Krulová M, Zajícová A, Fric J, Holán V
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague.
Transpl Int. 2002 Mar;15(2-3):108-16. doi: 10.1007/s00147-002-0378-0. Epub 2002 Mar 1.
The immunological rejection reaction occurring after organ or tissue transplantation is characterized by a strong infiltration of the graft by T cells and macrophages. Since the rejection reaction is highly specific, we tested the role of T cells in the activation of macrophages and in the induction of nitric oxide (NO) production during graft rejection. The rejection of both MHC and non-MHC antigen-disparate skin allografts was associated with a significantly increased production of NO in the graft. The kinetics of NO production after transplantation correlated with the rejection reaction and with the fate of the allograft. A significant reduction in NO production was found in immunologically hyporeactive mice treated with cyclosporine, and no specific production of NO was found in tolerated skin allografts from neonatally tolerant mice. The production of NO was completely suppressed in graft explants from mice with depleted CD4(+) cells, but remained at a normal level in skin allografts from mice treated with anti-CD8 monoclonal antibody. The treatment of recipients of fully allogeneic skin grafts with 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), a specific inhibitor of the inducible NO synthase, resulted in a significant prolongation of graft survival. The results thus show CD4(+) T-cell-dependent, alloantigen-induced production of NO by graft-infiltrating macrophages and the role of NO in the rejection reaction. We suggest that this pathway may represent one of the local effector mechanisms of graft rejection.
器官或组织移植后发生的免疫排斥反应的特征是T细胞和巨噬细胞对移植物的强烈浸润。由于排斥反应具有高度特异性，我们测试了T细胞在移植物排斥过程中巨噬细胞活化和一氧化氮（NO）产生诱导中的作用。MHC和非MHC抗原不相合的皮肤同种异体移植物的排斥均与移植物中NO产生的显著增加有关。移植后NO产生的动力学与排斥反应以及同种异体移植物的命运相关。在用环孢素治疗的免疫低反应性小鼠中发现NO产生显著减少，在新生耐受小鼠的耐受皮肤同种异体移植物中未发现NO的特异性产生。来自CD4(+)细胞耗竭小鼠的移植物外植体中NO的产生完全被抑制，但在用抗CD8单克隆抗体治疗的小鼠的皮肤同种异体移植物中NO水平保持正常。用诱导型NO合酶的特异性抑制剂2-氨基-5,6-二氢-6-甲基-4H-1,3-噻嗪（AMT）治疗完全同种异体皮肤移植物的受体，导致移植物存活时间显著延长。因此，结果表明移植浸润巨噬细胞产生CD4(+) T细胞依赖性、同种异体抗原诱导的NO以及NO在排斥反应中的作用。我们认为该途径可能代表移植物排斥的局部效应机制之一。
