bluuebunny/crossref_metadata_2025 huggingface dataset:
Fusion proteins comprising annexin V and Kunitz protease inhibitors are highly potent thrombogenic site-directed anticoagulants
Authors: Chen Hsiu-Hui , Vicente Cristina P. , He Li , Tollefsen Douglas M. , Wun Tze-Chein
Published: January 2005

The anionic phospholipid, phosphatidyl-l-serine (PS), is sequestered in the inner layer of the plasma membrane in normal cells. Upon injury, activation, and apoptosis, PS becomes exposed on the surfaces of cells and sheds microparticles, which are procoagulant. Coagulation is initiated by formation of a tissue factor/factor VIIa complex on PS-exposed membranes and propagated through the assembly of intrinsic tenase (factor VIIIa/factor IXa), prothrombinase (factor Va/factor Xa), and factor XIa complexes on PS-exposed activated platelets. We constructed a novel series of recombinant anticoagulant fusion proteins by linking annexin V (ANV), a PS-binding protein, to the Kunitz-type protease inhibitor (KPI) domain of tick anticoagulant protein, an aprotinin mutant (6L15), amyloid β-protein precursor, or tissue factor pathway inhibitor. The resulting ANV-KPI fusion proteins were 6- to 86-fold more active than recombinant tissue factor pathway inhibitor and tick anticoagulant protein in an in vitro tissue factor–initiated clotting assay. The in vivo antithrombotic activities of the most active constructs were 3- to 10-fold higher than that of ANV in a mouse arterial thrombosis model. ANV-KPI fusion proteins represent a new class of anticoagulants that specifically target the anionic membrane-associated coagulation enzyme complexes present at sites of thrombogenesis and are potentially useful as antithrombotic agents.
Tie2Cre-mediated gene ablation defines the stem-cell leukemia gene (SCL/tal1)–dependent window during hematopoietic stem-cell development
Authors: Schlaeger Thorsten M. , Mikkola Hanna K. A. , Gekas Christos , Helgadottir Hildur B. , Orkin Stuart H.
Published: January 2005

The stem-cell leukemia gene (SCL/tal1) is essential for the formation of all blood lineages. SCL is first expressed in mesodermal cells that give rise to embryonic blood cells, and continues to be expressed in fetal and adult hematopoietic stem cells (HSCs). However, SCL is not required for the maintenance of established long-term repopulating (LTR) HSCs in the adult. The time point at which HSC development becomes SCL independent has not been defined. Tyrosine kinase with immunoglobulin and epidermal growth factor homology domains–2 (Tie2) expression appears in hemogenic and vasculogenic sites shortly after SCL. We therefore used the Tie2Cre mouse to inactivate SCL early during embryonic and fetal hematopoiesis. Tie2Cre completely inactivated SCL in yolk sac, the aortagonad-mesonephros (AGM) region, and fetal liver hematopoietic cells and circulating blood cells. However, the fetal liver was colonized by functional LTR-HSCs. Yet SCL remained crucial for proper differentiation of both primitive and definitive red cells and megakaryocytes. These results indicate that the SCL-dependent phase of HSC development ends before Tie2Cre-mediated gene ablation becomes effective.
Graph-representation of oxidative folding pathways
Authors: Ágoston Vilmos , Cemazar Masa , Kaján László , Pongor Sándor
Published: January 2005

Background

The process of oxidative folding combines the formation of native disulfide bond with conformational folding resulting in the native three-dimensional fold. Oxidative folding pathways can be described in terms of disulfide intermediate species (DIS) which can also be isolated and characterized. Each DIS corresponds to a family of folding states (conformations) that the given DIS can adopt in three dimensions.

Results

The oxidative folding space can be represented as a network of DIS states interconnected by disulfide interchange reactions that can either create/abolish or rearrange disulfide bridges. We propose a simple 3D representation wherein the states having the same number of disulfide bridges are placed on separate planes. In this representation, the shuffling transitions are within the planes, and the redox edges connect adjacent planes. In a number of experimentally studied cases (bovine pancreatic trypsin inhibitor, insulin-like growth factor and epidermal growth factor), the observed intermediates appear as part of contiguous oxidative folding pathways.

Conclusions

Such networks can be used to visualize folding pathways in terms of the experimentally observed intermediates. A simple visualization template written for the Tulip package http://www.tulip-software.org/ can be obtained from V.A.
Inter-species horizontal transfer resulting in core-genome and niche-adaptive variation within Helicobacter pylori
Authors: Saunders Nigel J , Boonmee Prawit , Peden John F , Jarvis Stephen A
Published: January 2005

Background

Horizontal gene transfer is central to evolution in most bacterial species. The detection of exchanged regions is often based upon analysis of compositional characteristics and their comparison to the organism as a whole. In this study we describe a new methodology combining aspects of established signature analysis with textual analysis approaches. This approach has been used to analyze the two available genome sequences of H. pylori.

Results

This gene-by-gene analysis reveals a wide range of genes related to both virulence behaviour and the strain differences that have been relatively recently acquired from other sequence backgrounds. These frequently involve single genes or small numbers of genes that are not associated with transposases or bacteriophage genes, nor with inverted repeats typically used as markers for horizontal transfer. In addition, clear examples of horizontal exchange in genes associated with 'core' metabolic functions were identified, supported by differences between the sequenced strains, including: ftsK, xerD and polA. In some cases it was possible to determine which strain represented the 'parent' and 'altered' states for insertion-deletion events. Different signature component lengths showed different sensitivities for the detection of some horizontally transferred genes, which may reflect different amelioration rates of sequence components.

