title: Modulation of nucleoside [correction of nucleotide] triphosphate diphosphohydrolase-1 (NTPDase-1)cd39 in xenograft rejection.
abstract: BACKGROUND
  There is increasing evidence showing that extracellular nucleosides [corrected] may be important mediators of vascular inflammation. Nucleoside [corrected] triphosphate diphosphohydrolase-1 (NTPDase-1, identical to CD39), the major vascular endothelial ectonucleotidase, is responsible for the hydrolysis of both extracellular ATP and ADP in the blood plasma to AMP. Studies were therefore conducted to evaluate the role of vascular NTPDase-1/cd39 in modulating platelet activation and vascular injury in cardiac xenografts.
  
  
  METHODS
  Cardiac xenografts from both wild-type and cd39 knockout mice (C57BL/6 x 129 Svj) were transplanted into Lewis rats. Alterations in cd39 mRNA transcripts and NTPDase activity expression were evaluated in wild-type grafts in untreated rats and then following complement depletion and immunosuppression. Rejection responses were studied with both mutant and wild-type grafts in the following models: presensitization with or without complement depletion, complement depletion alone, and with chronic immunosuppression to induce long-term graft survival.
  
  
  RESULTS
  NTPDase biochemical activity in wild-type xenografts rapidly decreased after transplantation but soon rebounded with graft survival. Elevated levels of cd39 mRNA with associated increases in NTPDase activity were observed in all long-term surviving wild-type grafts. Hyperacute xenograft rejection times were comparable in wild-type and mutant grafts but cd39-deficient grafts were subject to more rapid rejection and exhibited pronounced vascular injury in complement-depleted, presensitized rats. The cd39-deficient grafts in immunosuppressed recipients were subject to increased intravascular platelet sequestration and fibrin deposition; this resulted in focal myocardial infarction in long-term surviving mutant xenografts.
  
  
  CONCLUSIONS
  Augmentation of NTPDase-1 activity may be an important adaptive response for graft survival. Our results suggest that NTPDase-1/cd39 influences pathways of vascular injury in cardiac xenografts.
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Imai
authors.forename: K
authors.initials: K
authors.lastname: Takigami
authors.forename: O
authors.initials: O
authors.lastname: Guckelberger
authors.forename: K
authors.initials: K
authors.lastname: Enjyoji
authors.forename: R N
authors.initials: RN
authors.lastname: Smith
authors.forename: Y
authors.initials: Y
authors.lastname: Lin
authors.forename: E
authors.initials: E
authors.lastname: Csizmadia
authors.forename: J
authors.initials: J
authors.lastname: Sévigny
authors.forename: R D
authors.initials: RD
authors.lastname: Rosenberg
authors.forename: F H
authors.initials: FH
authors.lastname: Bach
authors.forename: S C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D000251:Adenosine Triphosphatases; D000818:Animals; D015703:Antigens, CD / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D001081:Apyrase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D015971:Gene Expression Regulation, Enzymologic; D006084:Graft Rejection / Q000201:enzymology*; D006085:Graft Survival; D016027:Heart Transplantation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D019007:P-Selectin / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous
chemical_list: D015703:Antigens, CD; D019007:P-Selectin; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; D001081:Apyrase; C067869:CD39 antigen