title: Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning.
abstract: BACKGROUND
  A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments.
  
  
  RESULTS
  We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells.
  
  
  CONCLUSIONS
  We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. lgraca@fm.ul.pt
authors.forename: Luis
authors.initials: L
authors.lastname: Graca
authors.forename: Stephen
authors.initials: S
authors.lastname: Daley
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fairchild
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Cobbold
authors.forename: Herman
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D003433:Crosses, Genetic; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival; D006183:H-2 Antigens / Q000276:immunology; D006648:Histocompatibility; D007108:Immune Tolerance; D007165:Immunosuppression Therapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D011828:Radiation Chimera / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D016176:T-Lymphocyte Subsets / Q000276:immunology; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D016827:CD8 Antigens; D006183:H-2 Antigens; D023201:CD40 Ligand