title: Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia.
abstract: Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp3+naturally occurring regulatory T cells (Tregs). This occurs via recipient iNKT- and STAT6-dependent expansion of recipient myeloid dendritic cells (MDCs) that induce contact-dependent expansion of donor Treg through PD-1/PD ligand signaling. After TLI/ATS + BMT, Gr-1lowCD11c+MDCs and Gr-1highCD11cnegmyeloid-derived suppressor cells (MDSCs) were enriched in GVHD target organs. We now report that the recovery of both recipient MDSCs (P< .01) and MDCs (P< .01) is significantly increased when the alkylator cyclophosphamide (CTX) is added to TLI/ATS conditioning. In a BALB/c → B6 lethal GVHD model, adoptive transfer of MDSCs from TLI/ATS/CTX-conditioned recipients is associated with significantly improved GVHD colitis and survival (P< .001), conversion of MDSCs to PD ligand-expressing MDCs, and increased donor naturally occurring Treg recovery (P< .01) compared with control treatment. Using BALB/c donors and β-thalassemic HW-80 recipients, we found significantly improved rates of engraftment and GVHD following TLI/ATS/CTX compared with TLI/ATS, lethal or sublethal total body irradiation/ATS/CTX, or CTX/ATS conditioning. These data provide preclinical support for trials of TLI/ATG/alkylator regimens for MHC-mismatched BMT for hemoglobinopathies. The data also delineate innate immune mechanisms by which TLI/ATS/CTX conditioning may augment transplantation tolerance.
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.|Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Department of Pediatrics, and.|Department of Microbiology and Immunology, University of Miami, Miami, FL; and.
authors.forename: Shuyu
authors.initials: S
authors.lastname: E
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Aman
authors.initials: A
authors.lastname: Seth
authors.affiliation: Division of Veterinary Pathology, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Peter
authors.initials: P
authors.lastname: Vogel
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Matt
authors.initials: M
authors.lastname: Sommers
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.
authors.forename: Taren
authors.initials: T
authors.lastname: Ong
authors.affiliation: Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN.|Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Department of Pediatrics, and.|Department of Microbiology and Immunology, University of Miami, Miami, FL; and.
authors.forename: Asha B
authors.identifier: 0000-0002-0488-3790
authors.initials: AB
authors.lastname: Pillai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use; D016026:Bone Marrow Transplantation / Q000379:methods*; D003520:Cyclophosphamide / Q000627:therapeutic use; D004195:Disease Models, Animal; D006085:Graft Survival; D006086:Graft vs Host Disease / Q000517:prevention & control; D007108:Immune Tolerance; D015182:Lymphatic Irradiation; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D018448:Models, Immunological; D000072737:Myeloid-Derived Suppressor Cells / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D017086:beta-Thalassemia / Q000276:immunology* / Q000628:therapy*
chemical_list: D000961:Antilymphocyte Serum; D003520:Cyclophosphamide