{"title":"TDO2 Deficiency Exacerbates the Immune Rejection Response in Rat Liver Transplantation via the Kyn-AHR Axis.","authors":"Shanbao Li, Lei Li, Junyong Weng, Zeping He, Jing Lu, Wanyue Cao, Fangbin Song, Zhonglin Zhu, Bingjie Guan, Jinyan Zhang, Junming Xu","doi":"10.1097/TP.0000000000005386","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The role of tryptophan 2,3-dioxygenase2 (TDO2), a key enzyme in the L-tryptophan (Trp)-kynurenine (Kyn) pathway, in liver transplant immunity is unclear. This study aims to explore the role of TDO2 in liver transplant rejection.</p><p><strong>Methods: </strong>We used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to construct a TDO2 knockout rat model for liver transplant rejection. We validated the effects of TDO2 on acute rejection and survival, assessed TDO2 expression, and measured Trp and Kyn levels. We studied how TDO2 deficiency affects inflammatory cytokines, analyzed immune cell subtypes and their spatial distribution, and examined programmed death 1 and programmed cell death-ligand 1 (PDL1) spatial distribution and expression using multiplex immunohistochemistry. We also validated the regulatory mechanism of TDO2 on transplant-related immune cells in vivo and in vitro.</p><p><strong>Results: </strong>TDO2 deficiency in the allograft liver worsens acute rejection and reduces survival rates. During transplant rejection, TDO2 expression increases, enhancing Trp metabolism and elevating serum Kyn levels. TDO2 knockout mitigates this process. The TDO2-Kyn-aryl hydrocarbon receptor pathway regulates acute rejection. TDO2 knockout reprograms immune cell distribution, decreasing regulatory T cells and M2 macrophages in the intermediate region while increasing CD8+ T cells and M1 macrophages in the portal area, leading to M1 polarization. Additionally, TDO2 deficiency raises programmed death 1 and programmed cell death-ligand 1 expression, varying with the spatial distribution and quantity of immune cells. TDO2 can regulate the proliferation and differentiation of various immune cells through the Kyn-aryl hydrocarbon receptor pathway.</p><p><strong>Conclusions: </strong>Collectively, we elucidated the mechanism of TDO2 in liver transplant immune rejection and used spatial immunity to reveal the impact of TDO2 on liver transplantation.</p>","PeriodicalId":23316,"journal":{"name":"Transplantation","volume":" ","pages":""},"PeriodicalIF":5.3000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transplantation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/TP.0000000000005386","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The role of tryptophan 2,3-dioxygenase2 (TDO2), a key enzyme in the L-tryptophan (Trp)-kynurenine (Kyn) pathway, in liver transplant immunity is unclear. This study aims to explore the role of TDO2 in liver transplant rejection.
Methods: We used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to construct a TDO2 knockout rat model for liver transplant rejection. We validated the effects of TDO2 on acute rejection and survival, assessed TDO2 expression, and measured Trp and Kyn levels. We studied how TDO2 deficiency affects inflammatory cytokines, analyzed immune cell subtypes and their spatial distribution, and examined programmed death 1 and programmed cell death-ligand 1 (PDL1) spatial distribution and expression using multiplex immunohistochemistry. We also validated the regulatory mechanism of TDO2 on transplant-related immune cells in vivo and in vitro.
Results: TDO2 deficiency in the allograft liver worsens acute rejection and reduces survival rates. During transplant rejection, TDO2 expression increases, enhancing Trp metabolism and elevating serum Kyn levels. TDO2 knockout mitigates this process. The TDO2-Kyn-aryl hydrocarbon receptor pathway regulates acute rejection. TDO2 knockout reprograms immune cell distribution, decreasing regulatory T cells and M2 macrophages in the intermediate region while increasing CD8+ T cells and M1 macrophages in the portal area, leading to M1 polarization. Additionally, TDO2 deficiency raises programmed death 1 and programmed cell death-ligand 1 expression, varying with the spatial distribution and quantity of immune cells. TDO2 can regulate the proliferation and differentiation of various immune cells through the Kyn-aryl hydrocarbon receptor pathway.
Conclusions: Collectively, we elucidated the mechanism of TDO2 in liver transplant immune rejection and used spatial immunity to reveal the impact of TDO2 on liver transplantation.
期刊介绍：
The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year.
Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal.
Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed.
The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.
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