bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast carcinoma in women over the age of 85: distinct histological pattern and androgen, oestrogen, and progesterone receptor status
Authors: Honma N , Sakamoto G , Akiyama F , Esaki Y , Sawabe M , Arai T , Hosoi T , Harada N , Younes M , Takubo K 
Published: March 2003

Aims:  The pathogenesis of breast carcinoma in very elderly women is of interest, because oestrogen levels are likely to be extremely low during the development of the disease. In an effort to understand the pathogenesis of breast carcinoma in these women, this study was undertaken to compare the histological patterns and hormone receptor status of breast carcinomas arising in very elderly and younger women.Methods and results:  Thirty‐seven breast carcinomas from women over the age of 85 years at the time of their operation were examined histologically and compared with those from a large group of premenopausal women. The proportions of mucinous carcinoma and apocrine carcinoma were significantly greater in older women. The expression of steroid hormone receptors was studied immunohistochemically. Androgen receptor‐positive carcinomas were significantly more frequent among older women, whereas progesterone receptor‐positive carcinomas were significantly less frequent. There was no statistically significant difference in oestrogen receptor‐α or ‐β expression between the tumours from both groups.Conclusion:  Breast carcinomas in women over the age of 85 years have a different morphological spectrum from carcinomas in younger age groups and may have different pathogenesis mechanisms that may be more dependent on androgen and androgen receptor interaction. Differences from the results of the other studies are discussed.
Interleukin‐15 strongly inhibits interleukin‐8 and monocyte chemoattractant protein‐1 production in human colonic epithelial cells
Authors: Lügering N. , Kucharzik T. , Maaser C. , Kraft M. , Domschke W. 
Published: March 2003

SummaryInterleukin‐15 (IL‐15) is a novel cytokine with actions similar to IL‐2 because of common receptor components. Although IL‐15 is expressed in colonic epithelial cells and may regulate epithelial cell function, its effects on these cells are not fully defined. We explored the regulatory effects of IL‐15 on IL‐8 and monocyte‐chemoattractant protein‐1 (MCP‐1) production in the colonic epithelial cell line Caco‐2 as well as in freshly isolated human colonic epithelial cells. IL‐15 was added to intestinal epithelial cells under various culture conditions. Levels of chemokines were determined by enzyme‐linked immunosorbent assay. To determine the elements of the IL‐2/IL‐15R complex involved we used neutralizing antibodies specific for individual receptor chains. IL‐15 down‐regulates IL‐8 and MCP‐1 production in Caco‐2 cells as well as in freshly isolated human colonic epithelial cells in a dose‐dependent manner. Intestinal epithelial cells became more responsive to IL‐15‐induced suppression when activated with greater IL‐1 doses. Strong chemokine suppression was seen when IL‐15 was given prior to, simultaneous with, or after stimulatory agent. Anti‐IL‐2Rγ antibodies efficiently blocked (82% inhibition) the suppression induced by IL‐15, while anti‐IL‐2Rβ antibodies were less effective. The involvement of β‐chain was further suggested by the finding that a mixture of both monoclonal antibodies (mAb) at a suboptimal concentration (1 µg/ml of each mAb) produced a synergistic inhibitory effect on down‐regulation of epithelial chemokine production. These results show that IL‐15 can suppress IL‐8 and MCP‐1 secretion by intestinal epithelial cells. A microenvironment containing high concentrations of IL‐15 may alter the recruitment of neutrophils to enterocytes at least partly by inhibiting IL‐8 and MCP‐1 production.
Suppression of the reactive oxygen intermediates production of human macrophages by colorectal adenocarcinoma cell lines
Authors: Siegert A. , Denkert C. , Leclere A. , Hauptmann S. 
Published: March 2003

