title: Deletional and regulatory mechanisms coalesce to drive transplantation tolerance through mixed chimerism.
abstract: Establishing donor-specific immunological tolerance could improve long-term outcome by obviating the need for immunosuppressive drug therapy, which is currently required to control alloreactivity after organ transplantation. Mixed chimerism is defined as the engraftment of donor hematopoietic stem cells in the recipient, leading to viable coexistence of both donor and recipient leukocytes. In numerous experimental models, cotransplantation of donor bone marrow (BM) into preconditioned (e.g., through irradiation or cytotoxic drugs) recipients leads to transplantation tolerance through (mixed) chimerism. Mixed chimerism offers immunological advantages for clinical translation; pilot trials have established proof of concept by deliberately inducing tolerance in humans. Widespread clinical application is prevented, however, by the harsh preconditioning currently necessary for permitting BM engraftment. Recently, the immunological mechanisms inducing and maintaining tolerance in experimental mixed chimerism have been defined, revealing a more prominent role for regulation than historically assumed. The evidence from murine models suggests that both deletional and regulatory mechanisms are critical in promoting complete tolerance, encompassing also the minor histocompatibility antigens. Here, we review the current understanding of tolerance through mixed chimerism and provide an outlook on how to realize widespread clinical translation based on mechanistic insights gained from chimerism protocols, including cell therapy with polyclonal regulatory T cells.
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Hock
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Mahr
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D046528:Chimerism; D002986:Clinical Trials as Topic; D005720:Gamma Rays / Q000627:therapeutic use; D005786:Gene Expression Regulation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D018183:Transplantation Chimera / Q000235:genetics / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015778:Minor Histocompatibility Antigens
keywords: Clonal deletion ⋅ Mixed chimerism ⋅ Nonmyeloablative conditioning ⋅ Transplantation tolerance ⋅ Treg cells