title: Tolerance to MHC class II disparate allografts through genetic modification of bone marrow.
abstract: Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here, we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-A(b) (I-A(b)) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow-derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow-derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction.
authors: Transplantation Research Center, Renal Division, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
authors: P T
authors: PT
authors: Jindra
authors: S
authors: S
authors: Tripathi
authors: C
authors: C
authors: Tian
authors: J
authors: J
authors: Iacomini
authors: J
authors: J
authors: Bagley
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D049109:Cell Proliferation; D046528:Chimerism; D005802:Genes, MHC Class II; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D051379:Mice; D012190:Retroviridae / Q000235:genetics; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology