title: Mixed chimerism, lymphocyte recovery, and evidence for early donor-specific unresponsiveness in patients receiving combined kidney and bone marrow transplantation to induce tolerance.
abstract: BACKGROUND
  We have previously reported operational tolerance in patients receiving human leukocyte antigen-mismatched combined kidney and bone marrow transplantation (CKBMT). We now report on transient multilineage hematopoietic chimerism and lymphocyte recovery in five patients receiving a modified CKBMT protocol and evidence for early donor-specific unresponsiveness in one of these patients.
  
  
  METHODS
  Five patients with end-stage renal disease received CKBMT from human leukocyte antigen-mismatched, haploidentical living-related donors after modified nonmyeloablative conditioning. Polychromatic flow cytometry was used to assess multilineage chimerism and lymphocyte recovery posttransplant. Limiting dilution analysis was used to assess helper T-lymphocyte reactivity to donor antigens.
  
  
  RESULTS
  Transient multilineage mixed chimerism was observed in all patients, but chimerism became undetectable by 2 weeks post-CKBMT. A marked decrease in T- and B-lymphocyte counts immediately after transplant was followed by gradual recovery. Initially, recovering T cells were depleted of CD45RA+/CD45RO(-) "naïve-like" cells, which have shown strong recovery in two patients, and CD4:CD8 ratios increased immediately after transplant but then declined markedly. Natural killer cells were enriched in the peripheral blood of all patients after transplant.For subject 2, a pretransplant limiting dilution assay revealed T helper cells recognizing both donor and third-party peripheral blood mononuclear cells. However, the antidonor response was undetectable by day 24, whereas third-party reactivity persisted.
  
  
  CONCLUSIONS
  These results characterize the transient multilineage mixed hematopoietic chimerism and recovery of lymphocyte subsets in patients receiving a modified CKBMT protocol. The observations are relevant to the mechanisms of donor-specific tolerance in this patient group.
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Samuel A
authors.initials: SA
authors.lastname: LoCascio
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Morokata
authors.forename: Meredith
authors.initials: M
authors.lastname: Chittenden
authors.forename: Frederic I
authors.initials: FI
authors.lastname: Preffer
authors.forename: David M
authors.initials: DM
authors.lastname: Dombkowski
authors.forename: Giovanna
authors.initials: G
authors.lastname: Andreola
authors.forename: Kerry
authors.initials: K
authors.lastname: Crisalli
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.forename: Susan L
authors.initials: SL
authors.lastname: Saidman
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: Nina
authors.initials: N
authors.lastname: Tolkoff-Rubin
authors.forename: A Benedict
authors.initials: AB
authors.lastname: Cosimi
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D016026:Bone Marrow Transplantation / Q000276:immunology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007676:Kidney Failure, Chronic / Q000601:surgery*; D016030:Kidney Transplantation / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000276:immunology; D008212:Lymphocyte Depletion; D013601:T-Lymphocytes / Q000276:immunology; D018183:Transplantation Chimera / Q000276:immunology*
chemical_list: D017493:Leukocyte Common Antigens