SummaryAlthough some in vitro studies indicate that macrophages exert cytotoxic responses against tumour cells by production of reactive oxygen intermediates (ROI), no obvious impairment of tumour cell growth is visible in various human malignant tumours, which contain a large number of tumour‐associated macrophages (TAM). We made use of an in vivo‐like co‐culture model of multicellular tumour spheroids of three colon carcinoma cell lines (HRT‐18, HT‐29, CX‐2) and three functionally different phenotypes of human macrophages (27E10, RM3/1, 25F9) to investigate if tumour cells deactivate macrophage cytotoxicity. The production of ROI was measured by a lucigenin‐amplified chemiluminescence assay in a 96‐well‐microplate luminometer. Different capabilities to produce ROI by different macrophage phenotypes were observed. However, independent of the macrophage phenotype and the tumour cell type a significant inhibition of ROI formation was found in co‐cultures after 1 hr, 1 and 2 days. Macrophages were also suppressed by tumour cell supernatants, which contained anti‐inflammatory cytokines transforming growth factor‐β1 (TGF‐β1) and negligible levels of interleukin‐4 (IL‐4) and IL‐10 as shown by enzyme‐linked immunosorbent assay (ELISA). Although recombinant human cytokines TGF‐β1, IL‐10 and IL‐4 inhibited the production of ROI in freshly isolated monocytes, these cytokines had no effect on differentiated macrophage phenotypes, indicating that these cytokines are not involved in mediating tumour‐induced suppression of ROI production by human macrophages.
Expression of cytokine genes in Marek's disease virus‐infected chickens and chicken embryo fibroblast cultures
Authors: Xing Z. , Schat K. A. 
Published: March 2003

SummaryThe role of cytokines in the pathogenesis and immunity of Marek's disease (MD), a herpesvirus‐induced T‐cell lymphoma in chickens, is poorly understood. Two different experiments were used to examine the potential role of particular cytokines in the pathogenesis and immune responses of MD. First, chicken embryo fibroblasts (CEF) were stimulated with lipopolysaccharide (LPS) and/or recombinant chicken interferon‐γ (rChIFN‐γ) and used to develop techniques for examining transcription of IFN‐α, IFN‐γ, inducible nitric oxide synthase (iNOS), interleukin (IL)‐1β, IL‐2, IL‐6 and IL‐8 by reverse transcription–polymerase chain reaction (RT–PCR). Addition of LPS and/or rChIFN‐γ resulted in the up‐regulation of mRNA for iNOS, IL‐1β and IL‐6, while IFN‐γ was up‐regulated by LPS alone. IL‐2 was down‐regulated by the treatments. Second, to determine the effects of Marek's disease herpesvirus (MDV) infection on cytokine transcription in vivo, chickens were infected with MDV at 21 days of age and examined at 7 days post‐infection (p.i.) (exp. 1) or were infected with MDV at 1 day of age and examined from 3 to 15 days p.i. (exp. 2). In MDV‐infected chickens, IFN‐γ transcription was up‐regulated as early as 3 days p.i. until the termination of the experiment at 15 days p.i., while iNOS and IL‐1β were up‐regulated between 6 and 15 days p.i. Infection of 1‐day‐old chicks increased levels of mRNA for IFN‐γ and iNOS between 16‐ and 64‐fold at 9 days p.i. These results suggest that IFN‐γ and iNOS may play an important role in the pathogenesis of MD.
Antibody repertoire development in fetal and newborn piglets, III. Colonization of the gastrointestinal tract selectively diversifies the preimmune repertoire in mucosal lymphoid tissues
Authors: Butler J. E. , Sun J. , Weber P. , Navarro P. , Francis D. 
Published: March 2003

