Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates

Academic Article

Abstract

  • The integrin αvβ6 activates latent transforming growth factor-β (TGF-β) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-β also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of αvβ6 inhibition remains undetermined. To assess the acute impact of interference with αvβ6 on acute rejection, we tested a humanized αvβ6- specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether αvβ6 blockade alters the risk of acute rejection during CNI-based immunosuppression. Rhesus monkeys underwent renal allotransplantation under standard CNI-based maintenance immunosuppression; 10 biopsy-confirmed rejection-free animals were randomized to receive weekly STX-100 or placebo. Animals treated with STX-100 experienced significantly decreased rejection-free survival compared to placebo animals (p = 0.049). Immunohistochemical analysis confirmed αvβ6 ligand presence, and αvβ6 staining intensity was lower in STX-100-treated animals (p = 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-β were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of αvβ6 blockade on local TGF-β. These data caution against the use of αvβ6 blockade to achieve TGF-β inhibition in kidney transplantation. The authors report on the use of an αvβ6 monoclonal antibody and its association with acute rejection when used in concert with calcineurin inhibitor-based immunosuppression in a nonhuman primate renal transplant model. © Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.
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    Digital Object Identifier (doi)

    Author List

  • Lo DJ; Farris AB; Song M; Leopardi F; Anderson DJ; Strobert EA; Ramakrishnan S; Turgeon NA; Mehta AK; Turnbull B
  • Start Page

  • 3085
  • End Page

  • 3093
  • Volume

  • 13
  • Issue

  • 12