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

Frontiers in transplantation Pub Date : 2025-06-23 eCollection Date: 2025-01-01 DOI:10.3389/frtra.2025.1612523

Kristine M Yarnoff, William N Daccarett-Bojanini, Andres F Villabona-Rueda, Manuel Sollmann, Franco R D'Alessio, Jeffrey M Dodd-O

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Abstract

Introduction: 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.

Methods: We sought to determine the effects of DAC treatment in a murine MHC-mismatched orthotopic lung transplant model.

Results: 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.

Discussion: Decitabine could offer a new line of treatment for acute lung allograft rejection, in part via its effects on Tregs.

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在小鼠肺移植模型中，低甲基化治疗可减轻急性同种异体移植排斥反应。

肺同种异体移植物移植的急性细胞排斥反应涉及细胞毒性T细胞活化和调节性T （Treg）细胞功能降低。钙调磷酸酶抑制剂，免疫抑制方案的基石，抑制T细胞的细胞毒性，但抑制Treg增殖。脱氧核糖核酸低甲基化剂地西他滨（DAC）可以消除T细胞的细胞毒性，同时刺激Treg增殖。方法：我们试图确定DAC治疗对小鼠mhc错配原位肺移植模型的影响。结果：DAC的抢救治疗维持了同种异体肺移植的大体和组织学完整性，减少了细胞毒性T细胞反应。与CD4+FoxP3+ T细胞充足小鼠相比，Foxp3DTR小鼠CD4+FoxP3+ T细胞缺失加重了排异肺损伤，并不能消除DAC在该模型中的保护作用。DAC的保护作用与宿主t细胞细胞因子产生的减少有关。讨论：地西他滨可能通过其对treg的作用，为急性同种异体肺移植排斥提供一条新的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Frontiers in transplantation

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