Antiperlecan antibodies are novel accelerators of immune-mediated vascular injury

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DOIResolve DOI: http://doi.org/10.1111/ajt.12168
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TypeArticle
Journal titleAmerican Journal of Transplantation
ISSN1600-6135
Volume13
Issue4
Pages861874; # of pages: 14
Subjectacute rejection; antibody; calcineurin inhibitor; CD4 antigen; immunoglobulin G; perlecan; animal experiment; antibody titer; apoptosis; blood vessel injury; endothelium cell; graft recipient; graft survival; immune mediated injury; immunoglobulin A nephropathy; kidney allograft rejection; kidney transplantation; neointima; protein function
AbstractAcute vascular rejection (AVR) is characterized by immune-mediated vascular injury and heightened endothelial cell (EC) apoptosis. We reported previously that apoptotic ECs release a bioactive C-terminal fragment of perlecan referred to as LG3. Here, we tested the possibility that LG3 behaves as a neoantigen, fuelling the production of anti-LG3 antibodies of potential importance in regulating allograft vascular injury. We performed a case-control study in which we compared anti-LG3 IgG titers in kidney transplant recipients with AVR (n = 15) versus those with acute tubulo-interstitial rejection (ATIR) (n = 15) or stable graft function (n = 30). Patients who experienced AVR had elevated anti-LG3 titers pre and posttransplantation compared to subjects with ATIR or stable graft function (p < 0.05 for both mediators). Elevated pretransplant anti-LG3 titers (OR: 4.62, 95% CI: 1.08-19.72) and pretransplant donor-specific antibodies (DSA) (OR 4.79, 95% CI: 1.03-22.19) were both independently associated with AVR. To address the functional role of anti-LG3 antibodies in AVR, we turned to passive transfer of anti-LG3 antibodies in an animal model of vascular rejection based on orthotopic aortic transplantation between fully MHC-mismatched mice. Neointima formation, C4d deposition and allograft inflammation were significantly increased in recipients of an ischemic aortic allograft passively transferred with anti-LG3 antibodies. Collectively, these data identify anti-LG3 antibodies as novel accelerators of immune-mediated vascular injury and obliterative remodeling.
Publication date
LanguageEnglish
AffiliationNational Research Council Canada (NRC-CNRC); Human Health Therapeutics
Peer reviewedYes
NPARC number21270524
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Record identifierb4f72186-6ae3-4377-9fd9-c8f6465dddd7
Record created2014-02-17
Record modified2016-05-09
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