Trametinib attenuates delayed rejection and preserves thymic function following rat lung transplantation
Trametinib attenuates delayed rejection and preserves thymic function following rat lung transplantation
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曲美替尼可减轻大鼠肺移植后的延迟排斥反应并保留胸腺功能
DOI：
10.1165/rcmb.2018-0188oc
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发表时间：
2019
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Date H
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作者：
150.Takahagi A;Shindo T;Chen-Yoshikawa TF;Yoshizawa A;Gochi F;Miyamoto E;Saito M;Tanaka S;MotoyamaH;Date H
人肺移植后的迟发性免疫排斥反应可引起慢性同种异体肺移植功能障碍，这与高死亡率有关。延迟排斥反应可能归因于宿主抗原呈递细胞的间接同种异体抗原呈递；然而，其病理生理机制尚不完全清楚。有丝分裂原激活的蛋白激酶途径在T细胞中受到刺激后被激活，我们之前发现MEK抑制剂曲美替尼可以抑制小鼠骨髓移植后的移植物抗宿主病。我们研究了曲美替尼是否抑制两种类型大鼠肺移植后的移植排斥反应，并分析了其免疫作用模式。将褐挪威大鼠的组织相容性复合体错配移植到Lewis大鼠，将Fischer 344大鼠的组织相容性抗原错配移植到Lewis大鼠。环孢素（CsA）和/或曲美替尼单独或连续给药。评估急性和迟发性排斥反应、淋巴细胞浸润和肺功能。CsA后给予曲美替尼可抑制延迟性排斥反应，减少移植物内炎症细胞浸润和纤维化，并在第28天保留肺功能。曲美替尼抑制外周T细胞和B细胞的功能分化，但保留胸腺T细胞的分化。移植物内的供体B细胞在第14天消失，表明移植物在第28天的延迟排斥反应主要是由于宿主抗原呈递细胞的间接呈递。最后，不经CsA预处理的曲美替尼可抑制轻微组织相容性抗原错配移植后的排斥反应。曲美替尼通过抑制间接呈现减轻主要组织相容性复合物错配移植的延迟排斥反应，是治疗人类慢性同种异体肺移植功能障碍的有希望的候选药物。
Delayed immunological rejection after human lung transplantation causes chronic lung allograft dysfunction, which is associated with high mortality. Delayed rejection may be attributable to indirect alloantigen presentation by host antigen-presenting cells; however, its pathophysiology is not fully understood. The mitogen-activated protein kinase pathway is activated in T cells upon stimulation, and we previously showed that the MEK inhibitor, trametinib, suppresses graft-versus-host disease after murine bone marrow transplantation. We investigated whether trametinib suppresses graft rejection after two types of rat lung transplantation and analyzed its immunological mode of action. Major histocompatibility complex–mismatched transplantation from brown Norway rats into Lewis rats and minor histocompatibility antigen–mismatched transplantation from Fischer 344 rats into Lewis rats were performed. Cyclosporine (CsA) and/or trametinib were administered alone or consecutively. Acute and delayed rejection, lymphocyte infiltration, and pulmonary function were evaluated. Administration of trametinib after CsA suppressed delayed rejection, reduced inflammatory cell infiltration and fibrosis within the graft, and preserved pulmonary functions at Day 28. Trametinib suppressed functional differentiation of T and B cells in the periphery but preserved thymic T cell differentiation. Donor B cells within the graft disappeared by Day 14, indicating that delayed graft rejection at Day 28 was mainly due to indirect presentation by host antigen-presenting cells. Finally, trametinib administration without CsA preconditioning suppressed rejection after minor histocompatibility antigen–mismatched transplantation. Trametinib attenuates delayed rejection upon major histocompatibility complex–mismatched transplantation by suppressing indirect presentation and is a promising candidate to treat chronic lung allograft dysfunction in humans.