title: Costimulatory blockade-mediated lung allograft acceptance is abrogated by overexpression of Bcl-2 in the recipient.
abstract: Lung allografts are considered to be more immunogenic than other solid organs. Little is known about the effectiveness of immunosuppressive regimens after lung transplantation. Herein, we describe a novel model of murine vascularized orthotopic lung transplantation we used to study the effects of costimulatory blockade on lung rejection. Transplants were performed in the Balb --> B6 strain combination. Recipients were either not immunosuppressed or received perioperative CD40/CD40L and CD28/B7 costimulatory blockade. Nonimmunosupressed Balb/c --> B6 lung transplants had severe acute rejection 7 days after transplantation and CD8(+) T cells outnumbered CD4(+) T cells within the allografts. Alternatively, B6 recipients that received perioperative costimulatory blockade had minimal inflammation and there were nearly equal numbers of CD8(+) and CD4(+) T cells in these grafts. Approximately one third of graft-infiltrating CD4(+) T cells expressed Foxp3. CD4(+) T cells isolated from these grafts induced apoptosis of alloreactive CD8(+) T cells that were stimulated with donor splenocytes in vitro. In contrast with wild-type B6 recipient mice, we observed severe rejection of Balb/c lungs 7 days after transplantation into Bcl-2 transgenic B6 recipients that had received costimulatory blockade. CD8(+) T cells outnumbered CD4(+) T cells in these immunosuppressed Bcl-2 transgenic recipients and, compared with immunosuppressed wild-type B6 recipients, a lower percentage of graft-infiltrating CD4(+) T cells expressed Foxp3, and a higher percentage of graft-infiltrating CD8(+) T cells expressed intereferon-gamma. Thus, our results show that perioperative blockade of the CD40/CD40L and CD28/B7 costimulatory pathways markedly ameliorates acute rejection of lung allografts in wild type but not Bcl-2 transgenic recipients.
authors.affiliation: Department of Surgery, Washington University in St. Louis, St. Louis, Missourri 63110-1013, USA.
authors.forename: M
authors.initials: M
authors.lastname: Okazaki
authors.forename: S
authors.initials: S
authors.lastname: Sugimoto
authors.forename: J
authors.initials: J
authors.lastname: Lai
authors.forename: C G
authors.initials: CG
authors.lastname: Kornfeld
authors.forename: R S
authors.initials: RS
authors.lastname: Hotchkiss
authors.forename: S B
authors.initials: SB
authors.lastname: Richardson
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.forename: F H
authors.initials: FH
authors.lastname: Kreisel
authors.forename: H J
authors.initials: HJ
authors.lastname: Huang
authors.forename: G A
authors.initials: GA
authors.lastname: Patterson
authors.forename: A S
authors.initials: AS
authors.lastname: Krupnick
authors.forename: A E
authors.initials: AE
authors.lastname: Gelman
authors.forename: D
authors.initials: D
authors.lastname: Kreisel
mesh_terms: D000069594:Abatacept; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000276:immunology; D018796:Immunoconjugates / Q000276:immunology; D016040:Lung Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014184:Transplantation, Homologous / Q000502:physiology*
chemical_list: D018796:Immunoconjugates; D019253:Proto-Oncogene Proteins c-bcl-2; D000069594:Abatacept