树突状细胞DC-SIGN在免疫介导实验性肾炎肾小管间质损伤中的作用及抗P选择素功能域单抗的干预调节

目的 探讨树突状细胞（DC）表面特异的胞间黏附分子3捕获非整合素 （DC-SIGN）在免疫介导肾毒血清性肾炎（NTN）肾小管间质损伤中的作用,以及抗P选择素功能域单抗（PsL-EGFmAb）的干预调节。 方法 WKY大鼠随机分为正常对照组、模型组及 PsL-EGFmAb干预组。模型组注射预制的兔抗大鼠肾毒血清1 ml/kg;PsL-EGFmAb组在注射肾毒血清同时及注射后2 h,注入PsL-EGFmAb 2 mg/kg;正常对照组则注射等量生理盐水。随后于实验第4、7、14 天,分别观察大鼠肾功能及肾组织病理变化,并采用免疫荧光法检测肾组织DC-SIGN+DC分布;实时定量 PCR 检测P选择素、T细胞表达和分泌因子（RANTES）、肿瘤坏死因子?琢（TNF-?琢）、白细胞介素（IL）-10、干扰素（IFN）-?酌、IL-4的mRNA 表达;流式细胞仪检测肾脏分离DC表面主要组织相容性复合体Ⅱ（MHCⅡ）、DC-SIGN、CD80表达;细胞迁移试验及混合淋巴细胞反应（MLR）检测DC迁移与刺激 T 细胞的能力;ELISA法测定MLR上清中IFN-γ、IL-4含量。 结果 NTN大鼠第4 天起,未成熟DC-SIGN+ DC即以肾间质为主浸润并于14 d成熟,且迁移及刺激 T 细胞增殖能力增强,其肾内分布与新月体形成、肾小管间质损伤程度及肾功能改变呈正相关。此外,大鼠第4 天起肾内趋化因子及促炎因子RANTES、 TNF-?琢 mRNA表达持续上调,而抗炎因子IL-10 mRNA于第4 天明显增强随后呈下调趋势;至14 d时IFN-γ/IL-4 mRNA比值增高,与DC成熟状况呈正相关。经PsL-EGFmAb干预,伴随DC 表面 DC-SIGN 及相应共刺激分子CD80表达下降,DC成熟、迁移及刺激 T 细胞增殖能力受抑,肾内促炎因子下降而抗炎因子上调,Th1/Th2 偏移受到抑制。同时大鼠肾内新月体形成减少,肾小管间质损伤程度减轻,且肾功能改善。 结论 DC-SIGN介导了DC 肾间质浸润,并可能是局部免疫反应失衡以及肾小管间质病变的重要调控因素。PsL-EGFmAb在抑制DC 迁移的同时可通过靶向DC-SIGN调抑 DC成熟及功能,进而发挥防治效应。     

Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis

The role of renal dendritic cells (DCs) in glomerulonephritis is unknown. This question was addressed in nephrotoxic nephritis, a murine model of human necrotizing glomerulonephritis, which is dependent on CD4(+) Th1 cells and macrophages. DCs in nephritic kidneys showed signs of activation, accumulated in the tubulo-interstitium, and infiltrated the periglomerular space surrounding inflamed glomeruli. In ex vivo coculture experiments with antigen-specific CD4(+) T cells, DCs stimulated the secretion of IL-10, which is known to attenuate nephrotoxic nephritis, and the Th1 cytokine IFNgamma. Endogenous renal CD4(+) T cells produced both of these cytokines as well, but those from nephritic mice secreted increased amounts of IL-10. Renal DCs were found to express ICOS-L, an inducer of IL-10. To evaluate the in vivo role of renal DCs in disease, CD11c(+) DCs were depleted on days 4 and 10 after the induction of nephritis by injecting CD11c-DTR/GFP mice with diphtheria toxin. Sparing DCs until day 4 did not affect the autologous phase of nephritis. The number of renal DCs was reduced by 70% to 80%, the number of renal macrophages was unchanged, and periglomerular infiltrates were eliminated. On days 11 to 14, we observed aggravated tubulointerstitial and glomerular damage, reduced creatinine clearance, and increased proteinuria. These findings demonstrate that renal DCs exert a renoprotective effect in nephrotoxic nephritis, possibly by expressing ICOS-L and/or by inducing IL-10 in infiltrating CD4(+) Th1 cells.     

Tubulointerstitial nephritis during the heterologous phase of nephrotoxic serum nephritis

This study was designed to characterize the immunopathology of acute tubulointerstitial disease in nephrotoxic serum nephritis in nonsensitized rats. Groups of Lewis rats were studied at 12 time periods ranging from 10 min to 28 days after nephrotoxic serum injection. Nephritic rats developed interstitial nephritis during the acute heterologous phase of renal injury. Coincident with the focal deposition of nephrotoxic antibodies along tubular basement membranes at 24 h, an influx of polymorphonuclear cells and macrophages was evident. The most prominent infiltrate, present between days 3 and 7, was dominated by macrophages with smaller numbers of lymphocytes that were mainly cytotoxic T cells. Dual-labeling studies demonstrated the colocalization of linear tubular basement membrane deposits of the nephrotoxic antibody with focal clusters of interstitial lymphohemopoietic cells. Increased complement deposition was not evident along the tubular basement membranes; moreover, C3 depletion with cobra venom factor failed to attenuate the interstitial inflammation. During the late autologous phase of glomerulonephritis, tubular basement membrane deposits of rat IgG did not appear and the interstitial disease resolved. The results of this study demonstrate that the heterologous phase of nephrotoxic serum nephritis is an antibody-mediated disease directed against the basement membranes not only of the glomeruli but also of some tubules. Antibody deposition is followed by an acute influx of phagocytic cells to both regions of the kidney. These cells may play an important role in the genesis of acute interstitial injury and chronic interstitial fibrosis associated with antiglomerular basement membrane nephritis.     

Chemokines play a critical role in the cross-regulation of Th1 and Th17 immune responses in murine crescentic glomerulonephritis

Th1 and Th17 subtype effector CD4(+) T cells are thought to play a critical role in the pathogenesis of human and experimental crescentic glomerulonephritis. The time course, mechanism, and functions of Th1 and Th17 cell recruitment, and their potential interaction in glomerulonephritis, however, remain to be elucidated. We performed interventional studies using IL-17- and IFN-γ-gene-deficient mice, as well as neutralizing antibodies that demonstrated the importance of the Th17-mediated immune response during the early phase of the disease. At a later stage, we found that Th1 cells were critical mediators of renal tissue injury. Early recruitment of IL-17-producing Th17 cells triggered expression of the chemokine CXCL9 in the kidney that drove the infiltration of Th1 cells bearing its receptor CXCR3. At a later stage, Th1 cell-derived IFN-γ was found to inhibit local chemokine CCL20 expression, acting through its receptor CCR6 on Th17 cells, thereby limiting the renal Th17 immune response. Thus, our findings provide mechanistic evidence for a cytokine-chemokine-driven feedback loop that orchestrates the observed differential Th1 and Th17 cell infiltration into the inflamed kidney. This contributes to the observed time-dependent function of these two major pathogenic effector CD4(+) T cell subsets in crescentic glomerulonephritis.     

