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Expression profiling of renal epithelial neoplasms - A method for tumor classification and discovery of diagnostic molecular markers

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AMERICAN JOURNAL OF PATHOLOGY 2001年第5期158卷 1639-1651页

作者： Young, AN Amin, MB Moreno, CS Lim, SD Cohen, C Petros, JA Marshall, FF Neish, AS Emory Univ Sch Med Dept Pathol & Lab Med Atlanta GA 30322 USA Emory Univ Sch Med Dept Urol Atlanta GA 30322 USA Emory Univ Sch Med Dept Biochem Atlanta GA 30322 USA Atlanta VA Med Ctr Decatur GA USA

The expression patterns of 7075 genes were analyzed in four conventional (clear cell) renal cell carcinomas (RCC), one chromophobe RCC, and two oncocytomas using cDNA microarrays. Expression profiles were compared among tumors using various clustering algorithms, thereby separating the tumors into two categories consistent with corresponding histopathological diagnoses. Specifically, conventional RCCs were distinguished from chromophobe RCC/oncoytomas based on large-scale gene expression patterns. Chromophobe RCC/oncocytomas displayed similar expression profiles, including genes involved with oxidative phosphorylation and genes expressed normally by distal nephron, consistent with the mitochondrion-rich morphology of these tumors and the theory that both lesions are related histogenetically to distal nephron epithelium. Conventional RCCs underexpressed mitochondrial and distal nephron genes, and were further distinguished from chromophobe RCC/oncocytomas by overexpression of vimentin and class II major histocompatibility complex-related molecules. Novel, tumor-specific expression of four genes-vimentin, class II major histocompatibility complex-associated invariant chain (CD74), parvalbumin, and galectin-3-was confirmed in an independent tumor series by immunohistochemistry, Vimentin was a sensitive, specific marker for conventional RCCs, and parvalbumin was detected primarily in chromophobe RCC/oncocytomas. In conclusion, histopathological subtypes of renal epithelial neoplasia were characterized by distinct patterns of gene expression, Expression patterns were useful for identifying novel molecular markers with potential diagnostic utility.

关键词：抗原分化/分析抗原分化 B淋巴细胞/分析癌肾细胞/遗传学癌肾细胞/病理学半乳糖凝集素3 基因表达谱基因表达调控肿瘤组织相容性抗原ⅱ类/分析免疫组织化学肾/化学肾/病理学肾肿瘤/分类肾肿瘤/遗传学肾肿瘤/病理学寡核苷酸序列分析小白蛋白/分析肿瘤标记生物学/分析波形蛋白/分析成年人老年人女(雌)性人类男(雄)性中年人

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Transgenic expression of granulocyte-macrophage colony-stimulating factor induces the differentiation and activation of a novel dendritic cell population in the lung

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BLOOD 2000年第7期95卷 2337-2345页

作者： Wang, J Snider, DP Hewlett, BR Lukacs, NW Gauldie, J Liang, H Xing, Z McMaster Univ Hlth Sci Ctr Dept Pathol & Mol Med Hamilton ON L8N 3Z5 Canada McMaster Univ Ctr Gene Therapeut Div Infect Dis Hamilton ON Canada Univ Michigan Dept Pathol Ann Arbor MI 48109 USA

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the differentiation of dendritic cells (DCs) during pulmonary viral infection was investigated by using a mouse model of GM-CSF transgene expression established with an adenoviral vector (AdGM-CSF). GM-CSF gene transfer resulted in increased levels of GM-CSF in the lung, which peaked at day 4 and remained increased up to day 19. A striking cellular response composed predominantly of macrophage-like cells was observed in the lung receiving AdGM-CSF but not control vector. By FAGS analysis, the majority of these cells were identified at an early time point as macrophages and later as mature/activated myeloid DCs characterized by CD11b(bright), CD11c(bright), MHC class IIbright, and B7.1(bright). In contrast, GM-CSF had a weak effect on a small DC population that was found present in normal lung and was characterized by CD11c(bright) and CD11b(low), By immunohistochemistry staining for MHC II, the majority of activated antigen-presenting cells were localized to the airway epithelium and peribronchial/perivascular areas in the lung. A concurrently enhanced Th1 immune response was observed under these conditions. The number of CD4 and CD8 T cells was markedly increased in the lung expressing GM-CSF, accompanied by increased release of interferon (IFN)gamma in the lung. Furthermore, lymphocytes isolated from either lung parenchyma or local draining lymph nodes of these mice but not the control mice released large amounts of IFN gamma on adenoviral antigen stimulation in vitro. These findings reveal that GM-CSF promotes the differentiation and activation of a myeloid DC population primarily by acting on macrophages during pulmonary immune responses. (Blood, 2000;95: 2337-2345) (C) 2000 by The American Society of Hematology.

关键词：腺病毒科/遗传学抗原呈递细胞/细胞学抗原 CD11/分析细胞分化树突细胞/细胞学树突细胞/生理学流式细胞术基因表达遗传载体粒细胞巨噬细胞集落刺激因子/遗传学粒细胞巨噬细胞集落刺激因子/生理学组织相容性抗原ⅱ类/分析动力学肺/细胞学肺/免疫学肺/代谢淋巴细胞计数巨噬细胞/细胞学小鼠近交BALBC 小鼠近交C3H 转染动物女(雌)性小鼠

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Generation of murine dendritic cells from flt3-ligand-supplemented bone marrow cultures

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BLOOD 2000年第9期96卷 3029-3039页

作者： Brasel, K De Smedt, T Smith, JL Maliszewski, CR Immunex Res & Dev Corp Dept Immunobiol Seattle WA 98101 USA Immunex Res & Dev Corp Dept Discovery Res Seattle WA 98101 USA

Murine dendritic cells (DCs) can be classified into at least 2 subsets, "myeloid-related" (CD11(bright), CD8 alpha (-)) and "lymphoid-related" (CD11b(dull), CD8 alpha (+)), but the absolute relationship between the 2 remains unclear. Methods of generating DCs from bone marrow (BM) precursors in vitro typically employ granulocyte-macrophage colony-stimulating factor (GM-CSF) as the principal growth factor, and the resultant DCs exhibit a myeloidlike phenotype, Here we describe a flt3-ligand (FL)-dependent BM culture system that generated DCs with more diverse phenotypic characteristics. Murine BM cells cultured at high density in recombinant human FL for 9 days developed into small lymphoid-sized cells, most of which expressed CD11c, CD86, and major histocompatibility complex (MHC) class II. The CD11c(+) population could be divided into 2 populations on the basis of the level of expression of CD11b, which may represent the putative myeloid- and lymphoid-related subsets. The FL in vitro-derived DCs, when treated with interferon-alpha or lipopolysaccharide during the final 24 hours of culture, expressed an activated phenotype that included up-regulation of MHC class II, CD1d, CD8 alpha, CD80, CD86, and CD40, The FL-derived DCs also exhibited potent antigen-processing and antigen-presenting capacity. Neutralizing anti-interleukin-6 (IL-6) antibody, but not anti-GM-CSF, significantly reduced the number of DCs generated in vitro with FL, suggesting that IL-6 has a role in the development of DCs from BM precursors. Stem cell factor, which exhibits some of the same bioactivities as FL, was unable to replace FL to promote DC development in vitro. This culture system will facilitate detailed analysis of murine DC development. (C) 2000 by The American Society of Hematology.

关键词：抗原 CD/分析抗原 CD86 骨髓细胞/细胞学骨髓细胞/免疫学 CD4阳性T淋巴细胞/细胞学 CD4阳性T淋巴细胞/免疫学细胞培养的树突细胞/细胞学树突细胞/免疫学粒细胞巨噬细胞集落刺激因子/药理学造血干细胞/细胞学造血干细胞/药物作用造血干细胞/免疫学组织相容性抗原ⅱ类/分析整合素αXβ2/分析白细胞介素12/分析白细胞介素6/缺乏白细胞介素6/遗传学白细胞介素6/生理学白细胞生成/免疫学淋巴细胞培养试验混合膜糖蛋白类/分析小鼠近交BALBC 小鼠近交C57BL 小鼠近交DBA 小鼠基因敲除原癌基因蛋白质类/药理学受体蛋白质酪氨酸激酶类/药理学重组蛋白质类/药理学脾/细胞学脾/免疫学 fms样酪氨酸激酶3 动物女(雌)性人类小鼠

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CD1d structure and regulation on human thymocytes, peripheral blood T cells, B cells and monocytes

