title: Long-term cardiac allograft survival across an MHC mismatch after "pruning" of alloreactive CD4 T cells.
abstract: Specific tolerance to allografts has been achieved by a variety of means. We have previously shown that ex vivo removal of dividing CD4(+) T cells from an MLR or "pruning" delays skin allograft rejection. We tested pruning of alloreactive T cells as a strategy for retaining a broad T cell repertoire while removing alloreactive T cells in a model of cardiac allograft transplant. Using CFSE staining of responder BALB/c cells with stimulator C57BL/6 cells in an MLR, SCID mice were reconstituted with either dividing (D) or nondividing (ND) CD4(+) T cells derived from an MLR and then challenged with heterotopic cardiac allografts. Mice reconstituted with D CD4(+) T cells rejected cardiac allografts from the stimulator strain with a median survival time (MST) of 29 days, while mice reconstituted with ND CD4(+) T cells maintained allografts from the stimulator strain (MST of >100 days) while rejecting third-party allografts (B10.BR) (MST = 11 days). ELISPOT assays demonstrate donor-specific hyporesponsiveness of the ND CD4(+) T cells. TCR beta-chain V region (TRBV) repertoire analysis demonstrates clonal expansion within both rejecting D cardiac allografts and ND cardiac allografts surviving for the long-term. Histology showed greater allograft infiltration by the D CD4(+) T cells. The surviving ND cardiac allografts demonstrated reduced cellular infiltration and reduced incidence of allograft vasculopathy, but with the development of chronic fibrosis. Thus, pruning of alloreactive T cells allows long-term-specific cardiac allograft survival while retaining the ability to reject third-party allografts.
authors.affiliation: Centre for Kidney Research and Department of Pathology, the Children's Hospital at Westmead, University of Sydney, NSW, Australia.
authors.forename: Min
authors.initials: M
authors.lastname: Hu
authors.forename: Debbie
authors.initials: D
authors.lastname: Watson
authors.forename: Geoff Y
authors.initials: GY
authors.lastname: Zhang
authors.forename: Nicole
authors.initials: N
authors.lastname: Graf
authors.forename: Yuan M
authors.initials: YM
authors.lastname: Wang
authors.forename: Mary
authors.initials: M
authors.lastname: Sartor
authors.forename: Brian
authors.initials: B
authors.lastname: Howden
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Fletcher
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006648:Histocompatibility; D007108:Immune Tolerance / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion / Q000379:methods*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013995:Time; D014184:Transplantation, Homologous
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta