title: Rapamycin and CTLA4Ig synergize to induce stable mixed chimerism without the need for CD40 blockade.
abstract: The mixed chimerism approach achieves donor-specific tolerance in organ transplantation, but clinical use is inhibited by the toxicities of current bone marrow (BM) transplantation (BMT) protocols. Blocking the CD40:CD154 pathway with anti-CD154 monoclonal antibodies (mAbs) is exceptionally potent in inducing mixed chimerism, but these mAbs are clinically not available. Defining the roles of donor and recipient CD40 in a murine allogeneic BMT model, we show that CD4 or CD8 activation through an intact direct or CD4 T cell activation through the indirect pathway is sufficient to trigger BM rejection despite CTLA4Ig treatment. In the absence of CD4 T cells, CD8 T cell activation via the direct pathway, in contrast, leads to a state of split tolerance. Interruption of the CD40 signals in both the direct and indirect pathway of allorecognition or lack of recipient CD154 is required for the induction of chimerism and tolerance. We developed a novel BMT protocol that induces mixed chimerism and donor-specific tolerance to fully mismatched cardiac allografts relying on CD28 costimulation blockade and mTOR inhibition without targeting the CD40 pathway. Notably, MHC-mismatched/minor antigen-matched skin grafts survive indefinitely whereas fully mismatched grafts are rejected, suggesting that non-MHC antigens cause graft rejection and split tolerance.
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Pilat
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Klaus
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Schwarz
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Hock
authors.affiliation: Department of Visceral, Transplant, and Thoracic Surgery, Center of Operative Medicine, Innsbruck Medical University, Austria.
authors.forename: R
authors.initials: R
authors.lastname: Oberhuber
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Schwaiger
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Gattringer
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Ramsey
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: U
authors.initials: U
authors.lastname: Baranyi
authors.affiliation: Institute of Pathology, Medical University of Innsbruck, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Zelger
authors.affiliation: Department of Plastic and Reconstructive Surgery, Vascularized Composite Allotransplantation (VCA) Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: G
authors.initials: G
authors.lastname: Brandacher
authors.affiliation: Institute of Clinical Pathology, Medical University of Vienna, Austria.
authors.forename: F
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Section of Transplantation Immunology, Department of Surgery, Medical University of Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016026:Bone Marrow Transplantation; D019013:CD40 Antigens / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D002678:Chimera / Q000276:immunology*; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D019172:Transplantation Conditioning / Q000379:methods; D023001:Transplantation Tolerance / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D023201:CD40 Ligand; D000069594:Abatacept; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Basic (laboratory) research / science; bone marrow / hematopoietic stem cell transplantation; immunobiology; tolerance: chimerism; tolerance: costimulation blockade; translational research / science