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LOCASCIO, Samuel A; MOROKATA, Tatsuaki; TOLKOFF RUBIN, Nina; BENEDICT COSIMI, A; SACHS, David H; SYKES, Megan; CHITTENDEN, Meredith; PREFFER, Frederic I; DOMBKOWSKI, David M; ANDREOLA, Giovanna; CRISALLI, Kerry; KAWAI, Tatsuo; SAIDMAN, Susan L; SPITZER, Thomas R
Transplantation, 12/2010, Letnik: 90, Številka: 12Conference Proceeding, Journal Article
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. 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. 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. 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.
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