黏膜方对IgA肾病小鼠免疫学机制的影响

目的：探讨以中医和解清热立法组方的黏膜方治疗实验性IgA肾病的作用机制。方法：采用口服牛血清白蛋白（BSA）、尾静脉注射葡萄球菌肠毒素B（SEB）及腹腔注射免疫佐剂的方法诱发小鼠IgA肾病模型。随机分为正常组、模型组、中药组及对照组4组,观察治疗后各组尿蛋白、血清IgA及循环免疫复合物、肾组织肠组织IgA的表达、肾组织病理学的改变。结果：模型组小鼠尿蛋白和尿白蛋白较正常组增加,中药组较模型组尿蛋白降低;正常组肾脏无IgA沉积、肠黏膜IgA微弱表达,模型组肾脏有IgA沉积,其中主要是多聚IgA1（pIgA1）沉积、肠黏膜IgA强表达,各治疗组肾脏IgA沉积较模型组减弱、肠黏膜IgA强表达;各治疗组在肾组织中系膜细胞和系膜基质均较模型组明显降低（P〈0.01）,而中药组更优于对照组（P〈0.01）。结论：中药黏膜方能有效改善尿蛋白并抑制IgA沉积至肾小球系膜区,表明中医和解法能成为治疗IgA肾病的有效方法之一。     

转铁蛋白受体在IgA肾病肾组织中的表达

目的阐明转铁蛋白受体（cD71、TfR）在IgA肾病（IgAN）肾组织中表达的分布特点及其与IgA表达的关系,探讨其在IgAN免疫发病机制中的作用。方法120例肾活检患者根据临床表现和肾活检病理诊断分为原发性IgAN组（原发组）44例、非IgAN性IgA沉积组（继发组）38例、无IgA沉积肾病组（肾病组）38例。用免疫荧光双套色法标记的抗体,在激光共聚焦荧光显微镜下观察四甲基罗丹明（TRITC）标记的CD71和异硫氰荧光素（FITC）标记的IgA在肾组织上的表达。结果CD71的表达强度与IgA的沉积程度相一致。CD71与IgA在原发组肾小球上高表达;在继发组低表达;在对照组微弱表达或不表达。激光共聚焦荧光显微镜下观察到CD71表达与IgA表达呈现共位现象。结论CD71在IgAN患者肾小球呈现高表达,其表达与IgA分子呈现共位状态,提示CD71可能参与了IgAN免疫发病过程。     

IgA-Ⅰ号对IgA肾病小鼠肾及肝脾肺组织病理的影响

目的：观察IgA-Ⅰ号对IgA肾病小鼠肾脏及肝、脾、肺组织病理的影响。方法：用金黄色葡萄球菌细胞膜20肽抗原决定簇（20PADSA）诱导IgA肾病模型。病理鉴定模型成功后,随机分为模型组、Ⅰ号高剂量组、Ⅰ号低剂量组、肾炎四味片组,并另设正常组,每组10只。治疗4周后处死全部小鼠,取双肾及部分肝、脾、肺组织进行组织病理检查。结果：（1）模型组的免疫荧光：IgA表达很强,IgG和C3次之;光镜：肾小球系膜细胞和基质增生;电镜：系膜区可见电子致密物沉积,表明模型建立成功;且肝、脾、肺组织的病理损害很轻。（2）IgA-Ⅰ号组和肾炎四味片组小鼠的肾脏病理损害均明显减轻,前者优于后者,Ⅰ号低剂量组优于Ⅰ号高剂量组。结论：IgA-Ⅰ号对IgAN小鼠疗效确切,值得进一步研究。     

复方积雪草2号对IgA肾病大鼠肾组织电镜形态及Nephrin表达的影响

目的：观察复方积雪草2号对IgA肾病（IgAN）大鼠肾组织病理电镜及Nephrin表达的影响。方法：复合免疫法制造IgAN大鼠模型,分设正常对照、模型、模型＋缬沙坦、模型＋复方积雪草2号高剂量、模型＋复方积雪草2号中剂量、模型＋复方积雪草2号低剂量6组。观察各组大鼠肾脏病理及肾组织Nephrin表达的变化。结果：（1）造模各组大鼠尿蛋白、镜下红细胞增多;免疫荧光镜下造模各组肾小球系膜区有不同程度IgA荧光,提示造模成功;（2）电镜下模型组系膜细胞增生,基质明显增多、有足突融合;而各治疗组足突融合情况均较模型组明显改善（P〈0.05）;（3）免疫组化法检测Nephrin显示模型组几乎没有阳性表达;RT-PCR显示模型组NephrinmRNA表达明显弱于正常组和其他各治疗组（P〈0.01）。结论：（1）Nephrin的下降可能是IgAN足细胞损伤、产生蛋白尿的病理机制之一;（2）Nephrin可能是复方积雪草2号、缬沙坦发挥肾小球足细胞保护作用的分子靶点之一。     

