title: Inhibition of αvβ6 promotes acute renal allograft rejection in nonhuman primates.
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.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lo
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: F
authors.initials: F
authors.lastname: Leopardi
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.forename: E A
authors.initials: EA
authors.lastname: Strobert
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
authors.forename: N A
authors.initials: NA
authors.lastname: Turgeon
authors.forename: A K
authors.initials: AK
authors.lastname: Mehta
authors.forename: B
authors.initials: B
authors.lastname: Turnbull
authors.forename: B
authors.initials: B
authors.lastname: Maroni
authors.forename: S M
authors.initials: SM
authors.lastname: Violette
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects* / Q000737:chemistry; D000951:Antigens, Neoplasm; D001706:Biopsy; D006084:Graft Rejection; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016023:Integrins / Q000037:antagonists & inhibitors*; D016030:Kidney Transplantation / Q000379:methods*; D008253:Macaca mulatta; D010865:Pilot Projects; D011897:Random Allocation; D053773:Transforming Growth Factor beta1 / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D007166:Immunosuppressive Agents; D016023:Integrins; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6
keywords: Acute rejection; TGF-β; αvβ6