title: Application of allogeneic bone marrow cells in view of residual alloreactivity: sirolimus but not cyclosporine evolves tolerogenic properties.
abstract: BACKGROUND
  Application of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity.
  
  
  METHODS
  The rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) → LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry.
  
  
  RESULTS
  Mixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC.
  
  
  CONCLUSIONS
  Srl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.
authors.affiliation: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Timrott
authors.affiliation: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany.
authors.forename: Florian W R
authors.initials: FW
authors.lastname: Vondran
authors.affiliation: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany.
authors.forename: Hueseyin
authors.initials: H
authors.lastname: Bektas
authors.affiliation: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klempnauer
authors.affiliation: Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule, Hannover, Germany.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Jäger
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D016572:Cyclosporine / Q000494:pharmacology*; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
chemical_list: D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016572:Cyclosporine; D020123:Sirolimus
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