ORIGINAL RESEARCH article

Front. Transplant.

Sec. Transplantation Immunology

Volume 4 - 2025 | doi: 10.3389/frtra.2025.1612523

This article is part of the Research TopicAdvances in Transplantation: From New Actors and Pathways of Rejection to Engineering OrgansView all articles

Hypomethylating Therapy Mitigates Acute Allograft Rejection in a Murine Lung Transplant Model

Provisionally accepted
Kristine M. YarnoffKristine M. YarnoffWilliam N. Daccarett-BojaniniWilliam N. Daccarett-BojaniniAndres Villabona-RuedaAndres Villabona-RuedaManuel SollmannManuel SollmannFranco R. D'AlessioFranco R. D'AlessioJeffrey M. Dodd-oJeffrey M. Dodd-o*
  • Johns Hopkins Medicine, Johns Hopkins University, Baltimore, United States

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Acute 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. We sought to determine the effects of DAC treatment in a murine MHC-mismatched orthotopic lung transplant model. Rescue 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. Decitabine could offer a new line of treatment for acute lung allograft rejection, in part via its effects on Tregs.

Keywords: Lung Transplantation, acute rejection, T regulatory cells, decitabine, Immune Tolerance

Received: 15 Apr 2025; Accepted: 04 Jun 2025.

Copyright: © 2025 Yarnoff, Daccarett-Bojanini, Villabona-Rueda, Sollmann, D'Alessio and Dodd-o. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Jeffrey M. Dodd-o, Johns Hopkins Medicine, Johns Hopkins University, Baltimore, United States

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