title: Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model.
abstract: BACKGROUND
  Mixed chimerism is an effective strategy for the induction of transplantation tolerance but the toxicity of recipient conditioning makes current bone marrow (BM) transplantation (BMT) protocols unsuitable for widespread clinical application. Therapies promoting BM engraftment under minimal conditioning would facilitate translation of this concept to the clinic. Recently, we have shown that regulatory T cell (Treg) therapy has potent engraftment-enhancing effects in an irradiation-free noncytotoxic BMT protocol, but only if it is combined with rapamycin treatment.
  
  
  METHODS
  Here, we investigated whether polyclonal Treg therapy is effective in promoting chimerism and tolerance in an otherwise unsuccessful BMT protocol using low-dose total body irradiation (1 Gy) and costimulation blockade and determined whether Tregs do so on their own without rapamycin.
  
  
  RESULTS
  The application of polyclonal FoxP3-transduced recipient Tregs led to durable multilineage chimerism and donor-specific skin graft tolerance whereas recipients receiving costimulation blockade alone or green flourescent protein (GFP)-transduced cells failed to develop chimerism. Infused Tregs had a limited life span as indicated by polymerase chain reaction analysis but rather contribute to de novo induction of subsequent Treg generations. Deletion of donor-reactive T cells was observed but progressed more slowly over time compared with recipients of a nonmyeloablative BMT protocol using 3 Gy total body irradiation.
  
  
  CONCLUSIONS
  In conclusion, Treg therapy promotes BM engraftment on its own in a low-dose irradiation BMT protocol, leading to chimerism and tolerance maintained through deletional and nondeletional mechanisms.
authors.affiliation: Division of Transplantation, Department of Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Nina
authors.initials: N
authors.lastname: Pilat
authors.forename: Christoph
authors.initials: C
authors.lastname: Klaus
authors.forename: Martina
authors.initials: M
authors.lastname: Gattringer
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Dela
authors.initials: D
authors.lastname: Golshayan
authors.forename: Ulrike
authors.initials: U
authors.lastname: Baranyi
authors.forename: Thomas
authors.initials: T
authors.lastname: Wekerle
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D007108:Immune Tolerance / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011829:Radiation Dosage; D020123:Sirolimus / Q000494:pharmacology; D016038:Skin Transplantation / Q000379:methods*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000528:radiation effects / Q000637:transplantation; D018183:Transplantation Chimera / Q000276:immunology; D019172:Transplantation Conditioning / Q000379:methods*; D014916:Whole-Body Irradiation
chemical_list: D007166:Immunosuppressive Agents; D049452:Green Fluorescent Proteins; D020123:Sirolimus