded alloantigen in hematopoietic cells is required to maintain donor-specific tolerance in molecular chimeras. To this end, mice were reconstituted with syngeneic bone marrow transduced with retroviruses carrying the gene encoding the allogeneic MHC class I molecule Kb. Following induction of molecular chimerism, mice were depleted of cells expressing Kb by administration of the anti-Kb monoclonal antibody Y-3. Mice that were effectively depleted of cells expressing the retrovirally encoded MHC class I antigen rejected Kb disparate skin allografts. In contrast, control molecular chimeras accepted Kb disparate skin allografts indefinitely. These data suggest maintenance of tolerance in molecular chimeras requires long-term expression of retrovirally transduced alloantigen on the progeny of retrovirally transduced HSCs.
Tian
C
C
Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Bagley
J
J
Iacomini
J
J
D000818:Animals; D016026:Bone Marrow Transplantation; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D006183:H-2 Antigens / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology; D051379:Mice; D011828:Radiation Chimera / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic; D018183:Transplantation Chimera / Q000276:immunology*; D023001:Transplantation Tolerance; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse