CD26 as a target against fibrous formation in chronic airway rejection lesions

Chronic lung allograft dysfunction (CLAD) after lung transplantation (Tx) is the clinical result of chronic airway rejection lesions (CARL), histomorphologically described as either obliterative remodeling of small airways or alveolar fibroelastosis, or as a combination of both. We here investigated the CD26-inhibitory effect on CD26-expressing CARL.

CARL were induced by BALB/c → C57BL/6 mouse Tx under mild immunosuppression. CARL-related pro-fibrotic mediators were determined by RT-qPCR and western blotting (WB), EMT and ERK markers by WB. CD26 co-expression by immunofluorescence. CD26 was inhibited by Vildagliptin, gene depleted by CD26^-/- mice. Primary lung fibroblasts were employed for ex vivo analyses. Samples from lung transplant patients with CLAD were analyzed by immunohistochemistry.

CARL revealed a significantly higher expression of profibrotic proteins vs. normal lungs (p < 0.05). CD26 and EMT co-expressed in CARL with significantly higher Vimentin, Slug, Hif-1α, α-SMA expression vs. normal lungs (p < 0.05). Vildagliptin decreased the expression of α-SMA and N-cadherin in wild type (WT) lung fibroblasts (p < 0.05). Primary lung fibroblasts from WT and CD26^-/- mice treated with TGF-β1, IFN-γ, and FGF showed a reduction of EMT protein expression, proliferation, and reduced activation of ERK in CD26^-/- mice vs. WT mice. CD26-positive cells were found in patient samples with CLAD in areas of loose fibrosis, but not in areas of dense fibrosis.

CD26 is expressed in CARL-developing lung transplants and CD26-inhibition downregulates fibrosis-forming mediators and fibroblast proliferation. CD26 thus qualifies as a target to attenuate the development of CARL mainly via modulation of ERK and the EMT pathway.