title: PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.
abstract: The PD-1:PDL pathway plays an important role in regulating alloimmune responses but its role in transplantation tolerance is unknown. We investigated the role of PD-1:PDL costimulatory pathway in peripheral and a well established model of central transplantation tolerance. Early as well as delayed blockade of PDL1 but not PDL2 abrogated tolerance induced by CTLA4Ig in a fully MHC-mismatched cardiac allograft model. Accelerated rejection was associated with a significant increase in the frequency of IFN-gamma-producing alloreactive T cells and expansion of effector CD8(+) T cells in the periphery, and a decline in the percentage of Foxp3(+) graft infiltrating cells. Similarly, studies using PDL1/L2-deficient recipients confirmed the results with Ab blockade. Interestingly, while PDL1-deficient donor allografts were accepted by wild-type recipients treated with CTLA4Ig, the grafts developed severe chronic rejection and vasculopathy when compared with wild-type grafts. Finally, in a model of central tolerance induced by mixed allogeneic chimerism, engraftment was not abrogated by PDL1/L2 blockade. These novel data demonstrate the critical role of PDL1 for induction and maintenance of peripheral transplantation tolerance by its ability to alter the balance between pathogenic and regulatory T cells. Expression of PDL1 in donor tissue is critical for prevention of in situ graft pathology and chronic rejection.
authors.affiliation: Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Tanaka
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Albin
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamaura
authors.forename: Antje
authors.initials: A
authors.lastname: Habicht
authors.forename: Takaya
authors.initials: T
authors.lastname: Murayama
authors.forename: Martin
authors.initials: M
authors.lastname: Grimm
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Waaga
authors.forename: Takuya
authors.initials: T
authors.lastname: Ueno
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: David M
authors.initials: DM
authors.lastname: Rothstein
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Nader
authors.initials: N
authors.lastname: Najafian
mesh_terms: D000069594:Abatacept; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D060890:B7-H1 Antigen; D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D018796:Immunoconjugates / Q000627:therapeutic use; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D011828:Radiation Chimera; D016038:Skin Transplantation / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D000069594:Abatacept