title: B-cell immunity in the context of T-cell tolerance after combined kidney and bone marrow transplantation in humans.
abstract: Five patients with end-stage kidney disease received combined kidney and bone marrow transplants from HLA haploidentical donors following nonmyeloablative conditioning to induce renal allograft tolerance. Immunosuppressive therapy was successfully discontinued in four patients with subsequent follow-up of 3 to more than 6 years. This allograft acceptance was accompanied by specific T-cell unresponsiveness to donor antigens. However, two of these four patients showed evidence of de novo antibodies reactive to donor antigens between 1 and 2 years posttransplant. These humoral responses were characterized by the presence of donor HLA-specific antibodies in the serum with or without the deposition of the complement molecule C4d in the graft. Immunofluorescence staining, ELISA assays and antibody profiling using protein microarrays demonstrated the co-development of auto- and alloantibodies in these two patients. These responses were preceded by elevated serum BAFF levels and coincided with B-cell reconstitution as revealed by a high frequency of transitional B cells in the periphery. To date, these B cell responses have not been associated with evidence of humoral rejection and their clinical significance is still unclear. Overall, our findings showed the development of B-cell allo- and autoimmunity in patients with T-cell tolerance to the donor graft.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Porcheray
authors.forename: W
authors.initials: W
authors.lastname: Wong
authors.forename: S L
authors.initials: SL
authors.lastname: Saidman
authors.forename: J
authors.initials: J
authors.lastname: De Vito
authors.forename: T C
authors.initials: TC
authors.lastname: Girouard
authors.forename: M
authors.initials: M
authors.lastname: Chittenden
authors.forename: J
authors.initials: J
authors.lastname: Shaffer
authors.forename: N
authors.initials: N
authors.lastname: Tolkoff-Rubin
authors.forename: B R
authors.initials: BR
authors.lastname: Dey
authors.forename: T R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: R B
authors.initials: RB
authors.lastname: Colvin
authors.forename: A B
authors.initials: AB
authors.lastname: Cosimi
authors.forename: T
authors.initials: T
authors.lastname: Kawai
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: M
authors.initials: M
authors.lastname: Sykes
authors.forename: E
authors.initials: E
authors.lastname: Zorn
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D002460:Cell Line; D015935:Complement C4b / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006084:Graft Rejection / Q000276:immunology; D006680:HLA Antigens / Q000737:chemistry; D006801:Humans; D007107:Immune System; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000379:methods*; D008856:Microscopy, Fluorescence / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry; D040081:Protein Array Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors
chemical_list: D006680:HLA Antigens; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d