title: Prolonged, low-dose anti-thymocyte globulin, combined with CTLA4-Ig, promotes engraftment in a stringent transplant model.
abstract: BACKGROUND
  Despite significant nephrotoxicity, calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression in solid organ transplantation. We, along with others, have reported tolerogenic properties of anti-thymocyte globulin (ATG, Thymoglobulin®), evinced by its ability both to spare Tregs from depletion in vivo and, when administered at low, non-depleting doses, to expand Tregs ex vivo. Clinical trials investigating B7/CD28 blockade (LEA29Y, Belatacept) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations.
  
  
  METHODS
  Rabbit polyclonal anti-murine thymocyte globulin (mATG) was administered as induction and/or prolonged, low-dose therapy, in combination with CTLA4-Ig, in a stringent, fully MHC-mismatched murine skin transplant model to assess graft survival and mechanisms of action.
  
  
  RESULTS
  Prolonged, low-dose mATG, combined with CTLA4-Ig, effectively promotes engraftment in a stringent transplant model. Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs, while CTLA4-Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment, and by inhibiting production of anti-rabbit antibodies in the maintenance phase, thereby promoting regulation of alloreactivity.
  
  
  CONCLUSIONS
  These data provide the rationale for development of novel, CNI-free clinical protocols in human transplant recipients.
authors: Renal Division, Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Francesca
authors: F
authors: D'Addio
authors: Olaf
authors: O
authors: Boenisch
authors: Ciara N
authors: CN
authors: Magee
authors: Melissa Y
authors: MY
authors: Yeung
authors: Xueli
authors: X
authors: Yuan
authors: Bechara
authors: B
authors: Mfarrej
authors: Andrea
authors: A
authors: Vergani
authors: Mohammed Javeed
authors: MJ
authors: Ansari
authors: Paolo
authors: P
authors: Fiorina
authors: Nader
authors: N
authors: Najafian
mesh_terms: D000069594:Abatacept; D000818:Animals; D000961:Antilymphocyte Serum / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D018796:Immunoconjugates / Q000008:administration & dosage* / Q000378:metabolism; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D051379:Mice; D016377:Organ Transplantation; D011817:Rabbits; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000961:Antilymphocyte Serum; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept