Dekel B, Böcher W O, Marcus H, Yussim A, Reisner Y
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel.
Int Immunol. 1999 Oct;11(10):1673-83. doi: 10.1093/intimm/11.10.1673.
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.
与T(h)1和T(h)2相关的细胞因子（γ干扰素、白细胞介素-2、白细胞介素-4、白细胞介素-10）、β趋化因子（调节激活正常T细胞表达和分泌的趋化因子、巨噬细胞炎性蛋白-1β）及其受体[趋化细胞因子受体(CCR)5]，以及溶细胞效应分子[Fas配体(FasL)]在调节和协调急性肾移植排斥反应中起重要作用。采用一种急性细胞排斥反应的嵌合模型，即将人肾组织包膜下移植到免疫缺陷大鼠的肾脏中，随后腹腔注射异基因人外周血单个核细胞(PBMC)，以研究这些关键炎症介质的细胞浸润模式和移植内基因表达顺序。我们发现，虽然在注射异基因人PBMC后的特定时间点，所有分子都在人肾移植物中表达，但γ干扰素、白细胞介素-2、调节激活正常T细胞表达和分泌的趋化因子和CCR5的mRNA表达峰值与移植破坏前（诱导期）人单核细胞浸润和聚集阶段相关。在诱导末期和移植恶化开始时发现FasL基因表达有短暂爆发。几乎检测不到的白细胞介素-4 mRNA和早期出现并在整个随访过程中持续高水平的白细胞介素-10 mRNA，在诱导期后随着移植破坏的出现而达到峰值。此外，用CTLA-4-Ig治疗几乎不影响人效应细胞向移植组织的迁移，与所有炎症介质的基因转录水平暂时降低有关，尤其是白细胞介素-2和白细胞介素-4，移植内细胞凋亡减少，组织损伤改善。因此，我们的嵌合模型中急性细胞排斥反应的发生涉及基因表达的协调模式，其中CTLA-4-Ig通过短暂灭活浸润的人细胞来发挥其作用。
