Inhibition of αvβ6 Promotes Acute Renal Allograft Rejection in Nonhuman Primates

Abstract

The integrin avb6 activates latent transforming growth factor-b (TGF-b) within the kidney and may be a target for the prevention of chronic allograft fibrosis after kidney transplantation. However, TGF-b also has known immunosuppressive properties that are exploited by calcineurin inhibitors (CNIs); thus, the net benefit of avb6 inhibition remains undetermined. To assess the acute impact of interference with avb6 on acute rejection, we tested a humanized avb6-specific monoclonal antibody (STX-100) in a randomized, double-blinded, placebo-controlled nonhuman primate renal transplantation study to evaluate whether avb6 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 ¼ 0.049). Immunohistochemical analysis confirmed avb6 ligand presence, and avb6 staining intensity was lower in STX-100-treated animals (p ¼ 0.055), indicating an apparent blockade effect of STX-100. LAP, LTBP-1 and TGF-b were all decreased in animals that rejected on STX-100 compared to those that rejected on standard immunosuppression alone, suggesting a relevant effect of avb6 blockade on local TGF-b. These data caution against the use of avb6 blockade to achieve TGF-b inhibition in kidney transplantation.

Inhibiting Integrin αvβ5 Reduces Ischemia–Reperfusion Injury in an Orthotopic Lung Transplant Model in Mice

“…This finding is consistent with a recent report from Bae et al describing a role for interactions between αvβ5 and TGFβ‐induced protein in regulating both vascular permeability and tissue inflammation . Blockade of the structurally related integrin αvβ6 has been well documented to cause tissue inflammation as a consequence of suppression of TGFβ activation, an effect that has been shown to be problematic in the setting of organ transplantation . However, αvβ5 does not play a prominent role in activation of TGFβ and has not been described to increase tissue inflammation in any setting.…”

Studies Introducing Costimulation Blockade for Vascularized Composite Allografts in Nonhuman Primates

“…Experimental groups had the following agents added: Group I tacrolimus (T); Group II CTLA‐4Ig, alefacept, and sirolimus; Group III CTLA‐4Ig, alefacept, and tacrolimus (CAT) with conversion to sirolimus; Group IV belatacept (replacing CTLA4‐Ig), in addition to alefacept, and tacrolimus (BAT) with conversion to sirolimus; and Group V belatacept and tacrolimus (BT) with conversion to sirolimus (Figure ). Intramuscular tacrolimus dosing was adjusted for target trough levels of 8–12 ng/mL and intramuscular sirolimus dosing was targeted for a range of 8–12 ng/mL with weekly monitoring of drug levels .…”

αv integrins: key regulators of tissue fibrosis

“…These findings were recapitulated in the unilateral ureteric obstruction model of renal fibrosis (Ma et al 2003). Although these data suggest a strong regulatory role for αvβ6 in renal fibrosis, the blockade of αvβ6 activity following renal transplantation has been reported to increase significantly the acute rejection of the transplanted organ (Lo et al 2013). …”