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IMMUNOLOGY 2000年第1期100卷 37-47页

作者： Exley, M Garcia, J Wilson, SB Spada, F Gerdes, D Tahir, SMA Patton, KT Blumberg, RS Porcelli, S Chott, A Balk, SP Beth Israel Deaconess Med Ctr Dept Med Div Hematol Oncol Canc Biol Program Boston MA 02215 USA Harvard Univ Sch Med Boston MA USA Massachusetts Gen Hosp Diabet Unit Boston MA 02114 USA Brigham & Womens Hosp Div Rheumatol Allergy & Immunol Lymphocyte Biol Sect Boston MA 02115 USA Brigham & Womens Hosp Div Gastroenterol Boston MA 02115 USA Univ Vienna Dept Clin Pathol A-1010 Vienna Austria

Human T cells expressing CD161 and an invariant T-cell receptor (TCR) alpha-chain (V alpha 24(invt) T cells) specifically recognize CD1d and appear to have immunoregulatory functions. However, the physiological target cells for this T-cell population, and whether alterations in CD1d expression contribute to the regulation of V alpha 24(invt) T-cell responses, remain to be determined. A series of antibodies were generated to assess CD1d expression, structure and regulation on human lymphoid and myeloid cells. CD1d was expressed at high levels by human cortical thymocytes and immunoprecipitation analyses showed it to be a 48 000-MW glycosylated protein. However, after solubilization, the majority of the thymocyte CD1d protein, but not CD1d expressed by transfected cells, lost reactivity with monoclonal antibodies (mAbs) against native CD1d, indicating that it was alternatively processed. Moreover, thymocytes were not recognized by CD1d-reactive V alpha 24(invt) T-cell clones. Medullary thymocytes and resting peripheral blood T cells were CD1d(-), but low-level CD1d expression was induced on activated T cells. CD1d was expressed by B cells in peripheral blood and lymph node mantle zones, but germinal centres were CD1d(-). Resting monocytes were CD1d(+) but, in contrast to CD1a, b and c, their surface expression of CD1d was not up-regulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) activation. These results demonstrate constitutive CD1d expression by human professional antigen-presenting cells and that post-translational processing of CD1d may contribute to regulation of the activity of CD1d-specific T cells.

关键词：抗体特异性抗原 CD1/化学抗原 CD1/代谢抗原分化 B淋巴细胞/分析 B淋巴细胞/免疫学细胞培养技术组织相容性抗原ⅱ类/分析白细胞/免疫学淋巴结/免疫学淋巴细胞活化/免疫学受体抗原 T细胞 α-β/分析 T淋巴细胞/免疫学胸腺/免疫学人类

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The MHC is a major determinant of viral status, but not fibrotic stage, in individuals infected with hepatitis C

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GASTROENTEROLOGY 2000年第6期118卷 1124-1130页

作者： McKiernan, SM Hagan, R Curry, M McDonald, GSA Nolan, N Crowley, J Hegarty, J Lawlor, E Kelleher, D St James Hosp Dept Clin Med Trin Ctr Hlth Sci Dublin 8 Ireland Univ Dublin Trinity Coll Dublin 2 Ireland Blood Transfus Serv Board Dublin Ireland St Vincents Hosp Dublin 4 Ireland

Background & Aims: In hepatitis C infection, several studies have examined the role of the major histocompatibility complex (MHC) in determining outcome, with variable results. To clarify the importance of MHC, we examined class II DR and DQ antigens in a homogenous cohort of women exposed to hepatitis C genotype Ib from a single inoculum, Methods: Of 243 participants, 95 had spontaneous viral clearance and 148 are chronically infected. The frequencies of HLA class II DR and DQ antigens were compared between the 2 groups and between liver biopsy findings of 145 chronically infected subjects, Results: DRB1*0101 and DQB1*0501 alleles were more frequent in subjects who sustained viral clearance than in chronically infected subjects (32.3% and 36.8% vs, 8.8% and 14.2%, respectively;P = 0.002). DRB1*03011 and DQB1*0201 occurred more frequently in chronically infected subjects than in those who cleared the virus (41.5% and 42.6% vs. 16.7% and 15.8%, respectively;P = 0.001), Both DRB1*03011 and DQB1*0201 were significantly less frequent in those with higher inflammatory scores on liver biopsy, Conclusions: We show that in a homogenous cohort of women infected with the same hepatitis C virus, several HLA antigens are associated with either viral clearance or persistence. This suggests a strong role for host immunogenetic factors in determining outcome in hepatitis C infection.