柴芩肾安方对IgA肾病大鼠肾组织TGF-β1和Smad 7的影响

目的：探讨柴芩肾安方对IgAN大鼠肾组织TGF-β1和Smad 7表达的影响。方法：采用灌服并定时静脉注射BSA复合感染SEB的方法制成大鼠IgAN模型,并用柴芩肾安方治疗,以氯沙坦为对照。第15周末,观察肾组织形态学变化和免疫复合物的沉积情况;采用免疫组化和RT—PCR的方法,分别检测肾组织TGF—β1和Smad 7蛋白及其mRNA的表达。结果：与正常组相比,模型组大鼠肾小球系膜细胞和系膜基质轻度增生,伴见弥漫的IgA和少量IgG沉积;TGF—β1和Smad 7蛋白及其mRNA表达均明显升高（P〈0．01）。柴芩肾安方治疗后上述指标均明显减轻（P〈0．01）,且作用效果与氯沙坦类似。结论：抑制肾组织TGF—β1和Smad 7蛋白及其mRNA的表达,可能是柴芩肾安方延缓IgAN肾脏病变进展的机制之一。     

LDLr表达失衡在阿霉素肾病大鼠肾小球硬化中的作用

目的：观察阿霉素肾病大鼠肾小球硬化过程中低密度脂蛋白受体（ LDLr）的表达情况,及辛伐他汀对LDLr表达的影响,探讨LDLr在脂质导致肾病大鼠肾脏损害过程中的作用及他汀类药物肾脏保护的机制。方法：雄性SD大鼠随机分为正常对照组、阿霉素肾病组（模型组）和阿霉素肾病辛伐他汀治疗组（治疗组）,12周后收集标本,光镜观察肾小球硬化情况,酶比色法和油红染色法检测肾组织内胆固醇含量,RT-PCR和Western-blot技术分别检测肾组织LDLr、胆固醇调节元件结合蛋白-2（SREBP-2） mRNA和蛋白质表达。结果：模型组出现明显肾小球硬化（P〈0.01）,LDLr、SREBP-2 mRNA和蛋白表达明显增强（P均〈0.01）,肾组织内胆固醇含量明显升高（P〈0.01）；线性回归分析显示肾组织LDLr、SREBP-2蛋白表达上调与肾组织胆固醇酯（CE）含量呈显著正相关性（P均〈0.01）。治疗组肾小球硬化明显减轻（P〈0.01）,LDLr、SREBP-2 mRNA和蛋白表达、肾组织内胆固醇含量均较模型组低（分别P〈0.05或P〈0.01）。结论：肾病大鼠肾小球硬化过程中,肾组织内SREBP-2、LDLr表达明显上调,脂质可能通过过度表达的LDLr途径在肾组织内沉积,加重肾小球硬化；辛伐他汀可能通过下调LDLr途径,减少脂质在肾脏组织内沉积,发挥肾脏保护作用。     

糖肾方对糖尿病肾病大鼠肾组织TGF-β1及MMP-9表达的影响

目的：研究糖肾方对糖尿病肾病大鼠肾组织TGF-β1、MMP-2、MMP-9及Ⅳ型胶原表达的影响,探讨糖肾方对糖尿病肾病大鼠肾脏的保护机制。方法：50只Wistar大鼠随机分为空白组、模型组、蒙诺组（0．833mg／kg）、糖肾方大剂量组（2．67g／kg）、糖肾方小剂量组（1．33g／kg）,每组10只,利用单侧肾切除加腹腔注射链脲佐菌素造成糖尿病肾病大鼠模型,连续给药20周。动态检测血糖和尿蛋白／肌酐水平;取肾组织进行病理组织学观察并对肾小球硬化和肾小管间质纤维化程度进行评分;RT-PCR方法检测TGF-β1、MMP-2及MMP-9 mRNA表达,免疫组化方法检测肾组织TGF-β1及Ⅳ型胶原表达。结果：大剂量糖肾方能显著降低糖尿病肾病大鼠尿蛋白／肌酐（P〈0．05）,降低肾小球硬化指数（P〈0．01）和肾小管间质纤维化指数（P〈0．01）,减少TGF-β1mRNA与蛋白表达（P〈0．05）,增加MMP-9mRNA表达（P〈0．05）,减少Ⅳ型胶原蛋白表达（P〈0．05）。结论：糖肾方可减轻实验大鼠肾小球硬化和肾小管间质纤维化,其作用机制可能与抑制TGF-β1表达和提高MMP-9mRNA水平有关。     

