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Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates.

Publication ,  Journal Article
Lo, DJ; Farris, AB; Song, M; Leopardi, F; Anderson, DJ; Strobert, EA; Ramakrishnan, S; Turgeon, NA; Mehta, AK; Turnbull, B; Maroni, B ...
Published in: Am J Transplant
December 2013

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.

Duke Scholars

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

December 2013

Volume

13

Issue

12

Start / End Page

3085 / 3093

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta1
  • Surgery
  • Random Allocation
  • Pilot Projects
  • Macaca mulatta
  • Kidney Transplantation
  • Integrins
  • Immunosuppressive Agents
  • Immunosuppression Therapy
  • Graft Rejection
 

Citation

APA
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MLA
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Lo, D. J., Farris, A. B., Song, M., Leopardi, F., Anderson, D. J., Strobert, E. A., … Kirk, A. D. (2013). Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates. Am J Transplant, 13(12), 3085–3093. https://doi.org/10.1111/ajt.12467
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

December 2013

Volume

13

Issue

12

Start / End Page

3085 / 3093

Location

United States

Related Subject Headings

  • Transforming Growth Factor beta1
  • Surgery
  • Random Allocation
  • Pilot Projects
  • Macaca mulatta
  • Kidney Transplantation
  • Integrins
  • Immunosuppressive Agents
  • Immunosuppression Therapy
  • Graft Rejection