Modulation of nucleotide triphosphate diphosphohydrolase-1 (NTPDase-1)/cd39 in xenograft rejection

Background: There is increasing evidence showing that extracellular nucleot ides may be important mediators of vascular inflammation. Nucleotide tripho sphate diphos-phohydrolase-1 (NTPDase-1, identical to CD39), the major vasc ular endothelial ectonucleotidase, is responsible for the hydrolysis of bot h extracellular ATP and ADP in the blood plasma to AMP. Studies were theref ore conducted to evaluate the role of vascular NTPDase-1/cd39 in modulating platelet activation and vascular injury in cardiac xenografts. Materials and Methods: Cardiac xenografts from both wild-type and cd39 knoc kout mice (C57BL/6 x 129 Svj) were transplanted into Lewis rats. Alteration s in cd39 mRNA transcripts and NTPDase activity expression were evaluated i n wild-type grafts in untreated rats and then following complement depletio n and immunosuppression. Rejection responses were studied with both mutant and wildtype grafts in the following models: presensitization with or witho ut complement depletion, complement depletion alone, and with chronic immun osuppression to induce long-term graft survival. Results: NTPDase biochemical activity in wild-type xenografts rapidly decre ased after transplantation but soon rebounded with graft survival. Elevated levels of cd39 mRNA with associated increases in NTPDase activity were obs erved in all long-term surviving wild-type grafts. Hyperacute xenograft rej ection times were comparable in wild-type and mutant grafts but cd39-defici ent grafts were subject to more rapid rejection and exhibited pronounced va scular injury in complement-depleted presensitized rats. The cd39-deficient grafts in immunosuppressed recipients were subject to increased intravascu lar platelet sequestration and fibrin deposition; this resulted in focal my ocardial infarction in long-term surviving mutant xenografts. Conclusions: Augmentation of NTPDase-1 activity may be an important adaptiv e response for graft survival. Our results suggest that NTPDase-1/cd39 infl uences pathways of vascular injury in cardiac xenografts.