关键词：等位基因活组织检查队列研究疾病遗传易感性 HLA-DQ抗原/分析 HLA-DQ抗原/遗传学 HLA-DQβ链 HLA-DR抗原/分析 HLA-DR抗原/遗传学 HLA-DRB1链单倍型丙型肝炎/遗传学丙型肝炎/免疫学丙型肝炎/病理学组织相容性抗原ⅱ类/分析组织相容性抗原Ⅱ类/遗传学组织相容性抗原Ⅱ类/免疫学组织相容性试验免疫表型分型肝硬化/遗传学肝硬化/免疫学肝硬化/病理学成年人老年人女(雌)性人类中年人

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Association of B7-1 co-stimulation with the development of graft arterial disease - Studies using mice lacking B7-1, B7-2, or B7-1/B7-2

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AMERICAN JOURNAL OF PATHOLOGY 2000年第2期157卷 473-484页

作者： Furukawa, Y Mandelbrot, DA Libby, P Sharpe, AH Mitchell, RN Harvard Univ Sch Med Brigham & Womens Hosp Dept PatholDiv Immunol Boston MA 02115 USA Harvard Univ Sch Med Brigham & Womens Hosp Dept Med Boston MA 02115 USA Harvard Univ Sch Med Brigham & Womens Hosp Cardiovasc DivVasc Med & Atherosclerosis Unit Boston MA 02115 USA

To investigate the roles of B7-1 and/or B7-2 co-stimulatory molecule in the development of graft arterial disease (GAD), major histocompatibility complex (MHC) class It-mismatched allograft hearts were transplanted into wild-type, B7-1(-/-), B7-2(-/-), or B7-1/B7-2(-/-) recipient mice. Grafts were explanted at 4 or 8 weeks and used for histological and immunohistochemical analyses, RNase protection assay, and now cytometry of graft infiltrating cells. Grafts In wild-type recipients showed macrophage, recipient MHC class II, and B7 molecule co-localization by immunohistochemistry to GAD lesions. Flow cytometry revealed that CD11b(+) and MHC class II(+) graft infiltrating cells expressed B7-1 more than B7-2, whereas B7-2 expression was predominant in CD11b(-) cells at 4 and 8 weeks. GAD was significantly attenuated in the allografts in B7-1(-/-) and B7-1/B7-2(-/-) but not in B7-2-/- recipients compared to wild-type hosts. Interferon-gamma mRNA levels were comparable in all graft combinations, whereas interleukin-4 mRNA levels decreased in grafts in B7-2 deficient hosts, but did not correlate with GAD attenuation. The findings indicate distinct roles for B7-1 and B7-2 co-stimulatory molecules in the development of GAD, potentially because of differential expression of B7-1 and B7-2 molecules on distinct stimulator and/or effector cell populations.

关键词：抗原呈递细胞/生理学抗原 CD/分析抗原 CD/遗传学抗原 CD/生理学抗原 CD80/分析抗原 CD80/遗传学抗原 CD80/生理学抗原 CD86 B淋巴细胞/化学 B淋巴细胞/细胞学 CD4阳性T淋巴细胞/化学 CD4阳性T淋巴细胞/细胞学 CD8阳性T淋巴细胞/化学 CD8阳性T淋巴细胞/细胞学炎症趋化因子类/遗传学细胞因子类/遗传学流式细胞术基因表达调控基因型移植物闭塞血管/病因学移植物排斥/并发症移植物排斥/病理生理学心脏移植组织相容性抗原ⅱ类/分析免疫组织化学巨噬细胞/化学巨噬细胞/细胞学膜糖蛋白类/分析膜糖蛋白类/遗传学膜糖蛋白类/生理学小鼠近交C57BL 时间因素移植同种动物女(雌)性男(雄)性小鼠

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The effects of DNA containing CpG motif on dendritic cells

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IMMUNOLOGY 2000年第3期99卷 361-366页