SummaryChanges in the VH‐region repertoire of isolator piglets reared for 6 weeks under germ‐free (GF) conditions and those colonized (COL) with a defined exclusion flora on the 1st day of life were compared. Although serum immunoglobulin levels were 20–100‐fold higher in COL piglets than GF piglets, an analysis of peripheral blood B cells (PBBs) indicated that: GF and COL piglets used the same four VH genes and two DH segments during the 6‐week period; proportional usage of VH genes and DH segments was the same as in fetal animals; and VH and DH usage did not differ between COL and GF animals. This pattern differed from the PBBs from 6‐week‐old conventional (CONV) piglets. When the sequences of 73 splenic CDR3 segments were analysed, DH usage and mutation frequency were the same in sequences from both 6‐week‐old GF and COL piglets; mutations were infrequent and occurred with the same frequency as in 110‐day fetal spleen. However, the median CDR3 length in COL piglets was shifted upward due to 3′ DH N‐nucleotide additions. Neither COL nor GF animals made specific serum antibodies to phosphoryl choline given parenterally on a T‐cell dependent carrier. In contrast to the near absence of a colonization effect in PBBs and splenic DNA, rearranged variable heavy‐chain gene segments (VDJs) recovered from the DNA of mucosal lymphoid tissues of COL piglets showed pronounced differences from those recovered from GF animals in usage of DHA‐, DHB‐and VHB‐ and in the frequency of point mutation. The mucosal VDJ transcripts and those from the spleen were similarly affected by colonization. This effect on mucosal lymphoid tissue was consistent with the five‐fold selective increase in serum immunoglobulin A (IgA) levels relative to IgM and IgG. Comparison of IgM and IgA transcripts from mucosal tissues suggested that IgA and IgM clones diversify in parallel. Our findings are the first to show that colonization of the gastrointestinal tract of offspring separated from their mothers, differs from ‘conventionalized’ GF animals in that colonization preferentially influences diversification and expansion of the preimmune IgM and IgA repertoire in mucosal lymphoid tissues but not in PBBs and seldom/modestly in VDJs from splenic DNA.
Ageing and the neutrophil: no appetite for killing?
Authors: Butcher S. , Chahel H. , Lord J. M. 
Published: March 2003

SummaryIn the armoury of the immune system developed to combat the various micro‐organisms that could invade the host, the neutrophil forms the first line of defence against rapidly dividing bacteria and fungi. However, as humans age they become more susceptible to infection with these microbes and this has been ascribed to a decline in immune status, termed immune senescence. Here we summarize the literature specifically concerning the attenuation of neutrophil function with age and the possible mechanisms underlying their reduced response to infectious agents.
Increased immunoglobulin A levels in milk by over‐expressing the murine polymeric immunoglobulin receptor gene in the mammary gland epithelial cells of transgenic mice
Authors: De Groot N. , Van Kuik‐Romeijn P. , Lee S. H. , De Boer H. A. 
Published: March 2003

SummaryThe polymeric immunoglobulin receptor (pIgR) transports dimeric immunoglobulin A (dIgA) across the epithelial cell layers into the secretions of various mucosal and glandular surfaces of mammals. At these mucosal sites, such as the gastrointestinal tract, respiratory tract, urogenital tract and the mammary glands, dIgA protects the body against pathogens. The pIgR binds dIgA at the basolateral side and transports it via the complex mechanism of transcytosis to the apical side of the epithelial cells lining the mucosa. Here, the extracellular part of the receptor is cleaved to form the secretory component (SC), which remains associated to dIgA, thereby protecting it from degradation in the secretions. One pIgR molecule transports only one dIgA molecule (1 : 1 ratio) and the pIgR is not recycled after each round of transport. This implies that the amount of available receptor could be a rate‐limiting factor determining both the rate and amount of IgA transported per cell and therefore determining the total IgA output into the lumen or, in case of the mammary gland, into the milk. In order to test this hypothesis, we set up an in vivo model system. We generated transgenic mice over‐expressing the murine pIgR gene under lactogenic control, by using a milk gene promoter, rather than under immunological control. Mice over‐expressing the pIgR protein, in mammary gland epithelial cells, from 60‐ up to 270‐fold above normal pIgR protein levels showed total IgA levels in the milk to be 1·5–2‐fold higher, respectively, compared with the IgA levels in the milk of non‐transgenic mice. This indicates that the amount of pIgR produced is indeed a limiting factor in the transport of dIgA into the milk under normal non‐inflammatory circumstances.
Polymorphonuclear neutrophils as accessory cells for T‐cell activation: major histocompatibility complex class II restricted antigen‐dependent induction of T‐cell proliferation
Authors: Radsak M. , Iking‐Konert C. , Stegmaier S. , Andrassy K. , Hänsch G. M. 
Published: March 2003

