Kristine M Yarnoff, William N Daccarett-Bojanini, Andres F Villabona-Rueda, Manuel Sollmann, Franco R D'Alessio, Jeffrey M Dodd-O
{"title":"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。","authors":"Kristine M Yarnoff, William N Daccarett-Bojanini, Andres F Villabona-Rueda, Manuel Sollmann, Franco R D'Alessio, Jeffrey M Dodd-O","doi":"10.3389/frtra.2025.1612523","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>We sought to determine the effects of DAC treatment in a murine MHC-mismatched orthotopic lung transplant model.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>Decitabine could offer a new line of treatment for acute lung allograft rejection, in part via its effects on Tregs.</p>","PeriodicalId":519976,"journal":{"name":"Frontiers in transplantation","volume":"4 ","pages":"1612523"},"PeriodicalIF":0.0000,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230056/pdf/","citationCount":"0","resultStr":"{\"title\":\"Hypomethylating therapy mitigates acute allograft rejection in a murine lung transplant model.\",\"authors\":\"Kristine M Yarnoff, William N Daccarett-Bojanini, Andres F Villabona-Rueda, Manuel Sollmann, Franco R D'Alessio, Jeffrey M Dodd-O\",\"doi\":\"10.3389/frtra.2025.1612523\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>We sought to determine the effects of DAC treatment in a murine MHC-mismatched orthotopic lung transplant model.</p><p><strong>Results: </strong>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.</p><p><strong>Discussion: </strong>Decitabine could offer a new line of treatment for acute lung allograft rejection, in part via its effects on Tregs.</p>\",\"PeriodicalId\":519976,\"journal\":{\"name\":\"Frontiers in transplantation\",\"volume\":\"4 \",\"pages\":\"1612523\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-06-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12230056/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in transplantation\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3389/frtra.2025.1612523\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in transplantation","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3389/frtra.2025.1612523","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
Hypomethylating therapy mitigates acute allograft rejection in a murine lung transplant model.
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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