Endothelial cell cytoprotection induced in vitro by allo- or xenoreactive antibodies is mediated by signaling through adenosine A2 receptors.
Endothelial cell (EC) expression of proteins such as hemoxygenase-1 or Bcl-xL is associated with enhanced survival of vascularized allo- or xenografts. These grafts are resistant to humoral rejection, a phenomenon called accommodation. In vitro, low concentrations of allo- and xenoreactive antibody (XNA) induce a cytoprotective phenotype in EC similar to that seen in accommodated grafts. In this study we examine whether adenosine plays a role in antibody-induced cytoprotection. Porcine EC were incubated with human anti-pig XNA or specific alloantibody. EC expressed Bcl-xL and were protected from TNF-mediated apoptosis. Bcl-xL expression was inhibited by an adenosine A2 receptor antagonist. Human anti-pig XNA were shown to bind and induce cyclic adenosine 3',5'-monophosphate (cAMP) generation through these receptors. This activity was abolished by depletion of anti-galalpha(1-3)gal-specific XNA. In contrast, alloantibody caused adenosine production. Protection from TNF-mediated apoptosis was also mediated through A2 receptor but involved additional non-cAMP-dependent signaling. This study indicates a molecular mechanism common to both antibody-mediated cytoprotection and ischemic preconditioning and suggests a potential therapeutic avenue based on adenosine for improving the outcome of transplanted grafts in those patients with pre-existing anti-graft antibody.
Department of Immunology, Imperial College London, Hammersmith Hospital, Du Cane Road, London, GB.
Alexandros
A
Delikouras
Lynette D
LD
Fairbanks
Anne H
AH
Simmonds
Robert I
RI
Lechler
Anthony
A
Dorling
D000241:Adenosine / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015925:Cryopreservation; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D043683:Receptors, Adenosine A2 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine / Q000276:immunology / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051020:bcl-X Protein
D000906:Antibodies; D019253:Proto-Oncogene Proteins c-bcl-2; D043683:Receptors, Adenosine A2; D019010:Vascular Cell Adhesion Molecule-1; D051020:bcl-X Protein; D000241:Adenosine