title: Various costimulatory pathways are essential for induction of regulatory cells by intratracheal delivery of alloantigen.
abstract: BACKGROUND
  We previously reported that intratracheal delivery of alloantigen induced regulatory cells in a mouse heart transplantation model. We investigated the roles of costimulatory pathways in the induction of regulatory cells by intratracheal delivery of alloantigen.
  
  
  METHODS
  CBA (H-2k) mice were pretreated with intratracheal delivery of splenocytes (1 x 10(7)) from C57BL/10 (H-2b) mice and administration of monoclonal antibodies (mAb) specific for programmed death (PD)-1 and its ligands, programmed death-ligand (PD-L)1 and PD-L2, CD70, CD134 ligand (CD134L), CD153, CD137L, or receptor activator of nuclear factor-kappaB (NF-kappaB) (RANK). Seven days later, naive CBA mice underwent adoptive transfer of splenocytes (5 x 10(7)) from the pretreated CBA mice and transplantation of C57BL/10 heart.
  
  
  RESULTS
  Adoptive transfer of splenocytes from CBA mice that had been pretreated with intratracheal delivery of C57BL/10 splenocytes significantly prolonged the survival of C57BL/10 allograft (median survival time [MST], 68 days) as compared with adoptive transfer from untreated CBA mice (MST, 12 days). Concomitant administration of control immunoglobulin (Ig)G, anti-PD-L2 mAb, or anti-CD137L along with intratracheal delivery did not significantly affect the prolongation (MST, 72, 68, and 65 days, respectively). In contrast, anti-PD-1, anti-PD-L1, anti-CD70, anti-CD134L, anti-CD153, or anti-RANK mAb abrogated the prolongation induced by adoptive transfer from the pretreated mice with intratracheal delivery (MST, 18, 17, 16, 14, 10, and 18 days, respectively).
  
  
  CONCLUSIONS
  The PD-1/PD-L1, CD27/CD70, CD134/CD134L, CD30/CD153, and tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE)/RANK interactions are independently required for generation of regulatory cells by intratracheal delivery of alloantigen.
authors.affiliation: Department of Surgery, Teikyo University, Japan. aramaki@med.teikyo-u.ac.jp
authors.forename: O
authors.initials: O
authors.lastname: Aramaki
authors.forename: F
authors.initials: F
authors.lastname: Inoue
authors.forename: T
authors.initials: T
authors.lastname: Takayama
authors.forename: M
authors.initials: M
authors.lastname: Shimazu
authors.forename: M
authors.initials: M
authors.lastname: Kitajima
authors.forename: Y
authors.initials: Y
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Okumura
authors.forename: H
authors.initials: H
authors.lastname: Yagita
authors.forename: N
authors.initials: N
authors.lastname: Shirasugi
authors.forename: M
authors.initials: M
authors.lastname: Niimi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D006085:Graft Survival / Q000502:physiology*; D007442:Intubation, Intratracheal; D007519:Isoantigens / Q000008:administration & dosage*; D017710:Lymphocyte Transfusion / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D023421:Models, Animal; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007519:Isoantigens