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Modulation of Nucleotide Triphosphate Diphosphohydrolase-1 (NTPDase-1)/cd39 in Xenograft Rejection

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Abstract

Background

There is increasing evidence showing that extracellular nucleotides may be important mediators of vascular inflammation. Nucleotide 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.

Materials and Methods

Cardiac xenografts from both wild-type and cd39 knockout mice (C57BL/6 × 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.

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Acknowledgments

Masato Imai and Ko Takigami contributed equally to this work. This study was supported in part by grants from National Institutes of Health HL 57307 (S.C.R.), PO1-41484 (R.D.R.) and American Heart Association GIA 9650490N. The authors are grateful to Elizbieta Kaczmarek and Christian Goepfert for expert assistance, as well as to members of our laboratory for discussion.

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Authors and Affiliations

  1. Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts, 02215, USA

    Masato Imai, Ko Takigami, Olaf Guckelberger, Yuan Lin, Fritz H. Bach &  Simon C. Robson

  2. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

    Eva Csizmadia, Jean Sévigny &  Simon C. Robson

  3. Second Department of Surgery, Asahikawa Medical College, Asahikawa, Hokkaido, Japan

    Masato Imai

  4. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Keiichi Enjyoji & Robert D. Rosenberg

  5. Laboratory of Clinical Pathology, National Cardiovascular Center, Suita, Osaka, Japan

    Keiichi Enjyoji

  6. Immunopathology Unit, Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA

    R. Neal Smith

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  1. Masato Imai
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  2. Ko Takigami
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Correspondence to Simon C. Robson.

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Imai, M., Takigami, K., Guckelberger, O. et al. Modulation of Nucleotide Triphosphate Diphosphohydrolase-1 (NTPDase-1)/cd39 in Xenograft Rejection. Mol Med 5, 743–752 (1999). https://doi.org/10.1007/BF03402098

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