title: Incomplete clonal deletion as prerequisite for tissue-specific minor antigen tolerization.
abstract: Central clonal deletion has been considered the critical factor responsible for the robust state of tolerance achieved by chimerism-based experimental protocols, but split-tolerance models and the clinical experience are calling this assumption into question. Although clone-size reduction through deletion has been shown to be universally required for achieving allotolerance, it remains undetermined whether it is sufficient by itself. Therapeutic Treg treatment induces chimerism and tolerance in a stringent murine BM transplantation model devoid of myelosuppressive recipient treatment. In contrast to irradiation chimeras, chronic rejection (CR) of skin and heart allografts in Treg chimeras was permanently prevented, even in the absence of complete clonal deletion of donor MHC-reactive T cells. We show that minor histocompatibility antigen mismatches account for CR in irradiation chimeras without global T cell depletion. Furthermore, we show that Treg therapy-induced tolerance prevents CR in a linked suppression-like fashion, which is maintained by active regulatory mechanisms involving recruitment of thymus-derived Tregs to the graft. These data suggest that highly efficient intrathymic and peripheral deletion of donor-reactive T cells for specificities expressed on hematopoietic cells preclude the expansion of donor-specific Tregs and, hence, do not allow for spreading of tolerance to minor specificities that are not expressed by donor BM.
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Nina
authors.initials: N
authors.lastname: Pilat
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Mahr
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Lukas
authors.initials: L
authors.lastname: Unger
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Karin
authors.initials: K
authors.lastname: Hock
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Farkas
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baranyi
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D017637:Clonal Deletion; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*
chemical_list: D015778:Minor Histocompatibility Antigens