AUTHOR=Yarnoff Kristine M. , Daccarett-Bojanini William N. , Villabona-Rueda Andres F. , Sollmann Manuel , D’Alessio Franco R. , Dodd-o Jeffrey M. 

TITLE=Hypomethylating therapy mitigates acute allograft rejection in a murine lung transplant model

JOURNAL=Frontiers in Transplantation

VOLUME=Volume 4 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/transplantation/articles/10.3389/frtra.2025.1612523

DOI=10.3389/frtra.2025.1612523

ISSN=2813-2440

ABSTRACT=IntroductionAcute cellular rejection of transplanted lung allografts involves activated cytotoxic T cells and reduced Regulatory T (Treg) cell function. Calcineurin inhibitors, the cornerstone of immunosuppressive regimens, suppress T cell cytotoxicity but inhibit Treg proliferation. The DNA hypomethylating agent decitabine (DAC) can abrogate T cell cytotoxicity while stimulating Treg proliferation.MethodsWe sought to determine the effects of DAC treatment in a murine MHC-mismatched orthotopic lung transplant model.ResultsRescue treatment with DAC maintains lung allograft gross and histologic integrity with a reduction in cytotoxic T cell responses. CD4+FoxP3+ T cell depletion in Foxp3DTR mice exacerbated rejection lung injury compared to CD4+FoxP3+ T cell sufficient mice and failed to abolish the protective effect of DAC in this model. The protective effect of DAC was associated with a reduction in cytokine production from host T-cells.DiscussionDecitabine could offer a new line of treatment for acute lung allograft rejection, in part via its effects on Tregs.