title: The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo.
abstract: The programmed death ligand 1 (PDL1)/programmed death 1 (PD1) costimulatory pathway plays an important role in the inhibition of alloimmune responses as well as in the induction and maintenance of peripheral tolerance. It has been demonstrated recently that PDL1 also can bind B7.1 to inhibit T cell responses in vitro. Using the bm12 into B6 heart transplant model, we investigated the functional significance of this interaction in alloimmune responses in vivo. PD1 blockade unlike PDL1 blockade failed to accelerate bm12 allograft rejection, suggesting a role for an additional binding partner for PDL1 other than PD1 in transplant rejection. PDL1 blockade was able to accelerate allograft rejection in B7.2-deficient recipients but not B7.1-deficient recipients, indicating that PDL1 interaction with B7.1 was important in inhibiting rejection. Administration of the novel 2H11 anti-PDL1 mAb, which only blocks the PDL1-B7.1 interaction, aggravated chronic injury of bm12 allografts in B6 recipients. Aggravated chronic injury was associated with an increased frequency of alloreactive IFN-γ-, IL-4-, and IL-6-producing splenocytes and a decreased percentage of regulatory T cells in the recipients. Using an in vitro cell culture assay, blockade of the interaction of PDL1 on dendritic cells with B7.1 on T cells increased IFN-γ production from alloreactive CD4(+) T cells, whereas blockade of dendritic cell B7.1 interaction with T cell PDL1 did not. These data indicate that PDL1 interaction with B7.1 plays an important role in the inhibition of alloimmune responses in vivo and suggests a dominant direction for PDL1 and B7.1 interaction.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Leonardo V
authors.initials: LV
authors.lastname: Riella
authors.forename: Susanne
authors.initials: S
authors.lastname: Chock
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.forename: Xiaozhi
authors.initials: X
authors.lastname: Zhao
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Alison M
authors.initials: AM
authors.lastname: Paterson
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Vijay
authors.initials: V
authors.lastname: Vanguri
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016038:Skin Transplantation / Q000276:immunology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D008024:Ligands; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor