title: An MHC-defined primate model reveals significant rejection of bone marrow after mixed chimerism induction despite full MHC matching.
abstract: In murine models, mixed hematopoietic chimerism induction leads to robust immune tolerance. However, translation to primates and to patients has been difficult. In this study, we used a novel MHC-defined rhesus macaque model to examine the impact of MHC matching on the stability of costimulation blockade-/sirolimus-mediated chimerism, and to probe possible mechanisms of bone marrow rejection after nonmyeloablative transplant. Using busulfan-based pretransplant preparation and maintenance immunosuppression with sirolimus, as well as CD28 and CD154 blockade, all recipients demonstrated donor engraftment after transplant. However, the mixed chimerism that resulted was compartmentalized, with recipients demonstrating significantly higher whole blood chimerism compared to T cell chimerism. Thus, the vast majority of T cells presenting posttransplant were recipient-rather than donor-derived. Surprisingly, even in MHC-matched transplants, rejection of donor hematopoiesis predominated after immunosuppression withdrawal. Weaning of immunosuppression was associated with a surge of antigen-experienced T cells, and transplant rejection was associated with the acquisition of donor-directed T cell alloreactivity. These results suggest that a reservoir of alloreactive cells was present despite prior costimulation blockade and sirolimus, and that the post-immunosuppression lymphocytic rebound may have lead to a phenotypic shift in these recipient T cells towards an activated, antigen-experienced phenotype, and ultimately, to transplant rejection.
authors.affiliation: The Emory Transplant Center, Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: A
authors.initials: A
authors.lastname: Page
authors.forename: K H
authors.initials: KH
authors.lastname: Linzie
authors.forename: M
authors.initials: M
authors.lastname: Russell
authors.forename: T
authors.initials: T
authors.lastname: Deane
authors.forename: L
authors.initials: L
authors.lastname: Stempora
authors.forename: E
authors.initials: E
authors.lastname: Strobert
authors.forename: M C T
authors.initials: MC
authors.lastname: Penedo
authors.forename: T
authors.initials: T
authors.lastname: Ward
authors.forename: R
authors.initials: R
authors.lastname: Wiseman
authors.forename: D
authors.initials: D
authors.lastname: O'Connor
authors.forename: W
authors.initials: W
authors.lastname: Miller
authors.forename: S
authors.initials: S
authors.lastname: Sen
authors.forename: K
authors.initials: K
authors.lastname: Singh
authors.forename: L S
authors.initials: LS
authors.lastname: Kean
mesh_terms: D000818:Animals; D002066:Busulfan / Q000627:therapeutic use; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility / Q000276:immunology*; D007108:Immune Tolerance; D007165:Immunosuppression Therapy; D008253:Macaca mulatta; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D020123:Sirolimus / Q000627:therapeutic use; D013375:Substance Withdrawal Syndrome / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods
chemical_list: D002066:Busulfan; D020123:Sirolimus