雷公藤内酯醇对IgA肾病大鼠的治疗作用及对肾系膜区CD71表达的影响

目的：观察雷公藤内酯醇（triptolide,TP）对IgA肾病（IgAN）大鼠肾系膜区CD71表达的影响及其对IgAN的治疗作用。方法：将雄性SD大鼠随机分为正常组、IgAN模型组（模型组）、IgAN＋TP干预组（TP组）、IgAN＋泼尼松干预组（Pred组）,每组8只。采用牛血清白蛋白（BSA）＋葡萄球菌肠毒素（SEB）＋四氯化碳（CCl4）的方法建立IgAN大鼠模型,TP组给予TP100μg·kg^-1·d^-1,Pred组给予Pred5.0mg·kg^-1·d^-1灌胃。分别于0、7、11周测24h尿蛋白定量及尿红细胞计数。12周处死大鼠取血测血肌酐（Scr）、尿素氮（BUN）;肾组织行光镜、荧光、电镜观察病理学改变。并对系膜区IgA沉积及CD71表达水平作半定量分析。RT-PCR法检测CD71mRNA在肾组织中的表达水平。结果：造模7周后模型组、TP组、Pred组大鼠尿蛋白及红细胞均较正常组显著增多,第11周时TP组及Pred组尿蛋白及红细胞较模型组显著减少,TP组尿红细胞下降尤为明显。模型组大鼠光镜下肾系膜基质增生,系膜细胞增多,部分毛细血管攀闭塞;荧光下IgA呈团块状在系膜区沉积;电镜下足突融合,系膜增生,有块状电子致密物沉积,TP组及Pred组病理较模型组显著改善,正常组未见病理改变。CD71的蛋白及mRNA水平在模型组大鼠肾组织高表达,TP组及Pred组表达显著减弱,正常组微弱表达。CD71在肾系膜区的表达与IgA的沉积呈正相关。结论：IgAN大鼠肾系膜区CD71高表达,与IgA的沉积呈正相关,TP能显著减少CD71在肾系膜区的表达,减少IgA沉积,改善临床及病理损伤指标。可见TP通过下调系膜区中CD71的表达,进而减少IgA的沉积是TP治疗IgAN的机制之一。     

复方积雪草合剂对IgA肾病大鼠肾组织炎症因子和ECM表达的影响

目的：探讨复方积雪草合剂对实验性IgA肾病（IgAN）模型大鼠肾脏组织细胞外基质（ECM）和炎症因子表达的干预作用。方法：采用改良口服牛血清白蛋白（BSA）和尾静脉注射葡萄球菌肠毒素B（SEB）的免疫复合法建立大鼠实验性IgAN模型,40只大鼠随机分为正常组、模型组及复方积雪草合剂治疗组（设高、中、低3个剂量）。药物干预12周,分别观察实验大鼠尿蛋白、肾功能、血尿及肾病理的变化,并用免疫组化及半定量法检测肾组织中FN、IL-6、TGF-β1的含量。结果：复方积雪草治疗组能显著减少实验大鼠尿红细胞和尿蛋白（P〈0.05）,同时对实验大鼠肾组织TGF-β1、FN的表达均有明显抑制作用（P〈0.05）,但对IL-6的表达未见显著作用,且无明显剂量依从性。结论：复方积雪草合剂对IgAN模型鼠具有显著的治疗作用,能有效减少蛋白尿和红细胞,减轻肾组织的免疫损伤。其作用机制可能与其抑制或降低炎症因子的分泌有关,并最终延缓IgA肾病的发展。     

