CD26-inhibition for the prevention of chronic lung allograft rejection

• Applicant: Professor Dr. Wolfgang Jungraithmayr
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528746109

Chronic lung allograft dysfunction (CLAD) is the major hurdle to long-term survival in lung transplant recipients. CLAD results from a progressive fibrotic remodeling of small airways and the lung parenchyma and clinically manifests as an irreversible loss of pulmonary function. Patients with CLAD have a high mortality and no causal therapy against CLAD is available up to now. CD26 is a transmembrane molecule with enzymatic and costimulatory activity regulating immune responses after transplantation. However, CD26 also has key functions in the initiation and progress of organ fibrosis. Several experimental studies have identified CD26 to promote the development of fibrosis, and increasing data suggest that when inhibiting CD26, fibrotic changes can be abrogated. In this proposal, we aim to attenuate or even prevent CLAD development by pharmacological inhibition of CD26/DPP4 by an (I) experimental and a (II) translational-clinical approach: (I) we evaluate the immunomodulatory and anti-fibrotic effects of systemic CD26 inhibition during the development of CLAD in a murine lung transplantation model of chronic rejection over time. Also, we will analyze for the potential protective effect of CD26-inhibition on transplant endothelium against ischemia-reperfusion injury to prevent key initial events and inflammatory cells influx directly and indirectly linked to CLAD. (II) In a translational-clinical approach, we wish to demonstrate the effects of CD26-inhibition in human chronic lung transplant rejection. To this end, we will employ an ex vivo spheroid cell culture model developed from pulmonary biopsy specimens from lung transplant recipients. This model will allow for an individual evaluation of the anti-fibrotic effect of CD26-inhibition in chronic lung allograft rejection. CD26-inhibitors are in routine clinical use as antidiabetics without significant side effects for many years, thus facilitating the repurpose of these compounds as therapeutics in other diseases. By studying the antifibrotic effect of CD26-inhibition in two highly relevant and established research models, we will gain substantial new insights into the therapy against CLAD. These data will then set the base for a clinical trial repurposing CD26-inhibitors as anti-fibrotic therapeutics in lung transplanted patients.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Sven Diederichs; Professor Dr. Gernot Zissel