Various costimulatory pathways are essential for induction of regulatory cells by intratracheal delivery of alloantigen.
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.
Aramaki
O
O
Department of Surgery, Teikyo University, Japan. aramaki@med.teikyo-u.ac.jp
Inoue
F
F
Takayama
T
T
Shimazu
M
M
Kitajima
M
M
Ikeda
Y
Y
Okumura
K
K
Yagita
H
H
Shirasugi
N
N
Niimi
M
M
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
D007519:Isoantigens