establishment-rat-model-acute-antibody-mediated-rejection-kidney

Establishment of Rat Model of Acute Antibody-Mediated Rejection in Kidney Transplantation

Acute antibody-mediated rejection (AAMR) remains a major obstacle to long-term graft survival in kidney transplantation. The pathophysiology of AAMR is ...

The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital

Cardiac transplantation is the preferred treatment option for patients with chronic heart failure. However, acute rejection remains as a the significant challenge that leads to cardiac allograft dysfunction, resulting from immune system activation and reactive oxygen species (ROS) production by inflammatory cells. Current immunosuppressive regimens have limitations, such as systemic administration, toxicity, and inefficient inhibition of B cells, macrophages, and natural killer (NK) cells. Targeted immunosuppressant delivery via nanomaterials is a promising approach for sustained release within allografts, significantly enhancing drug efficiency. Manganese dioxide (MnO) possesses the characteristics of chemotaxis towards inflammatory sites, scavenging ROS, and facilitating drug transport. In this study, tacrolimus (FK506)-loaded MnO nanoparticles (NPs) are synthesized via in-situ polymerization, using polydopamine (PDA) as an intermediate. The resulting FK506@MnO/PDA NPs exhibit excellent safety and cytocompatibility. This targeted delivery system significantly increases FK506 accumulation in murine cardiac allografts, effectively mitigating acute rejection and prolonging allograft survival. Furthermore, the mechanism by which FK506@MnO/PDA NPs alleviate acute rejection is investigated, validating that FK506 release inhibits T-cell activation while modulating the inflammatory environment by reducing oxidative stress and scavenging ROS. Fluorescence imaging demonstrates that FK506@MnO/PDA NPs exhibit prolonged retention and more pronounced accumulation in cardiac allografts compared with free FK506. This study presents a novel strategy for immunosuppressive therapy following cardiac transplantation, potentially improving allograft prognosis.

Targeted tacrolimus delivery via manganese dioxide nanoparticles for mitigating acute allograft rejection in murine cardiac transplantation.

Follicular helper T (Tfh), B and regulatory T (Treg) cells are involved in the pathogenesis of chronic rejection (CR) after transplantation. Dihydroartemisinin (DHA) is an antimalarial drug with anti-inflammatory activity; however, the effects and mechanisms of DHA on Tfh, B and Treg cells have not been comprehensively elucidated. The aim of this study was to investigate the effect of DHA on Tfh, B and Treg cells and its preventive effect on CR. In vitro assays demonstrated that DHA not only blocks the induction of Tfh cells and alleviates their supportive effect on B cell differentiation but also directly suppresses B cell activation, differentiation and antibody production. Additionally, DHA promotes the induction of Treg cells and enhances their stability in an inflammatory environment. In vivo studies showed that DHA effectively alleviated CR by suppressing neointimal hyperplasia, myocardial injury and interstitial fibrosis and reducing inflammatory cell infiltration and C4d deposition in allografts. Moreover, DHA decreased the levels of Tfh, germinal centre Tfh, B, germinal centre B, IgG-producing and plasma cells in recipients but increased Treg cell levels in recipients and allografts. Mechanistically, we confirmed that DHA inhibits Tfh cells by blocking IL-2-inducible T cell kinase signalling, suppresses B cells by blocking Bruton's tyrosine kinase signalling, and enhances Treg cells by blocking mTOR signalling while promoting STAT5 signalling. In conclusion, our results verified that DHA inhibits Tfh and B cells and enhances Treg cells to attenuate CR in mice, highlighting its potential applicability in the development of robust treatment options.

Article	Year
Targeted tacrolimus delivery via manganese dioxide nanoparticles for mitigating acute allograft rejection in murine cardiac transplantation. Biomaterials\| PubMed ID: 41056839	2026
Dihydroartemisinin Alleviates Chronic Allograft Rejection by Inhibiting Tfh and B Cells While Promoting Treg Cells in Murine Cardiac Transplantation. Immunology\| PubMed ID: 41437677	2025

Jinru Zhang

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