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首页> 外文期刊>International immunology. >Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation
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Acute cellular rejection of human renal tissue by adoptive transfer of allogeneic human peripheral blood mononuclear cells into chimeric rats: sequential gene expression of cytokines, chemokines and cytolytic effector molecules, and their regulation

机译：通过将同种异体人外周血单核细胞过继转移到嵌合大鼠中而导致人肾组织的急性细胞排斥：细胞因子，趋化因子和溶细胞因子的顺序基因表达及其调控

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T(h)1- and T(h)2-related cytokines (IFN-gamma, IL-2, IL-4, IL-10), beta-chemokines (RANTES, macrophage inflammatory protein-1beta) and their receptor [chemotatic cytokine receptor (CCR) 5], and the cytolytic effector molecule [Fas ligand (FasL)] play an essential role in regulating and co-ordinating acute renal allograft rejection. A chimeric model of acute cellular rejection which involves subcapsular grafting of human renal tissue in the kidneys of immunodeficient rats and subsequent i.p. infusion of allogeneic human peripheral blood mononuclear cells (PBMC) was used to study cellular infiltration patterns and sequential intragraft gene expression of these key inflammatory mediators. We found that while all molecules are expressed within the human renal implant at specific time points following infusion of allogeneic human PBMC, peak mRNA expression of IFN-gamma, IL-2, RANTES and CCR5 is associated with a phase of human mononuclear infiltration and accumulation, prior to graft destruction (induction phase). A short burst of FasL gene expression is found at the end of induction and at the onset of graft deterioration. IL-4 mRNA, which is hardly detectable, and IL-10 mRNA, which appears early and persists throughout follow-up at high levels, both peak after the induction phase with the advent of graft destruction. Furthermore, treatment with CTLA-4-Ig, which hardly affects migration of human effector cells into graft tissue, is associated with a temporary reduction in gene transcript levels for all inflammatory mediators, especially IL-2 and IL-4, reduced apoptosis in the graft and amelioration of tissue injury. Thus, development of acute cellular rejection in our chimeric model involves a co-ordinated pattern of gene expression, in which CTLA-4-Ig promotes its effects by transient inactivation of infiltrating human cells.
机译：T（h）1和T（h）2相关的细胞因子（IFN-γ，IL-2，IL-4，IL-10），β-趋化因子（RANTES，巨噬细胞炎性蛋白-1beta）及其受体[趋化性细胞因子受体（CCR）5]和溶细胞效应分子[Fas配体（FasL）]在调节和协调急性同种异体移植排斥中起重要作用。急性细胞排斥的嵌合模型，涉及在免疫缺陷大鼠的肾脏中进行人肾组织的亚包膜移植以及随后的腹膜内注射。输注同种异体人类外周血单个核细胞（PBMC）用于研究这些关键炎性介质的细胞浸润模式和移植后基因表达。我们发现，尽管所有分子均在输注同种异体人PBMC后的特定时间点在人肾植入物中表达，但IFN-γ，IL-2，RANTES和CCR5的峰值mRNA表达与人单核浸润和蓄积阶段有关，在移植物破坏之前（诱导阶段）。在诱导结束时和移植物退化开始时，发现FasL基因表达短暂爆发。几乎无法检测到的IL-4 mRNA和早期出现的IL-10 mRNA并在高水平的随访期间持续存在，两者均在诱导阶段后随着移植物破坏的出现达到峰值。此外，用CTLA-4-Ig治疗几乎不影响人类效应细胞向移植组织的迁移，它与所有炎症介质（尤其是IL-2和IL-4）的基因转录水平暂时降低有关，从而减少了炎症细胞的凋亡。移植和改善组织损伤。因此，在我们的嵌合模型中，急性细胞排斥反应的发展涉及基因表达的协调模式，其中CTLA-4-Ig通过浸润人细胞的瞬时失活来促进其作用。

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