肾综合征出血热患者多种免疫促炎因子及抗炎因子变化及其作用

目的探讨肾综合征出血热（HFRS）患者急性期（包括发热期、低血压休克期、少尿期）与恢复期促炎因子和抗炎因子的变化及其作用。 方法检测2016年4月至2017年6月哈尔滨医科大学第四附属医院和黑龙江省农垦红兴隆管理局中心医院收治的30例确诊为HFRS急性期和恢复期患者血清中肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）、白细胞介素-6（IL-6）和抗炎因子转化生长因子-β1（TGF-β1）、白细胞介素-10（IL-10）的水平,同期检测患者的胱抑素C（Cys-C）、肌酐（Cr）、乳酸脱氢酶（LDH）以及部分凝血活酶时间（APTT）等指标。另选同期13名健康志愿者作对照组,检测TNF-α、IFN-γ、IL-6、TGF-β1和IL-10水平。应用SAS 9.3国际标准统计学编程软件对结果进行分析。 结果HFRS患者急性期IFN-γ（χ²= 4.273、P= 0.0336）、TNF-α（χ²= 16.3562、P < 0.0001）、IL-6（χ²= 9.752、P = 0.0018）和IL-10（χ²= 6.3352、P= 0.0118）水平均显著高于对照组,差异均有统计学意义。HFRS患者急性期TGF-β1水平显著低于对照组,差异有统计学意义（χ²= 7.822、P= 0.0056）。HFRS患者恢复期TGF-β1水平与对照组接近或略低,差异无统计学意义（χ²= 3.000、P = 0.0833）。HFRS患者发病不同时期Cys-C、Cr、LDH和APTT等指标均于急性期升高,于恢复期下降,与IFN-γ、TNF-α、IL-6和IL-10变化趋势一致。 结论HFRS急性期时IFN-γ、TNF-α和IL-6等促炎因子分泌增加,主要因CD4⁺CD25⁺FoxP3 Treg细胞（调节性T细胞）产生的抗炎因子TGF-β1分泌不足,细胞因子失衡是导致机体免疫病理损伤的重要机制。     

补肾活血法防治大鼠膝骨性关节炎的实验研究

目的:探讨补肾活血法、活血法、补肾法、祛风法对SD大鼠膝骨性关节炎血液流变学及滑液IL-1β、TNF-α的作用及其机制,明确筋痹到骨痹的演变及中药疗效的比较。方法:取体重为(200±15)g的3月龄雄性SD大鼠180只,采用木瓜蛋白酶大鼠膝关节腔注射的方法制作膝骨性关节炎动物模型,随机分为活血组、预防组、祛风组、补肾组、补肾活血组和模型组。于中药灌胃后30、60、90d分批处死动物后进行各种指标的检测,包括对大鼠的精神状态、活动度、皮毛、体重、关节肿胀情况,大体形象,血流变学,炎症指标和HE染色的病理切片。结果:大鼠造模成功后出现膝关节瘀血肿胀,爬行困难。中药治疗30,60,90d后对比,补肾活血汤组血液流变学各项指标较模型组差异有统计学意义;病理组织学表现软骨面较模型组光滑,完整,软骨细胞排列整齐;白细胞介素-1β(IL-1β)及肿瘤坏死因子α(TNF-α)含量明显低于模型组。模型组早期IL-1β及TNF-α含量高于晚期。结论:膝骨性关节炎早期主要表现为滑膜炎症,早期炎症反应较晚期严重。补肾活血方能抑制大鼠膝关节软骨损伤,改善血液循环及抑制局部炎症反应。早期活血方、补肾活血方均有一定疗效,但晚期补肾活血方疗效较活血方,补肾方更显著。     

IL-17A Production by Renal γδ T Cells Promotes Kidney Injury in Crescentic GN

The Th17 immune response appears to contribute to the pathogenesis of human and experimental crescentic GN, but the cell types that produce IL-17A in the kidney, the mechanisms involved in its induction, and the IL-17A-mediated effector functions that promote renal tissue injury are incompletely understood. Here, using a murine model of crescentic GN, we found that CD4(+) T cells, γδ T cells, and a population of CD3(+)CD4(-)CD8(-)γδT cell receptor(-)NK1.1(-) T cells all produce IL-17A in the kidney. A time course analysis identified γδ T cells as a major source of IL-17A in the early phase of disease, before the first CD4(+) Th17 cells arrived. The production of IL-17A by renal γδ T cells depended on IL-23p19 signaling and retinoic acid-related orphan receptor-γt but not on IL-1β or IL-6. In addition, depletion of dendritic cells, which produce IL-23 in the kidney, reduced IL-17A production by renal γδ T cells. Furthermore, the lack of IL-17A production in γδ T cells, as well as the absence of all γδ T cells, reduced neutrophil recruitment into the kidney and ameliorated renal injury. Taken together, these data suggest that γδ T cells produce IL-17A in the kidney, induced by IL-23, promoting neutrophil recruitment, and contributing to the immunopathogenesis of crescentic GN.     

The loss of renal dendritic cells and activation of host adaptive immunity are long-term effects of ischemia/reperfusion injury following syngeneic kidney transplantation

Ischemia/reperfusion injury associated with kidney transplantation induces profound acute injury, influences early graft function, and affects long-term graft outcomes. To determine whether renal dendritic cells play any role during initial innate ischemia/reperfusion injury and the subsequent development of adaptive immune responses, we studied the behavior and function of renal graft and host infiltrating dendritic cells during early and late phases of renal ischemia/reperfusion injury. Wild type to green fluorescent protein (GFP) transgenic rat kidney transplantation was performed with and without 24-h cold storage. Ischemia/reperfusion injury in cold-stored grafts resulted in histopathological changes of interstitial fibrosis and tubular atrophy by 10 weeks, accompanied by upregulation of mRNAs of mediators of interstitial fibrosis and inflammation. In normal rat kidneys, we identified two populations of renal dendritic cells, predominant CD103(-)CD11b/c(+) and minor CD103(+)CD11b/c(+) cells. After transplantation without cold storage, grafts maintained CD103(-) but not CD103(+) GFP-negative renal dendritic cells for 10 weeks. In contrast, both cell subsets disappeared from cold-stored grafts, which associated with a significant GFP-expressing host CD11b/c(+) cell infiltration that included CD103(+) dendritic cells with a TNF-α-producing phenotype. These changes in graft/host dendritic cell populations were associated with progressive infiltration of host CD4(+) T cells with effector/effector-memory phenotypes and IFN-γ secretion. Thus, renal graft ischemia/reperfusion injury caused graft dendritic cell loss and was associated with progressive host dendritic cell and T-cell recruitment. Renal-resident dendritic cells might function as a protective regulatory network.     

Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice

The chemokine receptor CXCR3 is highly expressed on Th1 polarized T cells and has been predicted to play an important role in T cell recruitment and immune response in a number of inflammatory and autoimmune diseases. For testing whether CXCR3 plays a role in renal inflammation, CXCR3-deficient mice were generated and nephrotoxic nephritis was induced in C57BL/6 CXCR3(-/-) and C57BL/6 wild-type mice. Induction of the nephrotoxic nephritis leads to an increased renal mRNA expression of IP-10/CXCL10 (8.6-fold), Mig/CXCL9 (2.3-fold), and I-TAC/CXCL11 (4.9-fold) during the autologous phase at days 7 and 14. This increased chemokine expression was paralleled by the renal infiltration of T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Compared with wild-type mice, CXCR3-deficient mice had significantly reduced renal T cell infiltrates. Moreover, CXCR3(-/-) mice developed less severe nephritis, with significantly lower albuminuria, better renal function, and a reduced frequency of glomerular crescent formation. Nephritic wild-type and CXCR3(-/-) mice both elicited an efficient systemic nephritogenic immune response in terms of antigen-specific IgG production and IFN-gamma expression by splenocytes in response to the nephritogenic antigen. These findings indicate that the ameliorated nephritis in CXCR3-deficient mice is due to impaired renal trafficking of effector T cells rather than their inability to mount an efficient humoral or cellular immune response. The neutralization of CXCR3 might be a promising therapeutic strategy for Th1-dependent inflammatory renal disease.     

肝再生相关分子的研究进展

肝细胞再生的调控是一个复杂的病理生理过程,伴随有大量细胞因子的参与,如早期阶段IL-6、TNF-α,增生阶段HGF、TGFa以及终止阶段TGFβ1等.这些因子相互协调,有序的调节肝细胞的增生.研究肝脏再生分子调控机制对肝切除和肝移植提高肝脏的再生能力具有重要的意义.本文就肝部分切除术后肝细胞再生的相关分子及其作用进行综述.     