罗格列酮对肾大部切除大鼠残肾细胞外基质的影响及其机制

目的：观察罗格列酮对肾大部切除大鼠残肾的细胞外基质（ECM）的影响并探讨其可能的机制。方法：将大鼠随机分为4组，每组8只：假手术组（SHAM组）、肾大部切除组（NX组）、肾大部切除加小剂量罗格列酮治疗组（XL组，罗格列酮5mg.kg^-1·d^-1）和肾大部切除加大剂量罗格列酮治疗组（DL组，罗格列酮15mg·kg^-1·d^-1）。8周后观察大鼠尿蛋白、血BUN、Scr和肾脏病理改变，用免疫组化检测基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶-9（MMP-9）在肾组织中的表达。用天狼星红染色半定量法检测肾脏胶原纤维含量。用RT～PCR的方法测定肾组织中纤连蛋白（FN）的表达。结果：（1）罗格列酮能降低大鼠24h尿蛋白定量、血BUN、Scr，与NX组比较有统计学差异（P〈0.01，P〈0．05）。（2）NX组可见肾小球硬化，ECM增生，肾组织大量胶原纤维沉积。用药后病变减轻，其中大剂量罗格列酮组肾小球MMP-2明显增多；肾小管、间质MMP-9明显减少；肾小球囊壁、肾小球基底膜及肾小管基底膜、血管周围胶原纤维沉积减少。（3）与SHAM组相比，NX组残肾组织FN mRNA的表达均明显升高（P〈0.05），XL组FN mRNA的表达较NX组有所降低，以大剂量XL组为明显（P〈0．01）。结论：罗格列酮可剂量依赖性地降低尿蛋白，改善肾功能肾脏病理损害；减少肾脏胶原纤维沉积和FN的表达；这可能与罗格列酮能抑制肾组织MMP-9表达和上调MMP-2表达有关。     

IgA–CD89 Complex in IgA Nephropathy: A Study on Molecular Function

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. The basic pathogenesis of this disease is believed to be due to the complex formation between Fc IgA, alphaRI (CD89), and transferrin receptor (CD71), leading to the damage of the glomerulus. However, studying the functional aberration in the human IgA, CD89, and CD71 complex formation in pathogenesis of IgA nephropathy is hard. Here, the author used a new gene ontology technology to predict the molecular function of human IgA, CD89, and CD71 complex. It can be seen that the two main functional aberrations of IgA–CD89 complex might be due to signal transduction and binding activity.     

IgA-CD89 complex in IgA nephropathy: a study on molecular function

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. The basic pathogenesis of this disease is believed to be due to the complex formation between Fc IgA, alphaRI (CD89), and transferrin receptor (CD71), leading to the damage of the glomerulus. However, studying the functional aberration in the human IgA, CD89, and CD71 complex formation in pathogenesis of IgA nephropathy is hard. Here, the author used a new gene ontology technology to predict the molecular function of human IgA, CD89, and CD71 complex. It can be seen that the two main functional aberrations of IgA-CD89 complex might be due to signal transduction and binding activity.     

芪蓟肾康颗粒对IgA肾病大鼠肾组织IL-13及血清CIC的影响

目的:观察芪蓟肾康颗粒对IgA肾病大鼠肾组织IL-13的表达及血清循环复合物(CIC)浓度的影响,探讨芪蓟肾康颗粒治疗IgA肾病的机制。方法:采用口服牛血清白蛋白(BSA)制备实验性IgA肾病大鼠模型。芪蓟肾康颗粒及替米沙坦于实验第8周开始灌胃给药,每日1次,连续5周,至实验12周末取血检测CIC含量,取肾脏组织检测IL-13表达。结果:与模型组比较:芪蓟肾康颗粒中、高剂量组IL-13表达下降(P<0.01),芪蓟肾康颗粒各剂量组血清CIC浓度均下降(P<0.01)。与替米沙坦组比较:芪蓟肾康颗粒中、高剂量组IL-13表达差异有统计学意义(P<0.01),中药各剂量组血清CIC浓度差异无统计学意义(P>0.05)。结论:芪蓟肾康颗粒有调节IgA肾病大鼠肾组织IL-13表达及血清CIC浓度的作用。     

