title: Mechanisms of donor-specific tolerance in recipients of haploidentical combined bone marrow/kidney transplantation.
abstract: We recently reported long-term organ allograft survival without ongoing immunosuppression in four of five patients receiving combined kidney and bone marrow transplantation from haploidentical donors following nonmyeloablative conditioning. In vitro assays up to 18 months revealed donor-specific unresponsiveness. We now demonstrate that T cell recovery is gradual and is characterized by memory-type cell predominance and an increased proportion of CD4⁺ CD25⁺ CD127⁻ FOXP3⁺ Treg during the lymphopenic period. Complete donor-specific unresponsiveness in proliferative and cytotoxic assays, and in limiting dilution analyses of IL-2-producing and cytotoxic cells, developed and persisted for the 3-year follow-up in all patients, and extended to donor renal tubular epithelial cells. Assays in two of four patients were consistent with a role for a suppressive tolerance mechanism at 6 months to 1 year, but later (≥ 18 months) studies on all four patients provided no evidence for a suppressive mechanism. Our studies demonstrate, for the first time, long-term, systemic donor-specific unresponsiveness in patients with HLA-mismatched allograft tolerance. While regulatory cells may play an early role, long-term tolerance appears to be maintained by a deletion or anergy mechanism.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Andreola
authors.forename: M
authors.initials: M
authors.lastname: Chittenden
authors.forename: J
authors.initials: J
authors.lastname: Shaffer
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.forename: P
authors.initials: P
authors.lastname: Cotter
authors.forename: S A
authors.initials: SA
authors.lastname: Locascio
authors.forename: T
authors.initials: T
authors.lastname: Morokata
authors.forename: B R
authors.initials: BR
authors.lastname: Dey
authors.forename: N T
authors.initials: NT
authors.lastname: Tolkoff-Rubin
authors.forename: F
authors.initials: F
authors.lastname: Preffer
authors.forename: T
authors.initials: T
authors.lastname: Bonnefoix
authors.forename: K
authors.initials: K
authors.lastname: Kattleman
authors.forename: T R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: M
authors.initials: M
authors.lastname: Sykes
mesh_terms: D016026:Bone Marrow Transplantation / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D016130:Immunophenotyping; D016030:Kidney Transplantation / Q000276:immunology; D014019:Tissue Donors