Ecto-5'-nucleotidase (CD73) attenuates allograft airway rejection through adenosine 2A receptor stimulation.
There are multiple drivers of leukocyte recruitment in lung allografts that contribute to lymphocytic bronchitis (LB) and bronchiolitis obliterans (BO). The innate mechanisms driving (or inhibiting) leukocyte trafficking to allografts remain incompletely understood. This study tested the hypothesis that CD73 (ecto-5'nucleotidase), an enzyme that catalyzes the conversion of AMP to adenosine, is a critical negative regulator of LB and BO. Implantation of tracheal allografts from wild type (WT) mice into CD73(-/-) recipients revealed a striking increase in airway luminal obliteration at 7 d (62 +/- 4% and 47 +/- 5% for CD73(-/-) and WT allograft recipients, respectively; p = 0.046). There was also a concordant increase in CD3(+) lymphocytic infiltration (523 +/- 41 cells and 313 +/- 43 cells for CD73(-/-) and WT allograft recipients, respectively; p = 0.013). Because real-time PCR revealed a 43-fold upregulation of mRNA for the adenosine A2A receptor (A2AR) in WT allografts compared with WT isografts (p = 0.032), additional experiments were performed to determine whether the protective effect of CD73 was due to generation of adenosine and its stimulation of the A2AR. Treatment of WT recipients with an A2AR agonist significantly reduced CD3(+) lymphocyte infiltration and airway luminal obliteration; similar treatment of CD73(-/-) recipients rescued them from LB and airway obliteration. These data implicate CD73 acting through adenosine generation and its stimulation of the A2AR as a critical negative modulator of lymphocyte recruitment into airway allografts. The CD73/adenosine axis might be a new therapeutic target to prevent BO.
Ohtsuka
Takashi
T
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Changelian
Paul S
PS
Bouïs
Diane
D
Noon
Kathleen
K
Harada
Hiroaki
H
Lama
Vibha N
VN
Pinsky
David J
DJ
D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000276:immunology / Q000517:prevention & control; D017252:CD3 Complex / Q000276:immunology; D002853:Chromatography, Liquid; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D007371:Interferon-gamma / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010627:Phenethylamines / Q000097:blood / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D053719:Tandem Mass Spectrometry; D014132:Trachea / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D014184:Transplantation, Homologous; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D017252:CD3 Complex; D007376:Interleukin-2; D010627:Phenethylamines; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D007371:Interferon-gamma; D015720:5'-Nucleotidase; D000241:Adenosine