SummaryPolymophonuclear cells (PMN) of healthy donors do not express major histocompatibility complex (MHC) class II antigens or the T‐cell costimulatory molecules CD80 or CD86. Expression of these receptors, however, is seen in patients with chronic inflammatory diseases. We now report that, by culturing PMN of healthy donors with autologous serum, interferon‐γ (IFN‐γ) and granulocyte–macrophage colony‐stimulating factor (GM‐CSF), de novo synthesis of MHC class II, CD80 and CD86 could be induced. MHC class II‐positive PMN acquired the capacity to present staphylococcus enterotoxin to peripheral T cells, apparent as induction of interleukin‐2 (IL‐2) synthesis and proliferation of the T cells. Moreover, the PMN also processed tetanus toxoid (TT) and induced proliferation of TT‐specific T cells in a MHC class II‐restricted manner. Taken together, these data indicate that PMN can be activated to function as accessory cells for T‐cell activation.
A critical role for alveolar macrophages in elicitation of pulmonary immune fibrosis
Authors: Zhang‐Hoover J. , Sutton A. , Van Rooijen N. , Stein‐Streilein J. 
Published: March 2003

SummaryHapten immune pulmonary interstitial fibrosis (HIPIF) is induced by a recall cell‐mediated immune response against the hapten 2,4,6‐trinitrobenzene sulphonic acid (TNBS) in the lung. Studies here dissect the role of the cellular components of the bronchoalveolar lavage (BAL) cells (alveolar macrophages [AMs] versus monocytes and immature dendritic cells) in the fibrogenic inflammatory response. BAL cells from HIPIF mice were generally more activated and produced a greater amount of tumour necrosis factor‐α (TNF‐α) than controls. Liposome‐encapsulated dichloromethylene diphosphonate (Cl2MDP) that was inoculated intranasally (i.n.) into mice selectively depleted AMs. Following AM depletion, the number of TNF‐α‐containing cells was reduced, and both the number of immune inflammatory cells recruited into the alveolar space and the subsequent collagen deposition (hydroxyproline) were decreased in the sensitized and intratracheally (i.t.) challenged mice. In conclusion, AMs are required, in part, for the development of pulmonary fibrosis in HIPIF because AM‐derived factors such as TNF‐α are needed for initiation of chemokine and cytokine pathways and accumulation of immune inflammatory cells.
Molecular cloning, genomic organization and cell‐binding characteristicsof mouse Spα
Authors: Gebe J. A. , Llewellyn M.‐B. C. , Hoggatt H. , Aruffo A. 
Published: March 2003

SummarySeveral group B scavenger receptor cysteine‐rich (SRCR) proteins have been shown to function as modulators in the immune response. Recently, we reported the cloning of a new member of this family, human Spα (hSpα). Herein we report the cloning and characterization of the mouse homologue of hSpα. Like its human counterpart, mouse Spα (mSpα), is a secreted protein containing three SRCR domains. Most lymphoid tissues express RNA transcripts encoding mSpα. Characterization of a genomic clone encoding the mature mSpα protein showed that each of the SRCR domains of mSpα is encoded by a single exon. Comparison of the sequence of mSPα with those of other published proteins indicates that it is the same as the recently reported protein named AIM (apoptosis inhibitor expressed by macrophages). Cell‐binding studies with a mSpα immunoglobulin (mSpα‐Rγ) fusion protein indicated that mSpα is capable of binding to spleen‐derived CD19+ B cells and minimally to peritoneal cavity‐derived CD19+ B cells but not to peripheral blood‐derived B cells. Spleen‐derived CD3+ T cells also bound mSpα‐Rγ; however, no binding was observed to either peripheral blood mononuclear cells or peritoneal cavity‐derived CD3+ T cells. The mSpα‐Rγ fusion protein was also shown to bind to the mouse cell lines WEHI3 (monocytic) and EL‐4 (thymoma, T cell). The cloning of cDNA and genomic clones encoding mSpα and the identification of cells expressing a putative mSpα receptor(s) should facilitate in vivo studies designed to investigate the function of Spα in the immune compartment.
The regulation of prostaglandin output from term intact fetal membranes byanti‐inflammatory cytokines
Authors: Brown N. L. , Alvi S. A. , Elder M. G. , Bennett P. R. , Sullivan M. H. F. 
Published: March 2003

