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移植前筛查预防猪-灵长类动物肾异种移植中的超急性移植物排斥反应。

Pretransplant Screening for Prevention of Hyperacute Graft Loss in Pig-to-primate Kidney Xenotransplantation.

机构信息

Department of Surgery, Division of Transplantation, The Johns Hopkins School of Medicine, Baltimore, MD.

出版信息

Transplantation. 2024 Aug 1;108(8):1749-1759. doi: 10.1097/TP.0000000000004958. Epub 2024 Jul 20.

DOI:10.1097/TP.0000000000004958
PMID:39042769
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11287055/
Abstract

BACKGROUND

Xenotransplantation using pig organs is now a clinical reality. However, the process for xenograft recipient screening lacks clarity and scientific rigor: no established thresholds exist to determine which levels of preformed antipig natural antibodies (Nabs) will be safe for clinical xenograft transplantation, and hyperacute rejection (HAR) or acute humoral xenograft rejection (AHXR), which still impacts pig-to-primate kidney xenograft survivals, may impede broader application of pig-to-human clinical xenograft transplantation.

METHODS

We retrospectively examined 28 cases of pig-to-baboon kidney xenotransplantation using GalTKO±human complement regulatory protein (hCRP)-transgenic (Tg) pig donors, as well as 6 cases of triple-KO multi-Tg (10GE) pig donors, and developed screening algorithms to predict risk of HAR/AHXR based on recipient antipig Nab levels. Preformed Nabs were evaluated using both complement-dependent cytotoxicity and antibody (IgM and IgG) binding flow-cytometry assays.

RESULTS

High complement-dependent cytotoxicity was associated with HAR/AHXR as expected. However, we also found that high levels of IgG were independently associated with HAR/AHXR, and we developed 2 indices to interpret and predict the risk of IgG-mediated HAR/AHXR.

CONCLUSIONS

Based on the data in this study, we have established a new 2-step screening, which will be used for future clinical kidney xenotransplantation trials.

摘要

背景

使用猪器官的异种移植现在已经成为临床现实。然而，异种移植物受者筛选的过程缺乏明确性和科学严谨性：目前尚不存在确定哪些水平的预先形成的抗猪天然抗体 (Nab) 将安全用于临床异种移植的既定阈值，并且仍然影响猪到灵长类动物肾脏异种移植物存活的超急性排斥反应 (HAR) 或急性体液性异种移植物排斥反应 (AHXR)，可能会阻碍猪到人类临床异种移植的更广泛应用。

方法

我们回顾性地检查了 28 例使用 GalTKO±人补体调节蛋白 (hCRP)-转基因 (Tg) 猪供体的猪到狒狒肾脏异种移植病例，以及 6 例三重 KO 多 Tg（10GE）猪供体，并开发了筛选算法，根据受者抗猪 Nab 水平预测 HAR/AHXR 的风险。预先形成的 Nab 使用补体依赖性细胞毒性和抗体 (IgM 和 IgG) 结合流式细胞术检测进行评估。

结果

高补体依赖性细胞毒性与 HAR/AHXR 相关，这是意料之中的。然而，我们还发现 IgG 水平高与 HAR/AHXR 独立相关，我们开发了 2 个指标来解释和预测 IgG 介导的 HAR/AHXR 的风险。

结论

基于本研究中的数据，我们已经建立了一种新的两步筛选方法，该方法将用于未来的临床肾脏异种移植试验。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/5560b016b2e3/nihms-1961331-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/cb1e11257d2b/nihms-1961331-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/697f5aa89772/nihms-1961331-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/4854e49d789c/nihms-1961331-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/bc9f5f7d4593/nihms-1961331-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/79d83f217622/nihms-1961331-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/0cd761e77f6c/nihms-1961331-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/5560b016b2e3/nihms-1961331-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/cb1e11257d2b/nihms-1961331-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/697f5aa89772/nihms-1961331-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/4854e49d789c/nihms-1961331-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/bc9f5f7d4593/nihms-1961331-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/79d83f217622/nihms-1961331-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/0cd761e77f6c/nihms-1961331-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/89ab/11287055/5560b016b2e3/nihms-1961331-f0007.jpg

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Patients on the Transplant Waiting List Have Anti-Swine Leukocyte Antigen Class I Antibodies.移植等待名单上的患者具有抗猪白细胞抗原 I 类抗体。
Immunohorizons. 2023 Sep 1;7(9):619-625. doi: 10.4049/immunohorizons.2300056.
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Xenografts Show Signs of Concentric Hypertrophy and Dynamic Left Ventricular Outflow Tract Obstruction After Orthotopic Pig-to-baboon Heart Transplantation.
2024年7月至12月异种移植文献更新
Xenotransplantation. 2025 Jan-Feb;32(1):e70027. doi: 10.1111/xen.70027.
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Allosensitisation in NHP results in cross-reactive anti-SLA antibodies not detected by a lymphocyte-based flow cytometry crossmatch.在非人类灵长类动物中，同种异体致敏会导致淋巴细胞交叉配型流式细胞术无法检测到的交叉反应性抗 SLA 抗体。
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Consistent survival in consecutive cases of life-supporting porcine kidney xenotransplantation using 10GE source pigs.使用 10GE 供体猪进行连续的生命支持猪肾异种移植，结果一致的存活。
Nat Commun. 2024 Apr 18;15(1):3361. doi: 10.1038/s41467-024-47679-6.
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