Impact of Decitabine on Native Lung Immune Profile in a Murine Single-lung Transplant Model

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Abstract Introduction: We previously showed that decitabine (DAC) protects against acute lung graft rejection by impacting adaptive and innate immunity in a murine model. In single-lung transplants, immune responses in the transplanted lung may influence the native lung, though this interaction remains understudied. Here, we investigate DAC's effects on immune cells in the native right lung, hypothesizing that DAC may modulate its inflammatory state, offering systemic protection. Objective: To determine the effect of DAC on immune cell populations in the host's native lung following a left-lung transplant. Methods: BALB/c (CD45.2) mouse left lungs were transplanted into wild-type C57BL/6 (Pep boy/JAXBoy – B6 CD45.1) hosts. Post-transplantation, recipient mice received intraperitoneal DAC (1 mg/kg) or dimethyl sulfoxide (DMSO) diluent control on days 3, 4, 5, and 8. On day 10, the native right lung was harvested for lung histopathology, rejection scoring (ISHLT-Grade), and immune cell analysis via high-dimensional flow cytometry. Results: DAC treatment significantly improved the ISHLT A Grade score in the native right lung of a C57BL/6 mouse hosting a BALB/c left lung transplant for 10 days, reducing the score from 1.9±0.1 to 0.6±0.3 (mean ± SEM, p <0.05). This improvement was associated with significantly reduced recruitment of neutrophils, interstitial macrophages, and pro-inflammatory (Ly6C+) monocyte-derived macrophages, alongside increased recruitment of anti-inflammatory (Ly6C-) monocyte-macrophages and alveolar macrophages. DAC treatment also significantly increased native lung CD4+ T cells and regulatory T cells (Tregs) without affecting total T cells or CD8+ T cells. Furthermore, DAC promoted an anti-inflammatory phenotype in macrophage subsets, marked by upregulation of M2 markers (e.g., CD206, CD36) and downregulation of pro-inflammatory markers (e.g., CD64, CCR2). Thus, single left lung transplantation can promote injury to the native right lung by a process that is minimized by effective anti-rejection therapy of the transplanted lung. Conclusion: DAC treatment reduced pro-inflammatory infiltration and promoted anti-inflammatory immune responses in the native lung, suggesting systemic immunoprotection in lung transplantation.

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