SummaryProstaglandins are some of the main mediators which control parturition, and their production by intrauterine tissues can be up‐regulated by pro‐inflammatory cytokines. Anti‐inflammatory cytokines may oppose these effects, and in this study we have investigated how two such cytokines affected fetal membrane function. Interleukin‐10 (IL‐10) inhibited the output of prostaglandin E2 (PGE2) from intact fetal membranes under basal and lipopolysaccharide (LPS)‐stimulated conditions, and there was a parallel decrease in the expression of mRNA for COX‐2. IL‐10 also inhibited the production of interleukin‐1β (IL‐1β) and the expression of mRNA for IL‐1β, indicating that this cytokine has a broad anti‐inflammatory effect. Transforming growth factor‐β1 (TGF‐β1), which is generally considered to be anti‐inflammatory had opposite effects on PGE2 production, in that it increased the output of PGE2 for up to 8 hr. TGF‐β1 increased levels of type‐2 cyclo‐oxygenase (COX‐2) and cytosolic phospholipase A2 (cPLA2) protein, and also activated the cPLA2 enzyme present; the profile of effects is similar to that of the pro‐inflammatory cytokine IL‐1β, and was not expected. Combinations of TGF‐β1 with IL‐1β also increased PGE2 output and caused appropriate changes in prostaglandin pathway enzymes, whereas TGF‐β1 and IL‐1α had more limited effects. Further studies are needed to establish the physiological significance of these findings, but TGF‐β1 does not seem to act as an inhibitory cytokine in intact fetal membranes at term.
Human invariant Vα24+ natural killer T cells activated by α‐galactosylceramide (KRN7000) have cytotoxic anti‐tumour activity through mechanisms distinct from T cells and natural killer cells
Authors: Nicol A. , Nieda M. , Koezuka Y. , Porcelli S. , Suzuki K. , Tadokoro K. , Durrant S. , Juji T. 
Published: March 2003

SummaryHuman Vα24 + NKT cells, a subpopulation of natural killer cell receptor (NKR‐P1A) expressing T cells with an invariant T‐cell receptor (TCR; Vα24JαQ) are stimulated by the glycolipid, α‐galactosylceramide (KRN7000), in a CD1d‐dependent, TCR‐mediated fashion. Little is known about Vα24 + NKT‐cell function. The murine counterpart, Vα14 + NKT cells, appear to have an important role in controlling malignancy. There are no human data examining the role of Vα24 + NKT cells in controlling human malignancy. We report that Vα24 + NKT cells have perforin‐mediated cytotoxicity against haemopoietic malignancies. Vα24 TCR, CD1d and α‐galactosylceramide may all play a role in cytotoxicity but are not absolute requirements. The greatest cytotoxicity was observed against the U937 tumour cell line (95 ± 5% lysis). THP‐1, Molt4, C1R cells and allogeneic mismatched dendritic cells were also sensitive to Vα24 + NKT cytotoxicity but neither the NK target, K562, nor lymphokine‐activated killer‐sensitive Daudi cells, were sensitive. These results indicate a killing pattern distinct from conventional major histocompatibility complex‐restricted T cells, NK cells and other cytotoxic lymphoid cells previously described. We conclude that human Vα24 + NKT cells have cytotoxic anti‐tumour activity against haemopoietic malignancies through effector mechanisms distinct from conventional T cells and NK cells and that their specific stimulator KRN7000 may have therapeutic potential.
An acidic microenvironment impairs the generation of non‐major histocompatibility complex‐restricted killer cells
Authors: Müller B. , Fischer B. , Kreutz W. 
Published: March 2003

