A Study of the Relationship of the Dynamics of Development and Characteristics of Chimerism with Manifestations of Graft-vs.-Host Disease in the Organs of Mice after Allogeneic Transplantation of Whole Bone Marrow

Q4 Biochemistry, Genetics and Molecular Biology Cell and Tissue Biology Pub Date : 2024-08-06 DOI:10.1134/s1990519x24700391

E. V. Bogdanenko, L. A. Sergievich, A. V. Karnaukhov, N. A. Karnaukhova, I. A. Lizunova

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Abstract

In сlinical practice, allogeneiс bone marrow transplantation (BMT) is often a cause of graft-vs.-host disease (GvHD). GvHD is explained by the fact that T-lymphocytes, which are administered simultaneously with hematopoietic cells during transplantation and form and mature anew in the timus of the recipient from donor progenitor cells thereafter, recognize and attack the cells of the host. However, a complete explanation of the phenomenon of the GvHD does not exist, and chimerization of the recipient’s organism as a possible cause of damage of its organs is not taken into account. Therefore, the aim of this work consisted in modeling of allogeneic transplantation of the whole bone marrow (experiment) and comparing its results with syngeneic transplantation (control) basing on an investigation of engraftment of cells of donor origin in the main GvHD target organs. The bone marrow donors were Tg(ACTB-EGFP)1Osb/J mice carrying a green fluorescent protein gene (EGFP), and the recipients were animals of CBA and C57BL/6 inbred strains of an age of 2–10 months. One day before BMT (1.5 × 10⁷ cells per mouse), all recipients were irradiated at a dose of 6.5 Gy (LD 50/30). After 1, 3, 5, 7, 11, 14, 21, 28, 35, and 55 days, the development of chimerism in the liver, skin, and colon of animals was examined using a fluorescent microscope. Already after 1 day, single fibroblast-like donor cells were found in the colon; after 7 days, in the skin and liver. From 14 to 28 days after BMT, donor cells formed mainly stroma in the liver, as well as fibroblasts and keratinocytes in the skin, and in the colon they substituted the cells of the villi, stroma, and parenchyma of Peyer’s patches that died after irradiation. Unlike control, in the experimental groups, GFP+ giant fibroblasts about 30 μm in length were found in the stroma of the liver, as well as in the skin and in the colon; in the liver there were many GFP+ bulkheads and fibroblast-like Ito’s cells of very intricate configuration. From 35 to 55 days after allogeneic BMT, cells of the donor origin in the liver and in the villi of the colon began to destroy, the villi became overgrown with GFP+ connective tissue cells and warped, the wall of the colon became thin, and the skin was fully replaced with a new one (these things were never observed in the control groups). We propose the hypothesis that, alongside GvHD traits like thinning of the colon wall and a large number of roundish GFP+ cells on the inner surface of the skin, other signs of the studied after allogeneic BMT organs suggest that the cells of the organs that are formed from mesenchymal stem cells of the whole bone marrow become targets for the recipient’s T cells, i.e., suggest the existence of a host-vs.-graft (HVG) reaction. The obvious manifestation of immune reactions after BMT directly coincides with the term of massive engraftment of the studied organs with cells of donor origin and restoration of the host’s own immune system; i.e., the development of chimerism determines the development of organ damage. This explains the GvHD symptoms known from medical practice—atrophy of the mucous membranes, excess production of collagen, sclerosis of the bile ducts, skin damage, colitis—and the timing of its manifestation.

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全骨髓异体移植后小鼠器官嵌合体的发育动态和特征与移植物宿主病表现的关系研究

摘要在临床实践中，同种异体骨髓移植（BMT）经常会引起移植物抗宿主疾病（GvHD）。移植物抗宿主病的原因是，T淋巴细胞在移植过程中与造血细胞同时输入受者体内，并在受者体内由供体祖细胞重新形成和成熟，从而识别并攻击宿主细胞。然而，目前还不存在对急性缺血性坏死现象的完整解释，也没有考虑到受体机体嵌合可能是其器官受损的原因之一。因此，这项工作的目的在于建立全骨髓异体移植模型（实验），并根据供体来源细胞在主要致病器官中的移植情况，将其结果与同种异体移植（对照）进行比较。骨髓供体为携带绿色荧光蛋白基因（EGFP）的 Tg(ACTB-EGFP)1Osb/J 小鼠，受体为 2-10 个月大的 CBA 和 C57BL/6 近交系动物。在进行 BMT（每只小鼠 1.5 × 107 个细胞）前一天，所有受体都接受了剂量为 6.5 Gy（LD 50/30）的照射。1、3、5、7、11、14、21、28、35 和 55 天后，使用荧光显微镜检查动物肝脏、皮肤和结肠中嵌合体的发育情况。1天后，在结肠中发现了单个成纤维细胞样的供体细胞；7天后，在皮肤和肝脏中发现了单个成纤维细胞样的供体细胞。BMT 后 14 至 28 天，供体细胞在肝脏中主要形成基质，在皮肤中主要形成成纤维细胞和角质细胞，而在结肠中，它们取代了绒毛细胞、基质细胞和在照射后死亡的派尔斑实质细胞。与对照组不同的是，实验组在肝脏基质、皮肤和结肠中发现了长度约为 30 μm 的 GFP+巨型成纤维细胞；肝脏中有许多 GFP+隔板和成纤维细胞样的伊藤细胞，其结构非常复杂。异体 BMT 后 35 至 55 天，肝脏和结肠绒毛中的供体来源细胞开始破坏，绒毛中 GFP+ 结缔组织细胞过度生长并翘起，结肠壁变薄，皮肤完全被新的皮肤取代（对照组从未观察到这些情况）。我们提出的假设是，除了结肠壁变薄和皮肤内表面出现大量圆形 GFP+ 细胞等 GvHD 特征外，异体 BMT 器官移植后的其他研究迹象表明，由整个骨髓间充质干细胞形成的器官细胞成为受者 T 细胞的靶细胞，即表明存在宿主对移植物（HVG）反应。BMT 后免疫反应的明显表现与供体来源细胞大量移植所研究器官和宿主自身免疫系统恢复的时间直接吻合；也就是说，嵌合体的发展决定了器官损伤的发展。这就解释了医学实践中已知的器官缺血缺氧症状--粘膜萎缩、胶原蛋白生成过多、胆管硬化、皮肤损伤、结肠炎--及其表现的时间。

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来源期刊

Cell and Tissue Biology Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

0.80

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0.00%

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期刊介绍： The journal publishes papers on vast aspects of cell research, including morphology, biochemistry, biophysics, genetics, molecular biology, immunology. The journal accepts original experimental studies, theoretical articles suggesting novel principles and approaches, presentations of new hypotheses, reviews highlighting major developments in cell biology, discussions. The main objective of the journal is to provide a competent representation and integration of research made on cells (animal and plant cells, both in vivo and in cell culture) offering insight into the structure and functions of live cells as a whole. Characteristically, the journal publishes articles on biology of free-living and parasitic protists, which, unlike Metazoa, are eukaryotic organisms at the cellular level of organization.