昆仙胶囊对阳离子化牛血清白蛋白所致大鼠肾病模型的保护作用

目的：观察昆仙胶囊对阳离子化牛血清白蛋白（C-BSA）诱导的大鼠原位免疫复合物型肾炎模型的肾脏保护作用。方法：Wistar大鼠72只,随机分为正常对照组、模型组、泼尼松组和昆仙胶囊大、中、小剂量组,每组12只。以C-BSA建立大鼠原位免疫复合物型肾炎模型。于预免疫同时给药,连续给药56d,给药期间动态观察各组大鼠体重、24h尿蛋白定量的变化,于正式免疫第5周结束时处死大鼠,腹主动脉取血,分离血清测定白蛋白、总蛋白、胆固醇、三酰甘油、尿素氮、肌酐的水平,留取肾脏,进行光镜和电镜病理形态学观察。结果：泼尼松组从第3周起,体重显著小于其余各组（P〈0.05）。模型组24h尿蛋白定量于第4周（正式免疫后2周）升高,与正常组相比（P〈0.01）。泼尼松组和昆仙胶囊大剂量组的尿蛋白水平降低,与模型组相比（P〈0.05）。昆仙胶囊大、中、小剂量组均可改善肾小球病理损伤,而对肾小管间质病理损伤无明显改善作用。电镜观察显示昆仙胶囊可以减轻足细胞损伤程度,减轻基底膜厚度,改善电子致密物沉积情况。结论：昆仙胶囊大剂量可以降低C-BSA大鼠模型的24h尿蛋白定量,改善肾小球病理损伤,其机制可能与昆仙胶囊降低免疫复合物在基底膜沉积有关。     

Localization and roles of CD44, hyaluronic acid and osteopontin in IgA nephropathy.

An important function of CD44 is to act as a cellular receptor for hyaluronic acid and osteopontin. Cell-matrix interactions mediated by the CD44/hyaluronic acid receptor-ligand pair are involved in the regulation of leukocyte migration and activation. Osteopontin is a molecule associated with cell adhesion and migration and functions through binding to CD44. This study examined whether CD44, hyaluronic acid and osteopontin participate in the progression of IgA nephropathy. CD44 was expressed in mesangial cells, crescents, tubular cells and interstitial infiltrating cells in areas of tubulointerstitial injury. Hyaluronic acid was deposited in the capillary tuft of adhesion, crescents and the periglomerular area, and around damaged tubules. Osteopontin was expressed in tubular cells and interstitial infiltrating cells in areas of tubulointerstitial injury. The glomerular and interstitial deposition of hyaluronic acid correlated with the glomerular and interstitial expression of CD44. The interstitial expression of CD44 correlated with the interstitial expression of osteopontin. The expression of both CD44 and osteopontin in the interstitium correlated with the extent of tubulointerstitial damage. The expression of CD44 in the interstitium correlated with the severity of chronic glomerular lesions. The glomerular and interstitial CD44 and hyaluronic acid expression correlated with proteinuria, and interstitial CD44 and hyaluronic acid expression correlated with creatinine clearance rate. In summary, this study suggests that CD44 participates in the progression of IgA nephropathy by binding hyaluronic acid and osteopontin.     

Podocytopenia and disease severity in IgA nephropathy

BACKGROUND: IgA nephropathy is a common form of progressive glomerular disease, associated with proliferation of mesangial cells and mesangial deposition of IgA. The present study was designed to investigate functional and morphological covariates of disease severity in patients with IgA nephropathy. METHODS: Glomerular hemodynamics, permselectivity and ultrastructure were studied in 17 adult patients with IgA nephropathy using inulin, para-aminohippuric acid (PAH) and 3H-Ficoll clearances and morphometric methods. A mathematical model of macromolecule permeation through a heteroporous membrane was used to characterize glomerular permselectivity. Controls consisted of 14 healthy living kidney donors and 12 healthy volunteers. RESULTS: The patients were heterogeneous in their disease severity, but as a group had a decreased glomerular filtration rate (GFR) and increased urinary protein excretion compared to controls [63 +/- 29 SD vs. 104 +/- 23 mL/min/1.73 m2, P < 0.001, and (median) 1.34 vs. 0.11 g/day, P < 0.0001, respectively). A multivariate analysis of structural and functional relationships revealed GFR depression to be most strongly correlated with the prevalence of global glomerular sclerosis (t = -4.073, P = 0.002). Those patients with the most severe glomerular dysfunction had a reduced number of glomerular visceral epithelial cells (podocytes) per glomerulus. The degree of podocytopenia was related to the extent of glomerular sclerosis and of impairment of permselectivity and GFR, with worsening injury below an apparent threshold podocyte number of about 250 cells per glomerulus. There were no corresponding correlations between these indices of injury and the number of mesangial and endothelial cells. CONCLUSIONS: Our findings show that podocyte loss is a concomitant of increasing disease severity in IgA nephropathy. This suggests that podocyte loss may either cause or contribute to the progressive proteinuria, glomerular sclerosis and filtration failure seen in this disorder.     

