title: Minor Antigen Disparities Impede Induction of Long Lasting Chimerism and Tolerance through Bone Marrow Transplantation with Costimulation Blockade.
abstract: Mixed chimerism and tolerance can be successfully induced in rodents through allogeneic bone marrow transplantation (BMT) with costimulation blockade (CB), but varying success rates have been reported with distinct models and protocols. We therefore investigated the impact of minor antigen disparities on the induction of mixed chimerism and tolerance. C57BL/6 (H2b) mice received nonmyeloablative total body irradiation (3 Gy), costimulation blockade (anti-CD40L mAb and CTLA4Ig), and 2 × 107bone marrow cells (BMC) from either of three donor strains: Balb/c (H2d) (MHC plus multiple minor histocompatibility antigen (mHAg) mismatched), B10.D2 (H2d) or B10.A (H2a) (both MHC mismatched, but mHAg matched). Macrochimerism was followed over time by flow cytometry and tolerance was tested by skin grafting. 20 of 21 recipients of B10.D2 BMC but only 13 of 18 of Balb/c BMC and 13 of 20 of B10.A BMC developed stable long-term multilineage chimerism (p< 0.05 for each donor strain versus B10.D2). Significantly superior donor skin graft survival was observed in successfully established long-term chimeras after mHAg matched BMT compared to mHAg mismatched BMT (p< 0.05). Both minor and major antigen disparities pose a substantial barrier for the induction of chimerism while the maintenance of tolerance after nonmyeloablative BMT and costimulation blockade is negatively influenced by minor antigen disparities.        .
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Sinda
authors.identifier: 0000-0002-4905-3811
authors.initials: S
authors.lastname: Bigenzahn
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Ines
authors.initials: I
authors.lastname: Pree
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Christoph
authors.initials: C
authors.lastname: Klaus
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Nina
authors.identifier: 0000-0003-4071-9397
authors.initials: N
authors.lastname: Pilat
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Mahr
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schwaiger
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nierlich
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Waehringer Guertel 18, 1090 Vienna, Austria.
authors.forename: Thomas
authors.identifier: 0000-0001-5159-2796
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D016026:Bone Marrow Transplantation; D005260:Female; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance; D008212:Lymphocyte Depletion; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D000941:Antigens; D015778:Minor Histocompatibility Antigens