不同诱导方法对人外周血树突状细胞体外成熟的影响

目的探讨不同诱导方式对于体外培养的树突状细胞（dendritic cells,DC）免疫刺激活性的影响。方法通过rhGM-CSF和IL-4体外诱导的人外周血单核细胞来源的DC,分别用肿瘤坏死因子α（TNF-α）、脂多糖（LPS）、细胞因子鸡尾酒法诱导成熟,再以流式细胞仪、FITC－Dxtran内吞检测、MLR、ELISA法检测DC的表面标志、内吞能力、刺激淋巴细胞增殖能力和IL－12分泌的变化。结果在不同方法促进DC成熟中,细胞因子鸡尾酒法诱导下的DC成熟状态最佳,CD83指数表达高达84．87％,IL-12的分泌量[（656．18±38．52ng／L）]高于其他各组,且刺激淋巴细胞增殖能力最强（P〈0．05）。结论细胞因子鸡尾酒法是体外诱导DC成熟的最佳方法。     

Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells

How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL(lpr/lpr) mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL(lpr/lpr) mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN-alpha levels. A course of 50 microg of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL(lpr/lpr) mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL(lpr/lpr) mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis.     

Inflammation-Induced IL-6 Functions as a Natural Brake on Macrophages and Limits GN

IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6–directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6^−/− mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6–mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6–directed therapies and supports the careful choice of recipient patients and timing.     

实验性肾毒血清性肾炎新月体形成机理的探讨

用羊抗兔肾毒血清在兔诱发肾毒血清性肾炎，然后用致死剂量的γ射线进行全身照射，以去除血中白细胞或静脉大剂量注射肝素，抑制纤维蛋白生成，从而抑制了肾毒血清性肾炎新月体的生成，并避免了晚期尿毒症的发生。结果表明，在肾毒血清性肾炎时，新月体细胞主要来源于血中单核细胞。而纤维蛋白作为一种趋化因子，吸引单核细胞进入肾小球球囊腔中，积聚形成新月体，单核细胞在吞噬纤维素过程中转变为上皮样细胞。     

Inhibition of p38 mitogen-activated protein kinase is effective in the treatment of experimental crescentic glomerulonephritis and suppresses monocyte chemoattractant protein-1 but not IL-1beta or IL-6

Activation of p38 mitogen-activated protein kinase (MAPK) is known to be important in cytokine production and cell survival in inflammation. This study examined the effect of inhibiting p38 MAPK after onset of renal injury in an experimental model of crescentic glomerulonephritis. Furthermore, this study investigated whether p38 MAPK inhibition would cause widespread suppression of the cytokine network in vivo or uncontrolled apoptosis. In the in vivo studies, daily treatment with a p38 MAPKalpha/beta inhibitor was started 1 h (early treatment study) or 4 d (late treatment study) after induction of nephrotoxic nephritis in Wistar Kyoto rats. The treated rats remained healthy with normal weight gain during the study. Both early and late treatment with p38 MAPK inhibitor reduced renal monocyte chemoattractant protein-1 (MCP-1) levels, the number of glomerular macrophages, the severity of tissue injury, and proteinuria compared with the vehicle group. Unexpected, treatment with p38 MAPK inhibitor did not suppress renal levels of IL-1beta or IL-6. In the in vitro study, the p38 MAPKalpha/beta inhibitor reduced production of MCP-1 and IL-6 by TNF-alpha-or IL-1beta-stimulated mesangial cells without any effect on cell viability or apoptosis. In conclusion, p38 MAPK inhibition is effective in reducing the severity of crescentic glomerulonephritis even when treatment is started after onset of disease. The therapeutic effect is associated with selective suppression of MCP-1, without widespread suppression of cytokine production or increased apoptosis. Therefore, p38 MAPK therapeutic blockade is a promising strategy in the treatment of antibody-mediated glomerulonephritis.     