The number of CD10-positive glomerular epithelial cells reflects renal prognosis in IgA nephropathy patients

BACKGROUND: The glomerular epithelial cells play an important role in glomerular filtration of the kidney. The disruption of these cells contributes to the development of glomerulosclerosis. The present study was performed to elucidate whether loss of the glomerular epithelial cells is associated with renal injury in patients with IgA nephropathy. PATIENTS AND METHODS: Thirty renal biopsy specimens from IgA nephropathy, 12 from minor glomerular abnormalities and 5 from normal controls were observed. The specimens from IgA nephropathy were divided into 2 groups: Group IgA-1, including 11 patients who had received a follow-up renal biopsy because of deterioration of renal function, and Group IgA-2, consisting of the remaining 19 patients without follow-up biopsy. Immunohistochemistry was performed using a monoclonal antibody against CD10 antigen that appears on mature epithelial cells of glomeruli. RESULTS: The average number of CD10-positive glomerular epithelial cells (GECs) was significantly lower in IgA nephropathy than in either minor glomerular abnormalities or the normal controls. In IgA nephropathy, there were significant correlations of the GECs with renal functions. The GECs were reduced along with the progression of histopathological damage. In group IgA-1, the GECs were significantly reduced at the second biopsy compared with the first biopsy, and significantly fewer in group IgA-1 than in group IgA-2 at the first biopsy. The GECs showed a significant correlation with renal prognosis during the follow-up period. CONCLUSIONS: The reduction of GECs was associated with renal dysfunction, histopathological damage and renal prognosis. The GECs may be a useful predictor of renal prognosis in IgA nephropathy.     

Effect of soluble form CTLA‐4 on spontaneous IgA nephropathy in ddY mice

The aim of the present study was to examine the role of CD28‐B7 signalling in the development of glomerulonephritis in ddY mice, an animal model for IgA nephropathy. To achieve this aim, we investigated whether the CTLA‐4 (CD152) fusion protein, which binds to B7.1 (CD80) and B7.2 (CD86), affects glomerular pathological changes (including IgA deposition), or functional parameters (such as serum creatinine and proteinuria). Each group (n = 4) was given either human CTLA‐4 fused with human IgG (CTLA4Ig) or control human IgG1. All treated groups of mice were injected intraperitoneally at a dose of 0.1 mg twice a week for the duration of the study. Mice given control human IgG1 progressively developed typical mesangioproliferative glomerulonephritis, with remarkable glomerular IgA deposits. In contrast, mice treated with CTLA4Ig showed a significant reduction in proteinuria and mesangioproliferative change, with an expansion of the mesangial matrix at 40 weeks of age. The serum IgA levels of these mice were considerably lower than those in mice given the control human IgG1. A direct immunofluorescence study showed the reduction of glomerular IgA deposits in CTLA4Ig‐treated mice. We have demonstrated for the first time that the development of spontaneously occurring IgA nephropathy can be prevented in ddY mice by blocking the CD28‐B7 interaction using a soluble form of CTLA4Ig. These results suggest that a costimulatory signal via CD28‐B7 may play a crucial role in the development and progression of IgA nephropathy.     

Effect of soluble form CTLA-4 on spontaneous IgA nephropathy in ddY mice

The aim of the present study was to examine the role of CD28-B7 signalling in the development of glomerulonephritis in ddY mice, an animal model for IgA nephropathy. To achieve this aim, we investigated whether the CTLA-4 (CD152) fusion protein, which binds to B7.1 (CD80) and B7.2 (CD86), affects glomerular pathological changes (including IgA deposition), or functional parameters (such as serum creatinine and proteinuria). Each group ( n = 4) was given either human CTLA-4 fused with human IgG (CTLA4Ig) or control human IgG1. All treated groups of mice were injected intraperitoneally at a dose of 0.1 mg twice a week for the duration of the study. Mice given control human IgG1 progressively developed typical mesangioproliferative glomerulonephritis, with remarkable glomerular IgA deposits. In contrast, mice treated with CTLA4Ig showed a significant reduction in proteinuria and mesangioproliferative change, with an expansion of the mesangial matrix at 40 weeks of age. The serum IgA levels of these mice were considerably lower than those in mice given the control human IgG1. A direct immunofluorescence study showed the reduction of glomerular IgA deposits in CTLA4Ig-treated mice. We have demonstrated for the first time that the development of spontaneously occurring IgA nephropathy can be prevented in ddY mice by blocking the CD28-B7 interaction using a soluble form of CTLA4Ig. These results suggest that a costimulatory signal via CD28-B7 may play a crucial role in the development and progression of IgA nephropathy.