title: Tolerance induction in HLA disparate living donor kidney transplantation by donor stem cell infusion: durable chimerism predicts outcome.
abstract: BACKGROUND
  We recently reported that durable chimerism can be safely established in mismatched kidney recipients through nonmyeloablative conditioning followed by infusion of a facilitating cell (FC)-based hematopoietic stem cell transplantation termed FCRx. Here we provide intermediate-term follow-up on this phase II trial.
  
  
  METHODS
  Fifteen human leukocyte antigen-mismatched living donor renal transplant recipients underwent low-intensity conditioning (fludarabine, cyclophosphamide, 200 cGy TBI), received a living donor kidney transplant on day 0, then infusion of cryopreserved FCRx on day +1. Maintenance immunosuppression, consisting of tacrolimus and mycophenolate, was weaned over 1 year.
  
  
  RESULTS
  All but one patient demonstrated peripheral blood macrochimerism after transplantation. Engraftment failure occurred in a highly sensitized (panel reactive antibody [PRA] of 52%) recipient. Chimerism was lost in three patients at 2, 3, and 6 months after transplantation. Two of these subjects had received either a reduced cell dose or incomplete conditioning; the other two had PRA greater than 20%. All demonstrated donor-specific hyporesponsiveness and were weaned from full-dose immunosuppression. Complete immunosuppression withdrawal at 1 year after transplantation was successful in all patients with durable chimerism. There has been no graft-versus-host disease or engraftment syndrome. Renal transplantation loss occurred in one patient who developed sepsis following an atypical viral infection. Two subjects with only transient chimerism demonstrated subclinical rejection on protocol biopsy despite donor-specific hyporesponsiveness.
  
  
  CONCLUSIONS
  Low-intensity conditioning plus FCRx safely achieved durable chimerism in mismatched allograft recipients. Sensitization represents an obstacle to successful induction of chimerism. Sustained T-cell chimerism is a more robust biomarker of tolerance than donor-specific hyporeactivity.
authors.affiliation: Comprehensive Transplant Center, Northwestern Memorial Hospital, Chicago, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Leventhal
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.forename: Joshua
authors.initials: J
authors.lastname: Miller
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Gallon
authors.forename: David
authors.initials: D
authors.lastname: Tollerud
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Elliott
authors.forename: Larry D
authors.initials: LD
authors.lastname: Bozulic
authors.forename: Christopher
authors.initials: C
authors.lastname: Houston
authors.forename: Nedjema
authors.initials: N
authors.lastname: Sustento-Reodica
authors.forename: Suzanne T
authors.initials: ST
authors.lastname: Ildstad
mesh_terms: D000328:Adult; D046528:Chimerism; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007108:Immune Tolerance; D016030:Kidney Transplantation; D019520:Living Donors; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D019172:Transplantation Conditioning