Early Elevation of Complement Factor Ba Is a Predictive Biomarker for Transplant-Associated Thrombotic Microangiopathy

研究チームは、同種造血幹細胞移植治療後の重大な合併症である血栓性微小血管症の発症を、移植後早期に補体たんぱく質Baの血中濃度測定により、高精度に予測できることを発見しました。健康な血液を作っているドナーの造血幹細胞を、白血病などの血液がんの患者に移植する同種造血幹細胞移植治療は、血液がんを完治できる可能性がある一方で、命に関わる多くの合併症が課題となっています。血栓性微小血管症もその合併症の一つですが、その発症メカニズムや治療法は確立していません。本研究では、同種造血幹細胞移植を行った患者において、免疫の役割を担っている補体というたんぱく質群の血中濃度を測定したところ、血栓性微小血管症を発症する患者は移植後早期にBaの血中濃度が異常に高くなっていることを発見しました。BaはB因子という補体が分解されたたんぱく質であることから、血栓性微小血管症の発症には移植後早期からB因子が作用していることが明らかになりました。本研究の成果により、移植後早期に血中Ba濃度の測定を行うことで、将来の血栓性微小血管症の発症を予測でき、その予防や早期治療が可能となることが期待されます。

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Abstract

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Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous reports suggest that TA-TMA is caused by complement activation by complement-related genetic variants; however, this needs to be verified, especially in adults. Here, we performed a nested case-control study of allo-HSCT-treated adults at a single center. Fifteen TA-TMA patients and 15 non-TA-TMA patients, matched according to the propensity score, were enrolled. Based on a previous report showing an association between complement-related genes and development of TA-TMA, we first sequenced these 17 genes. Both cohorts harbored several genetic variants with rare allele frequencies; however, there was no difference in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants, or in the average number of rare variants per patient. Second, we measured plasma concentrations of complement proteins. Notably, levels of Ba protein on Day 7 following allo-HSCT were abnormally and significantly higher in TA-TMA than in non-TA-TMA cases, suggesting that complement activation via the alternative pathway contributes to TA-TMA. All other parameters, including soluble C5b-9, on Day 7 were similar between the groups. The levels of C3, C4, CH50, and complement factors H and I in the TA-TMA group after Day 28 were significantly lower than those in the non-TA-TMA group. Complement-related genetic variants did not predict TA-TMA development. By contrast, abnormally high levels of Ba on Day 7 did predict development of TA-TMA and non-relapse mortality. Thus, Ba levels on Day 7 after allo-HSCT are a sensitive and prognostic biomarker of TA-TMA.

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This research was supported by a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI (number 20K07788 to MH and number JP17H04108 to NW, KO, and NI) and by a research grant from the Smoking Research Foundation (to NW). This research was also supported by the Japanese Association for Complement Research (JACR), which is funded by Alexion GK as company sponsored research. Alexion GK was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

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Frontiers

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eng

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ORIGINAL RESEARCH

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http://purl.org/coar/resource_type/c_6501

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journal article

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VoR

出版タイプResource

http://purl.org/coar/version/c_970fb48d4fbd8a85

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https://doi.org/10.3389/fimmu.2021.695037

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書誌情報

en : Frontiers in Immunology

巻 12, p. 695037, 発行日 2021-07-13

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収録物識別子

1664-3224

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