title: The indirect alloresponse impairs the induction but not maintenance of tolerance to MHC class I-disparate allografts.
abstract: We studied the effects of indirect allorecognition on the induction and maintenance phases of tolerance in miniature swine cotransplanted with heart and kidney allografts. MHC class I-mismatched heart and kidney grafts were cotransplanted in recipients receiving CyA for 12 days. Recipients were unimmunized or immunized with a set of donor-derived or control third-party MHC class I peptides either 21 days prior to transplantation or over 100 days after transplantation. T-cell proliferation, delayed type hypersensitivity reaction (DTH) and antibody production were assessed. All animals injected with donor MHC class I peptides developed potent indirect alloresponses specific to the immunizing peptides. While untreated recipients developed stable tolerance, all animals preimmunized with donor allopeptides rejected kidney-heart transplants acutely. In contrast, when peptide immunization was delayed until over 100 days after kidney-heart transplantation, no effects were observed on graft function or in vitro measures of alloimmunity. Donor peptide immunization prevented tolerance when administered to recipients pre transplantation but did not abrogate tolerance when administered to long-term survivors post transplantation. This suggests that the presence of T cells activated via indirect allorecognition represent a barrier to the induction but not the maintenance of tolerance.
authors.affiliation: Transplantation Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: D A
authors.initials: DA
authors.lastname: Guenther
authors.forename: J D
authors.initials: JD
authors.lastname: Mezrich
authors.forename: H
authors.initials: H
authors.lastname: Sahara
authors.forename: C Y
authors.initials: CY
authors.lastname: Ng
authors.forename: A J
authors.initials: AJ
authors.lastname: Meltzer
authors.forename: J K
authors.initials: JK
authors.lastname: Sayre
authors.forename: M E
authors.initials: ME
authors.lastname: Cochrane
authors.forename: A C
authors.initials: AC
authors.lastname: Pujara
authors.forename: S L
authors.initials: SL
authors.lastname: Houser
authors.forename: D H
authors.initials: DH
authors.lastname: Sachs
authors.forename: B R
authors.initials: BR
authors.lastname: Rosengard
authors.forename: J S
authors.initials: JS
authors.lastname: Allan
authors.forename: G
authors.initials: G
authors.lastname: Benichou
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006968:Hypersensitivity, Delayed; D007108:Immune Tolerance; D016030:Kidney Transplantation / Q000276:immunology*; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous
chemical_list: D015395:Histocompatibility Antigens Class I