SummaryThe microenvironment within solid tumours has often been shown to exhibit an acidic local pH. In recent studies we could demonstrate that an acidic extracellular pH (pHe) inhibits the non‐major histocompatibility complex (MHC) ‐restricted cytotoxicity of immunocompetent effector cells. However, within tumours the activation of cytotoxic cells may already be impaired by low pHe. Therefore, we investigated the influence of acidic conditions on the generation of active killer cells. The cytotoxic activity of natural killer (NK) as well as lymphokine‐activated killer (LAK) cells against K562, Daudi and Raji cells was analysed after an activation period of 3 days at pHe 7·2–6·5. A minor reduction of pHe from 7·2 to 7·0 during the culture period resulted in a strong inhibition of the natural cytotoxicity of NK cells. Furthermore, acidic pHe below 7·2 prevented the generation of activated LAK cells by interleukin‐2 (IL‐2). The cytotoxic capacity could not be reconstituted if cells cultured at a pHe of 6·5 were returned to physiological pH for another 24 hr. Analysis of the cellular subtypes within the various cultures did not reveal differences regarding the frequencies of NK cells, CD8+ T cells, or CD4+ T cells. However, an acidic pHe clearly inhibited the activation‐induced increase of relevant adhesion molecules. The production of cytokines which are involved in the regulation of the cytotoxic process (tumour necrosis factor‐α, interferon‐γ, IL‐10, IL‐12 and transforming growth factor‐β1) was also affected by pHe, as their release was strongly inhibited at pHe 7·0. Furthermore, we observed a considerable decrease in the metabolic activity of effector cells at acidic pHe. In summary, our findings suggest that an acidic microenvironment impairs the induction of an anti‐tumoral immune response within solid tumours.
Gene gun‐mediated delivery of an interleukin‐12 expression plasmid protects against infections with the intracellular protozoan parasites Leishmania major and Trypanosoma cruzi in mice
Authors: Sakai T. , Hisaeda H. , Nakano Y. , Ishikawa H. , Maekawa Y. , Ishii K. , Nitta Y. , Miyazaki J. , Himeno K. 
Published: March 2003

SummaryAn interleukin‐12 (IL‐12) expression plasmid was transferred, using a gene gun, to mice infected with Leishmania major or Trypanosoma cruzi. Transfer of the IL‐12 gene to susceptible BALB/c mice resulted in regression of lesion size and reduced the number of parasites in draining lymph nodes (LN) at the site of L. major infection. Coincident with these protective effects, the T‐helper type (Th) response shifted towards Th1, as evaluated by cytokine production in vitro and L. major‐specific antibody responses. Protective effects of the IL‐12 gene were also observed in T. cruzi infection. Treatment of BALB/c mice infected with T. cruzi enhanced the production of interferon‐γ (IFN‐γ) by spleen cells, while suppressed production of interleukin‐10 (IL‐10) compared with control mice. Administration of anti‐CD4 or anti‐CD8 monoclonal antibody (mAb) abolished the protective immunity against T. cruzi infection, and treatment with the IL‐12 gene could not restore the resistance in these mice. Mice depleted of natural killer (NK) cells with anti‐asialo GM1 also became susceptible to infection, while the resistance was restored when these mice were treated with the IL‐12 gene. Thus, target cells for the treatment appear to be CD4+ and CD8+ T cells, which are ordinarily activated by NK cells. These results suggest that the transfer of cytokine genes using a gene gun is an effective method for investigating the roles of cytokines and gene therapy in infectious diseases.