作者： Behboudi, S Chao, D Klenerman, P Austyn, J Univ Oxford John Radcliffe Hosp Nuffield Dept Surg Oxford OX3 9DU England Univ Oxford John Radcliffe Hosp Nuffield Dept Med Oxford OX3 9DU England

Dendritic cells (DC) are specialized antigen-presenting cells. DC can acquire and process antigens in the periphery before maturing and migrating to secondary lymphoid tissues where they present the antigens and deliver co-stimulatory signals to T cells. We describe an immunostimulatory oligonucleotide containing a CpG motif that stimulated murine DC to up-regulate co-stimulatory molecules, induce T-cell proliferative responses and secrete interleukin-12 in vitro. Administration of this oligonucleotide, but not of a control oligonucleotide lacking this motif, to mice led to the disappearance of DC from the marginal zone and T-cell areas of spleen, but not from heart or kidney. The same CpG did not cause maturation of monocyte-derived human DC in vitro, but lipopolysaccharide-treated monocyte-derived DC showed enhanced functional activity and up-regulated co-stimulatory molecules.

关键词：抗原 CD/分析抗原 CD40/分析抗原 CD86 细胞运动细胞培养的 CpG岛树突细胞/免疫学流式细胞术组织相容性抗原ⅱ类/分析免疫组织化学整合素αXβ2/免疫学白细胞介素12/生物合成外源凝集素类 C型脂多糖类/药理学膜糖蛋白类/分析小鼠近交BALBC 小鼠近交C57BL 寡核苷酸类/药理学受体细胞表面/分析脾/免疫学动物女(雌)性人类小鼠

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An immunohistochemical study of histiocytic ulcerative colitis in boxer dogs

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JOURNAL OF COMPARATIVE PATHOLOGY 2000年第2-3期122卷 163-175页

作者： German, AJ Hall, EJ Kelly, DF Watson, ADJ Day, MJ Univ Bristol Dept Vet Clin Sci Bristol BS40 5DU Avon England Univ Bristol Dept Pathol & Microbiol Bristol BS40 5DU Avon England Univ Liverpool Dept Vet Pathol Liverpool L69 3BX Merseyside England Univ Sydney Dept Vet Clin Sci Sydney NSW 2006 Australia

Histiocytic ulcerative colitis (HUC) is an inflammatory bowel disease (IBD) that occurs predominantly in dogs of the boxer breed. The lesions are characterized by mucosal ulceration and mixed inflammatory cell infiltrate that includes the presence of periodic acid-Schiff (PAS)-positive macrophages. However, the phenotype of the inflammatory cells has not been characterized further. In the present study, immunohistochemistry and computer-aided morphometric analysis were used to define populations of leucocyte subsets in the colon of 14 boxer dogs with HUG. Biopsies from six of these dogs included both lesional and non-lesional regions. Colonic tissue from 11 dogs of various breeds without evidence of gastrointestinal disease served as controls. In HUC lesions there were significantly more IgG(+), IgG3(+), IgG4(+) plasma cells, CD3(+) T cells, MHC class II+ cells, Ll(+) cells and PAS(+) cells in the lamina propria than in both control colon and non-lesional colonic regions of affected dogs. In the epithelial compartment, goblet cells were significantly decreased in HUC lesions compared to both control and non-lesional HUC colon, and intensity of enterocyte MHC class II expression was significantly increased. These observations are similar to those documented in human IBD, especially ulcerative colitis, and suggest an important role for the mucosal immune system in the pathogenesis of canine HUG. (C) 2000 Harcourt Publishers Ltd.

关键词：抗原 CD3/分析繁殖细胞计数结肠炎溃疡性/代谢结肠炎溃疡性/病理学结肠炎溃疡性/兽医学结肠/化学结肠/病理学狗疾病/代谢狗疾病/病理学上皮细胞/细胞学上皮细胞/免疫学组织相容性抗原ⅱ类/分析组织细胞化学免疫球蛋白A/分析免疫球蛋白G/分析免疫球蛋白M/分析免疫组织化学白细胞L1抗原复合物膜糖蛋白类/分析神经细胞黏附分子类/分析高碘酸-雪夫染色反应浆细胞/细胞学浆细胞/免疫学回顾性研究 T淋巴细胞/细胞学 T淋巴细胞/免疫学动物狗女(雌)性男(雄)性

