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PMID: 17911605 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 179 ·No. 8 ·2007-10-15 ·Pages 5204-10

Tanaka K, Albin MJ, Yuan X, Yamaura K, Habicht A, Murayama T, Grimm M, Waaga AM, Ueno T, Padera RF, Yagita H, Azuma M, Shin T, Blazar BR, Rothstein DM, Sayegh MH, Najafian N

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.

MeSH Terms
Abatacept Animals B7-1 Antigen/genetics,physiology B7-H1 Antigen Chronic Disease Graft Rejection/immunology,pathology,prevention & control H-2 Antigens/genetics,immunology Heart Transplantation/immunology,pathology Immunoconjugates/therapeutic use Lymphocyte Culture Test, Mixed Membrane Glycoproteins/antagonists & inhibitors,deficiency,genetics,physiology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Peptides/antagonists & inhibitors,deficiency,genetics,physiology Programmed Cell Death 1 Ligand 2 Protein Radiation Chimera Skin Transplantation/immunology Transplantation Tolerance/genetics,immunology
Chemicals
B7-1 Antigen B7-H1 Antigen Cd274 protein, mouse H-2 Antigens H-2Kb protein, mouse Immunoconjugates Membrane Glycoproteins Pdcd1lg2 protein, mouse Peptides Programmed Cell Death 1 Ligand 2 Protein Abatacept
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Tanaka Katsunori
Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Albin Monica J
Yuan Xueli
Yamaura Kazuhiro
Habicht Antje
Murayama Takaya
Grimm Martin
Waaga Ana Maria
Ueno Takuya
Padera Robert F
Yagita Hideo
Azuma Miyuki
Shin Tahiro
Blazar Bruce R
Rothstein David M
Sayegh Mohamed H
Najafian Nader
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
0022-1767
DOI
10.4049/jimmunol.179.8.5204
Published
2007-10-15
Pages
5204-10
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2291549
Subset
IM
Grants
NIAID NIH HHS · P01 AI056299 · United States
NIAID NIH HHS · K08 AI064335-01A2 · United States
NHLBI NIH HHS · 2 R37 HL56067 · United States
NIAID NIH HHS · R01 AI051559 · United States
NIAID NIH HHS · P01 AI041521 · United States
NHLBI NIH HHS · R01-HL63452 · United States
NIAID NIH HHS · P01-AI041521 · United States
NHLBI NIH HHS · R37 HL056067 · United States
NIAID NIH HHS · K08 AI064335 · United States
NIAID NIH HHS · P01-AI56299 · United States
NIAID NIH HHS · 1K08AI064335 · United States
NIAID NIH HHS · R01-AI34495 · United States
NIAID NIH HHS · R01-AI51559 · United States
NIAID NIH HHS · R01 AI034495 · United States
NHLBI NIH HHS · R01 HL063452 · United States
External Links
PubMed source DOI: 10.4049/jimmunol.179.8.5204 PMC Full Text View journal details
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