利奈唑胺对严重烧伤家兔炎症因子水平的影响

目的：研究利奈唑胺（LZD）对严重烧伤家兔促炎症因子肿瘤坏死因子-α（TNFα）、白介素-1β（IL-1β）、白介素-6（IL-6）水平的影响。方法：随机将24只家兔分为假烫组、烫伤组、假烫＋LZD治疗组、烫伤＋LZD治疗组4组,每组6只。将两烫伤组家兔背部皮肤置于98℃热水18s制备30％TBSAI III度烫伤模型;假烫组用37℃温水代替热水。两LZD治疗组家兔静脉注射10mg／kg利奈唑胺。组织病理学观察烫伤深度,采用放射免疫分析方法检测烧伤后家兔血清TNF—α、IL-1、β、IL-6水平。结果：与假烫组家兔比较,烧伤家兔TNF-α、IL-1β及IL-6显著升高,IL-1β在伤后12h达峰值,TNF-α及IL-6在伤后24h达峰值。利奈唑胺能显著降低烫伤家兔TNF-α、IL-1β及IL-6水平（P〈0．05）,降幅分别为28．19％、38．54％和28．48％,但利奈唑胺对假烫家兔3种细胞因子的水平无显著影响（P〉0．05）。结论：利奈唑胺能显著降低烫伤家兔的促炎症因子水平。     

Dendritic cells facilitate accumulation of IL-17 T cells in the kidney following acute renal obstruction

Acute urinary obstruction causes interstitial inflammation with leukocyte accumulation and the secretion of soluble mediators. Here we show that unilateral ureteral ligation caused a progressive increase in renal F4/80(+) and F4/80(-) dendritic cells, monocytes, neutrophils and T-cells 24-72 h following obstruction. Depletion of dendritic cells by clodronate pretreatment showed these cells to be the most potent source of tumor necrosis factor and other pro-inflammatory mediators in the obstructed kidney. F4/80(+) dendritic cells and T-cells co-localized in the cortico-medullary junction and cortex of the obstructed kidney. Cytokine secretion patterns and surface phenotypes of T-cells from obstructed kidneys were found to include interferon-gamma-secreting CD4(+) and CD8(+) memory T-cells as well as interleukin 17 (IL-17)-secreting CD4(+) memory T-cells. Depletion of the intra-renal dendritic cells prior to ligation did not numerically reduce T-cells in obstructed kidneys but attenuated interferon-gamma and IL-17-competent T-cells. Our study shows that intra-renal dendritic cells are a previously unidentified early source of proinflammatory mediators after acute urinary obstruction and play a specific role in recruitment and activation of effector-memory T-cells including IL-17-secreting CD4(+) T-cells.     

Mesangial cell accessory functions: mediation by intercellular adhesion molecule-1

Mesangial cell (MC) proliferation is an early pathologic alteration characteristic of many forms of immune mediated glomerulonephritis. The intracapillary position, contractile capacity, and production of cytokines and other inflammatory molecules place MC in a pivotal position to initiate, mediate, and direct glomerular damage. We as well as others have noted increased levels of cytokines including IFN gamma, TNF, and IL-1 and the cell surface MHC class II and ICAM-1 molecules in the kidneys of mice with lupus nephritis. MHC class II and ICAM-1 molecules are central to the interaction of T cells with antigen presenting cells (APC). Since cytokines can increase both MHC class II and ICAM-1 molecules, we investigated whether mesangial cells could function as APC or accessory cells after cytokine stimulation. For these studies we established a permanent MC line through transformation with origin-deficient SV40 DNA. Surface expression of ICAM-1 was similar in untransformed MC as well as SV40 transformed MC from normal mice and in untransformed cells from mice with lupus nephritis. Basal expression of ICAM-1 was upregulated rapidly by IFN gamma, TNF, and IL-1. MHC class II expression could not be induced with TNF or IL-1 alone but required prolonged stimulation with IFN gamma. MC adhered and presented antigen to an antigen specific IaK restricted T cell hybridoma. Anti-ICAM-1 mAb decreased adhesion and antigen presentation of cytokine stimulated MC. By comparison, MHC class II mAb abrogated antigen presentation by MC bearing MHC class II but did not block adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)