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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

CD26+ Epithelial Cell Clusters as a Novel Biomarker and Therapeutic Target in Chronic Lung Allograft Dysfunction

      Purpose

      Novel diagnostic and therapeutic strategies for chronic lung allograft dysfunction (CLAD) are pressing priorities. We previously reported that CD26/DPP-4 inhibition attenuated ischemia-reperfusion injury, acute rejection and chronic fibrosis in mouse lung transplantation (LTx), and in our recent clinical study, a CD26/DPP-4 inhibitor improved CLAD-free survival (ISHLT 2020 abstract). To elucidate the mechanism of CD26/DPP-4 inhibitors in LTx, and apply them in the clinic, we investigated CD26 expression in CLAD clinical specimens.

      Methods

      Among patients who underwent LTx in our institution, we retrieved pathological specimens from re-LTx and autopsy cases. We also included two native lung samples from LTx recipients. We performed hematoxylin-eosin and Elastica-Masson staining and immunohistochemistry using a CD26 antibody. We evaluated the pathological findings and clinical characteristics.

      Results

      We evaluated 11 patients (6 females, 5 males) with a median age of 43 (8-58) years. The pathological samples were nine allografts and two native lung specimens. Of the allografts, six were obtained at autopsy, performed 38 (12-71) [median (range)] months after LTx, and three were obtained by resection during re-LTx, performed 20 (17-59) months after the initial LTx. Seven patients had diabetes mellitus, but none received CD26/DPP-4 inhibitors. Seven patients (four autopsy and three re-LTx cases) had CLAD with bronchiolitis obliterans (BO) pathology. Immunohistochemistry revealed clusters of CD26+ epithelial cells adjacent to the BO lesions or in the obstructed bronchial lumen in six of the seven CLAD patients. One CLAD patient without CD26 expression died from lung cancer, rather than CLAD, which was diagnosed at autopsy. In the non-CLAD or native lung samples, the CD26+ epithelial cell clusters were not detected.

      Conclusion

      Clusters of CD26+ epithelial cells were detected in CLAD, but not non-CLAD, samples. CD26 might be a novel biomarker and therapeutic target for CLAD.