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In vivo macrophage activation in chickens with Acemannan, a complex carbohydrate extracted from Aloe vera

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INTERNATIONAL JOURNAL OF IMMUNOPHARMACOLOGY 2000年第5期22卷 365-372页

作者： Djeraba, A Quere, P INRA Pathol Aviaire & Parasitol Stn F-37380 Nouzilly France

Acemannan (ACM 1), a beta-(1,4) -acetylated mannan isolated from Aloe vera, can be used as an effective adjuvant in vaccination against some avian viral diseases. Our results demonstrate a quick and lasting in vivo priming effect of ACM 1 on macrophage response after intramuscular inoculation in chickens (500 mu g per 2-month-old bird). In response to IFN-gamma in vitro, monocytes from ACM 1-treated chickens exhibited a strong enhancement of NO production from 3 to 9 days p.i., but a weaker effect on MHC II cell surface antigen expression on day 3 p.i.. A stimulating effect of ACM 1 treatment was also observed on spontaneous and inducible NO production for splenocytes only on day 3 p.i.. By that time, splenocytes exhibited a strong higher capacity to proliferate in response to the T cell-mitogen PHA. At the same time, the in vivo capacity to produce NO, measured by the (NO2-+NO3-) serum level after intravenous LPS injection, increased greatly from 3 to 9 days p.i.. In conclusion, ACM 1 was able efficiently and durably to increase the activation capacity of macrophages from the systemic immune compartment (in particular from the blood and spleen after an intramuscular injection) in chickens, especially for NO production. These findings provide a better understanding of the adjuvant activity of ACM 1 for viral and tumoral diseases. (C) 2000 International Society for Immunopharmacology. Published by Elsevier Science Ltd. All rights reserved.

关键词：佐剂免疫/药理学鸡组织相容性抗原Ⅰ类/分析组织相容性抗原ⅱ类/分析淋巴细胞活化/药物作用巨噬细胞活化/药物作用甘露聚糖类/药理学单核细胞/代谢一氧化氮/生物合成一氧化氮/血液动物

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T-cell-rich B-cell lymphoma in the cat

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JOURNAL OF COMPARATIVE PATHOLOGY 1999年第2期120卷 155-167页

作者： Day, MJ Kyaw-Tanner, M Silkstone, MA Lucke, VM Robinson, WF Univ Bristol Dept Pathol & Microbiol Langford BS40 5DU England Univ Queensland Sch Vet Sci & Anim Prod Dept Vet Pathol & Anat Brisbane Qld 4072 Australia Abbey Vet Serv Newton Abbot TQ12 2HW Devon England

The clinical and pathological features of eight cases of feline T-cell-rich B-cell lymphoma are described. The disease occurred in older cats (mean age 11.4 +/- 3.9 pears), which on initial examination generally showed enlargement of a single submandibular or cervical lymph node. After excision, there was no recurrence of the lesions at 6 months in three cats. In one further case, however? the lesion had recurred 6 months later;it was again excised but recurred after an additional 6 months. Microscopically, there was effacement of normal lymph node architecture by a nodular (n = 4) or diffuse (n = 4) proliferation of small to blastic lymphocytes, accompanied by a characteristic population of bizarre giant, or multinucleate, cells. The mitotic rate was low and mitoses were restricted to the atypical population. Immunophenotyping revealed the smaller lymphocytes to be a mixture of CD3(+) MHC Class II T lymphocytes and BLA36(+)CD79(variable) MHC Class IIvariable B lymphocytes. The atypical cells were of the B-cell lineage (BLA36(+)MHC Class IIvariable). Polymerase chain reaction analysis revealed no proviral DNA products of feline leukaemia virus or feline immunodeficiency virus in tissue from an!: tumour, confirming that these neoplasms were not associated with either virus. The clinical, histological and immunophenotypic findings in these cats were identical with those of "nodular lymphocyte predominance lymphocytic and histiocytic/L&H) Hodgkin's disease" in man. (C) 1999 W.B. Saunders Company Limited.

关键词：年龄因素猫疾病/免疫学猫疾病/病理学猫疾病/病毒学组织相容性抗原ⅱ类/分析免疫缺陷病毒猫/分离和提纯免疫组织化学白血病病毒猫/分离和提纯原病毒/分离和提纯动物猫女(雌)性男(雄)性

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