Immunosuppressive drugs such as cyclosporine A (CSA) can disrupt thymic structure and functions, ultimately inducing syngeneic/autologous graft-versus-host disease together with involuted medullas. To elucidate the effects of CSA on the thymus more precisely, we analyzed the effects of CSA on the thymus and T cell system using rats. In addition to confirming the phenomena already reported, we newly found that the proportion of recent thymic emigrants also greatly decreased, suggesting impaired supply. Immunohistologically, the medullary thymic epithelial cells (mTECs) presented with a relative decrease in the subset with a competent phenotype and downregulation of class II major histocompatibility complex molecules. In control rats, thymic dendritic cells (DCs) comprised two subsets, XCR1⁺SIRP1α⁻CD4⁻ and XCR1⁻SIRP1α⁺CD4⁺. The former had a tendency to selectively localize in the previously-reported epithelium-containing areas of the rat medullas, and the number was significantly reduced by CSA treatment. The epithelium-free areas, another unique domains in the rat medullas, contained significantly more Foxp3⁺ thymic Tregs. With CSA treatment, the epithelium-free areas presented strong involution, and the number and distribution of Tregs in the medulla were greatly reduced. These results suggest that CSA inhibits the production of single-positive thymocytes, including Tregs, and disturbs the microenvironment of the thymic medulla, with a decrease of the competent mTECs and disorganization of epithelium-free areas and DC subsets, leading to a generation of autoreactive T cells with selective medullary involution.

环孢素 A (CSA) 等免疫抑制药物可破坏胸腺结构和功能，最终诱发同源/自体移植物抗宿主病以及退化的髓质。为了更准确地阐明 CSA 对胸腺的影响，我们使用大鼠分析了 CSA 对胸腺和 T 细胞系统的影响。除了证实已经报道的现象外，我们新发现近期胸腺移民的比例也大大下降，表明供应受损。免疫组织学上，髓胸腺上皮细胞 (mTECs) 呈现出相对减少的亚群，具有合格的表型和 II 类主要组织相容性复合物分子的下调。在对照大鼠中，胸腺树突细胞 (DC) 包含两个亚群，XCR1 ⁺ SIRP1α ^-CD4 ^-和 XCR1 ^- SIRP1α ⁺ CD4 ⁺。前者倾向于选择性地定位于先前报道的大鼠髓质的含有上皮细胞的区域，并且通过 CSA 治疗显着减少了数量。无上皮区域，大鼠髓质中的另一个独特区域，含有明显更多的 Foxp3 ⁺胸腺 Tregs。经CSA处理后，无上皮区域呈现强烈的退化，髓质中Tregs的数量和分布大大减少。这些结果表明，CSA 抑制包括 Tregs 在内的单阳性胸腺细胞的产生，并扰乱胸腺髓质的微环境，导致感受态 mTECs 的减少和无上皮区域和 DC 亚群的紊乱，导致产生自身反应性具有选择性髓质复旧的 T 细胞。