Trichosanthin-Derived Peptide Tk-PQ Attenuates Immune Rejection in Mouse Tracheal Allotransplant Model by Suppressing PI3K-Ak and Inducing Type II Immune Polarization

Abstract

Obliterative bronchiolitis (OB) is the major complication affecting long-term survival of post-lung transplantation patients. In this study, we evaluated the efficacy of Tk-PQ (a peptide derived from trichosanthin) in alleviating OB in a mouse ectopic tracheal transplant model. We found that post-transplantation treatment of Tk-PQ significant ameliorated OB symptoms including decreased luminal occlusion, reduced epithelial cells loss and less fibrosis in the allograft. Further, Tk-PQ caused an immune suppressive environment by inducing Th2 polarization and increasing Treg population which caused elevated anti-inflammatory IL-4, IL-10, IL-33 and decreased pro-inflammatory IL-1β. Mechanistically, transcriptome analysis of splenic T cells from allografted mice showed Tk-PQ treatment down-regulated the PI3K-Akt pathway. In addition, we recapitulated the phenotypes of Tk-PQ in suppression using an inhibitor LY294002. Together, Tk-PQ regulates post-transplantation immuno-rejection by modulating the balance of T cell response via the PI3K-Akt pathway, making it a promising peptide based immune rejection suppressant for patients receiving allotransplant.

Note:
Funding declaration: . This study was supported by the National Natural Science Foundation of China (grant numbers: 82071856, 81671579, 31370904); Program for scientific and technological innovation from the Science and Technology Commission of Shanghai Municipality (22490760400); Shanghai Municipal Commission of Health, Scientific Research Program of Traditional Chinese medicine (2020JP009); Shuguang Planning of Shanghai Municipal Education Commission (16SG14); The National Key Research and Development Program (2020YFA0113101).

Conflict of Interests: The authors declare no conflict of interest exists.

Ethical Approval: All animal experiments in this study were conducted following protocols approved by the Institutional Animal Care and Use Committee, Shanghai Jiao Tong University School of Medicine.

Keywords: Tk-PQ, Immune rejection, Th2/Treg cell, PI3K-Akt pathway, Ectopic tracheal transplant