title: Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment.
abstract: Allogeneic bone marrow transplantation (in immunocompetent adults) has always required cytoreductive treatment of recipients with irradiation or cytotoxic drugs to achieve lasting engraftment at levels detectable by non-PCR-based techniques ('macrochimerism' or 'mixed chimerism'). Only syngeneic marrow engraftment at such levels has been achieved in unconditioned hosts. This requirement for potentially toxic myelosuppressive host pre-conditioning has precluded the clinical use of allogeneic bone marrow transplantation for many indications other than malignancies, including tolerance induction. We demonstrate here that treatment of naive mice with a high dose of fully major histocompatibility complex-mismatched allogeneic bone marrow, followed by one injection each of monoclonal antibody against CD154 and cytotoxic T-lymphocyte antigen 4 immunoglobulin, resulted in multi-lineage hematopoietic macrochimerism (of about 15%) that persisted for up to 34 weeks. Long-term chimeras developed donor-specific tolerance (donor skin graft survival of more than 145 days) and demonstrated ongoing intrathymic deletion of donor-reactive T cells. A protocol of high-dose bone marrow transplantation and co-stimulatory blockade can thus achieve allogeneic bone marrow engraftment without cytoreduction or T-cell depletion of the host, and eliminates a principal barrier to the more widespread use of allogeneic bone marrow transplantation. Although efforts have been made to minimize host pre-treatment for allogeneic bone marrow transplantation for tolerance induction, so far none have succeeded in eliminating pre-treatment completely. Our demonstration that this can be achieved provides the rationale for a safe approach for inducing robust transplantation tolerance in large animals and humans.
authors.affiliation: BMT Section, Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH East, Bldg. 149-5102, 13th Street, Boston, Massachusetts 02129, USA.
authors.forename: T
authors.initials: T
authors.lastname: Wekerle
authors.forename: J
authors.initials: J
authors.lastname: Kurtz
authors.forename: H
authors.initials: H
authors.lastname: Ito
authors.forename: J V
authors.initials: JV
authors.lastname: Ronquillo
authors.forename: V
authors.initials: V
authors.lastname: Dong
authors.forename: G
authors.initials: G
authors.lastname: Zhao
authors.forename: J
authors.initials: J
authors.lastname: Shaffer
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D016026:Bone Marrow Transplantation; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D005260:Female; D007108:Immune Tolerance; D018796:Immunoconjugates; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*; D014181:Transplantation Immunology / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D023201:CD40 Ligand; D000069594:Abatacept