Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates

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);...

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Bibliographic Details
Published in:American journal of transplantation 2013-12, Vol.13 (12), p.3085-3093
Main 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.
Format: Article
Language:English
Subjects:
Acute rejection
Allografts
Animals
Antibodies, Monoclonal - adverse effects
Antibodies, Monoclonal - chemistry
Antigens, Neoplasm
Biological and medical sciences
Biopsy
Graft Rejection
Immunosuppression Therapy
Immunosuppressive Agents - adverse effects
Integrins - antagonists & inhibitors
Kidney Transplantation - methods
Macaca mulatta
Medical sciences
Pilot Projects
Random Allocation
Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases
TGF‐β
Transforming Growth Factor beta1 - blood
αvβ6
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Summary: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.
ISSN:1600-6135
1600-6143
DOI:10.1111/ajt.12467