Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates. Issue 12 (1st October 2013)

• Record Type: Journal Article
• Authors: Lo, D. J.; Farris, A. B.; Song, M.; Leopardi, F.; Anderson, D. J.; Strobert, E. A.; Ramakrishnan, S.; Turgeon, N. A.; Mehta, A. K.; Turnbull, B.; Maroni, B.; Violette, S. M.; Kirk, A. D.
• Is Part Of: American journal of transplantation. Volume 13:Issue 12(2013)
• Page Start: 3085
• Page End: 3093
• Publication Date: 2013-10-01
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; 617.95
• DOI: 10.1111/ajt.12467
• Languages: English
• ISSNs: 1600-6135

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ajt12467-sec-0001" sec-type="section"> <p>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.</p> </sec> </abstract>