CD26/DPP4 Inhibitor: A Novel Prophylactic Drug for Chronic Allograft Dysfunction after Clinical Lung Transplantation

Purpose Prevention of chronic lung allograft dysfunction (CLAD) is still an issue. In mouse/rat lung transplantation (LTx) models, we have shown the efficacy of dipeptidyl peptidase 4 inhibitors (DPP4i), drugs for diabetes mellitus (DM). We assumed that the key mechanism might be stromal cell-derived factor-1 (SDF-1). This is a chemokine for regenerative stem cells to repair injured tissue, regarded as a direct injury marker. It is also induced by DPP4i to reinforce tissue repair. This study aims to elucidate the efficacy of DPP4i in clinical LTx, and to search for a new biomarker for CLAD or overall survival (OS). Methods The patients who underwent cadaveric or living-donor LTx in our institution between 2002 and 2018 were retrospectively reviewed. Patients with DM were extracted and divided into two groups regarding the usage of DPP4i in perioperative periods. DPP4i therapy was based on the guideline for DM. SDF-1 and IL-10 in the serum samples in the 3rd and the 6th month after LTx were measured by ELISA. Patients’ characteristics, postoperative outcomes, and the ELISA data were analyzed. Finally, we performed risk analyses for CLAD and OS. Results In a total of 95 LTx recipients with DM, 29 were treated with DPP4i, while 66 were not. 5-year CLAD-free survivals were 63% in the DPP4i group and 41% in the non-DPP4i group (p=0.044) (Figure). Other surgical outcomes were comparable. In three of four patients, SDF-1 levels increased after the initiation of DPP4i between the 3rd and the 6th month. In the evaluation of all, there was a positive correlation between IL-10 in the 6th month and SDF-1 in the 3rd month. According to the Cox regression model, the ratio of SDF-1 in the 6th month to the 3rd month was identified as the adverse prognostic factor for CLAD and OS. Conclusion DPP4i may be a novel prophylactic drug for CLAD by inducing anti-inflammatory cytokine in LTx recipients with DM. The ratio of SDF-1 level in the 6th to the 3rd month may predict CLAD and OS. We will extend the research for non-DM patients as well.