Segerer S, Cui Y, Eitner F, Goodpaster T, Hudkins K L, Mack M, Cartron J P, Colin Y, Schlondorff D, Alpers C E
University of Washington, Seattle, WA, USA.
Am J Kidney Dis. 2001 Mar;37(3):518-31.
Infiltration of renal allografts by leukocytes is a hallmark of acute transplant rejection. Chemokines attract leukocytes bearing specific chemokine receptors, and the specific leukocyte chemokine receptor phenotype is associated with types of immune responses, ie, T helper subtype 1 (Th1; CXC chemokine receptor 3 [CXCR3], CC chemokine receptor 5 [CCR5]) versus Th2 (CCR3, CCR4, CCR8). We studied the expression of the chemokine monocyte chemoattractant protein-1 and the chemokine receptors CCR2B and CXCR4 messenger RNA (mRNA) by in situ hybridization, as well as the chemokine receptors Duffy antigen receptor for chemokines (DARC) and CCR5 protein by immunohistochemistry in renal biopsy specimens with acute cellular rejection (n = 12) and acute vascular rejection (n = 8), transplant nephrectomy specimens (n = 6), and normal areas of tumor nephrectomy specimens (n = 5). CC chemokines and CC chemokine receptor mRNA expression were evaluated by ribonuclease protection assay in specimens from four transplant nephrectomies and one tumor nephrectomy. Upregulation of mRNAs for the chemokines, interferon-inducible protein-10 (IP-10); regulated on activation normal T-cell expressed and secreted; macrophage inflammatory protein-1alpha (MIP-1alpha); MIP-1beta; and lymphotactin, as well as the chemokine receptors, CCR2 and CCR5, were documented during allograft rejection. CCR1 mRNA was detectable in both allografts and controls, but CCR3 and CCR8 were absent. The number of CXCR4, CCR5, and CCR2B mRNAs expressing leukocytes and DARC-positive vessels increased during rejection episodes. CXCR4 mRNA was the most widely expressed. Leukocytes in diffuse interstitial infiltrates were mainly CCR5 positive, but in areas in which leukocytes formed nodular aggregates of infiltrating cells, the number of CCR5-positive cells was low. Instead, leukocytes in these nodular aggregates mainly expressed CXCR4. DARC was expressed on peritubular capillaries, where it was upregulated in areas of interstitial infiltration. Induction of chemokines during renal allograft rejection is accompanied by infiltration of leukocytes bearing the respective chemokine receptors. The upregulation of the CXCR3 ligand IP-10, as well as CCR5 and its ligands, in the absence of CCR3 and CCR8 is indicative that renal allograft rejection is primarily the result of a Th1-type immune response.
白细胞浸润肾移植同种异体移植物是急性移植排斥反应的一个标志。趋化因子吸引带有特定趋化因子受体的白细胞，而特定的白细胞趋化因子受体表型与免疫反应类型相关，即辅助性T细胞1型（Th1；CXC趋化因子受体3 [CXCR3]、CC趋化因子受体5 [CCR5]）与Th2（CCR3、CCR4、CCR8）。我们通过原位杂交研究趋化因子单核细胞趋化蛋白-1以及趋化因子受体CCR2B和CXCR4信使核糖核酸（mRNA）的表达，并用免疫组织化学法研究趋化因子受体趋化因子达菲抗原受体（DARC）和CCR5蛋白在急性细胞排斥反应（n = 12）和急性血管排斥反应（n = 8）的肾活检标本、移植肾切除标本（n = 6）以及肿瘤肾切除标本正常区域（n = 5）中的表达。通过核糖核酸酶保护试验对4例移植肾切除标本和1例肿瘤肾切除标本中的CC趋化因子和CC趋化因子受体mRNA表达进行评估。在同种异体移植排斥反应期间，记录到趋化因子、干扰素诱导蛋白10（IP-10）、活化正常T细胞表达和分泌调节因子、巨噬细胞炎性蛋白1α（MIP-1α）、MIP-1β和淋巴细胞趋化因子的mRNA上调，以及趋化因子受体CCR2和CCR5的上调。CCR1 mRNA在同种异体移植物和对照中均能检测到，但CCR3和CCR8缺失。在排斥反应发作期间，表达CXCR4、CCR5和CCR2B mRNA的白细胞数量以及DARC阳性血管数量增加。CXCR4 mRNA表达最为广泛。弥漫性间质浸润中的白细胞主要为CCR5阳性，但在白细胞形成浸润性细胞结节聚集的区域，CCR5阳性细胞数量较少。相反，这些结节聚集中的白细胞主要表达CXCR4。DARC在肾小管周围毛细血管上表达，在间质浸润区域上调。肾移植同种异体移植物排斥反应期间趋化因子的诱导伴随着携带相应趋化因子受体的白细胞浸润。在缺乏CCR3和CCR8的情况下，CXCR3配体IP-10以及CCR5及其配体的上调表明肾移植同种异体移植物排斥反应主要是Th1型免疫反应的结果。
