Panzer Ulf, Reinking Rüdiger R, Steinmetz Oliver M, Zahner Gunther, Sudbeck Ulrike, Fehr Susanne, Pfalzer Benjamin, Schneider André, Thaiss Friedrich, Mack Matthias, Conrad Stefan, Huland Hartwig, Helmchen Udo, Stahl Rolf A K
Medizinische Klinik IV, Universitätsklinikum Hamburg Eppendorf, Germany.
Transplantation. 2004 Nov 15;78(9):1341-50. doi: 10.1097/01.tp.0000140483.59664.64.
Experimental studies suggest that the infiltration of activated T cells into the allograft, the key event in the development of acute renal allograft rejection, depends on the expression of chemokines and their interaction with chemokine receptors expressed on T cells.
For a more detailed comprehension of the pathogenesis of T-cell recruitment in human acute rejection, the in situ expression of chemokines and chemokine receptors in allografts of 26 patients between day 3 and 9 after renal transplantation was examined in the present prospective study.
Immunohistochemical staining showed a significantly increased number of CXCR3 (P<0.01) and CCR5 positive T cells (P<0.01) in the tubulointerstitium of patients with acute allograft rejection according to Banff grade Ia-IIb. Likewise the intrarenal RNA expression of the CXCR3 ligands IP-10 (5.2-fold) and I-TAC (7.2-fold) and the CCR5 ligand RANTES (5.7-fold), was significantly up-regulated in rejecting organs. In situ hybridization revealed that IP-10 but not I-TAC was predominantly expressed by infiltrating leukocytes in the tubulointerstitial area, co-localizing with CXCR3 positive T cells. To a lesser degree expression by tubular cells could be detected, providing a possible explanation for the increased urinary IP-10 excretion we found in patients with rejecting organs.
These data from a prospective, biopsy-controlled study indicate that the local expression of IP-10 and RANTES leads to the directional movement of activated CXCR3 and CCR5 bearing T cells into the renal allograft and mediates acute rejection. Our data provide a rationale that blocking CXCR3 and CCR5 may offer a unique therapeutic approach to prevent episodes of acute rejection in the early phase after renal transplantation.
实验研究表明，活化T细胞浸润至同种异体移植物中是急性肾移植排斥反应发生发展的关键事件，这一过程依赖于趋化因子的表达及其与T细胞表面趋化因子受体的相互作用。
为更详细地了解人类急性排斥反应中T细胞募集的发病机制，在本前瞻性研究中，检测了26例肾移植患者术后第3天至第9天同种异体移植物中趋化因子及其受体的原位表达情况。
免疫组化染色显示，根据Banff分级Ia-IIb，急性移植排斥反应患者肾小管间质中CXCR3阳性T细胞数量显著增加（P<0.01），CCR5阳性T细胞数量也显著增加（P<0.01）。同样，在发生排斥反应的器官中，CXCR3配体IP-10（5.2倍）、I-TAC（7.2倍）以及CCR5配体RANTES（5.7倍）的肾内RNA表达也显著上调。原位杂交显示，IP-10主要由肾小管间质区域浸润的白细胞表达，而非I-TAC，且与CXCR3阳性T细胞共定位。在肾小管细胞中也能检测到程度较轻的表达，这可能解释了我们在发生排斥反应的患者中发现的尿IP-10排泄增加的现象。
这项前瞻性活检对照研究的数据表明，IP-10和RANTES的局部表达导致携带CXCR3和CCR5的活化T细胞向肾同种异体移植物定向移动，并介导急性排斥反应。我们的数据为阻断CXCR3和CCR5可能提供一种独特的治疗方法以预防肾移植术后早期急性排斥反应发作提供了理论依据。