Conclusion

New implementations of signature analysis that can be applied on a gene-by-gene basis for the identification of horizontally acquired sequences are described. These findings highlight the central role of the availability of homologous substrates in evolution mediated by horizontal exchange, and suggest that some components of the supposedly stable 'core genome' may actually be favoured targets for integration of foreign sequences because of their degree of conservation.
Synaptogenesis and outer segment formation are perturbed in the neural retina of Crx mutant mice
Authors: Morrow Eric M , Furukawa Takahisa , Raviola Elio , Cepko Constance L
Published: January 2005

Background

In Leber's congenital amaurosis (LCA), affected individuals are blind, or nearly so, from birth. This early onset suggests abnormal development of the neural retina. Mutations in genes that affect the development and/or function of photoreceptor cells have been found to be responsible in some families. These examples include mutations in the photoreceptor transcription factor, Crx.

Results

A Crx mutant strain of mice was created to serve as a model for LCA and to provide more insight into Crx's function. In this study, an ultrastructural analysis of the developing retina in Crx mutant mice was performed. Outer segment morphogenesis was found to be blocked at the elongation stage, leading to a failure in production of the phototransduction apparatus. Further, Crx-/- photoreceptors demonstrated severely abnormal synaptic endings in the outer plexiform layer.

Conclusions

This is the first report of a synaptogenesis defect in an animal model for LCA. These data confirm the essential role this gene plays in multiple aspects of photoreceptor development and extend our understanding of the basic pathology of LCA.
Managing change in the nursing handover from traditional to bedside handover – a case study from Mauritius
Authors: Kassean Hemant K , Jagoo Zaheda B
Published: January 2005

Background

The shift handover forms an important part of the communication process that takes place twice within the nurses' working day in the gynaecological ward. This paper addresses the topic of implementing a new system of bedside handover, which puts patients central to the whole process of managing care and also addresses some of the shortcomings of the traditional handover system.

Methods

A force field analysis in terms of the driving forces had shown that there was dissatisfaction with the traditional method of handover which had led to an increase in the number of critical incidents and complaints from patients, relatives and doctors. The restraining forces identified were a fear of accountability, lack of confidence and that this change would lead to more work. A 3 – step planned change model consisting of unfreezing, moving and refreezing was used to guide us through the change process. Resistance to change was managed by creating a climate of open communication where stakeholders were allowed to voice opinions, share concerns, insights, and ideas thereby actively participating in decision making.

Results

An evaluation had shown that this process was successfully implemented to the satisfaction of patients, and staff in general.

Conclusion

This successful change should encourage other nurses to become more proactive in identifying areas for change management in order to improve our health care system.
The role of 'confounding by indication' in assessing the effect of quality of care on disease outcomes in general practice: results of a case-control study
Authors: de Koning Johan S , Klazinga Niek S , Koudstaal Peter J , Prins Ad , Borsboom Gerard JJM , Mackenbach Johan P
Published: January 2005

Background

In quality of care research, limited information is found on the relationship between quality of care and disease outcomes. This case-control study was conducted with the aim to assess the effect of guideline adherence for stroke prevention on the occurrence of stroke in general practice. We report on the problems related to a variant of confounding by indication, that may be common in quality of care studies.

Methods

Stroke patients (cases) and controls were recruited from the general practitioner's (GP) patient register, and an expert panel assessed the quality of care of cases and controls using guideline-based review criteria.

Results

A total of 86 patients was assessed. Compared to patients without shortcomings in preventive care, patients who received sub-optimal care appeared to have a lower risk of experiencing a stroke (OR 0.60; 95% CI 0.24 to 1.53). This result was partly explained by the presence of risk factors (6.1 per cases, 4.4 per control), as reflected by the finding that the OR came much closer to 1.00 after adjustment for the number of risk factors (OR 0.82; 95% CI 0.29 to 2.30). Patients with more risk factors for stroke had a lower risk of sub-optimal care (OR for the number of risk factors present 0.76; 95% CI 0.61 to 0.94). This finding represents a variant of 'confounding by indication', which could not be fully adjusted for due to incomplete information on risk factors for stroke.

Conclusions

At present, inaccurate recording of patient and risk factor information by GPs seriously limits the potential use of a case-control method to assess the effect of guideline adherence on disease outcome in general practice. We conclude that studies on the effect of quality of care on disease outcomes, like other observational studies of intended treatment effect, should be designed and performed such that confounding by indication is minimized.
Clash of kingdoms or why Drosophila larvae positively respond to fungal competitors
Authors: Rohlfs Marko
Published: January 2005

Background

Competition with filamentous fungi has been demonstrated to be an important cause of mortality for the vast group of insects that depend on ephemeral resources (e.g. fruit, dung, carrion). Recent data suggest that the well-known aggregation of Drosophila larvae across decaying fruit yields a competitive advantage over mould, by which the larvae achieve a higher survival probability in larger groups compared with smaller ones. Feeding and locomotor behaviour of larger larval groups is assumed to cause disruption of fungal hyphae, leading to suppression of fungal growth, which in turn improves the chances of larval survival to the adult stage. Given the relationship between larval density, mould suppression and larval survival, the present study has tested whether fungal-infected food patches elicit communal foraging behaviour on mould-infected sites by which larvae might hamper mould growth more efficiently.

Results

Based on laboratory experiments in which Drosophila larvae were offered the choice between fungal-infected and uninfected food patches, larvae significantly aggregated on patches containing young fungal colonies. Grouping behaviour was also visible when larvae were offered only fungal-infected or only uninfected patches; however, larval aggregation was less strong under these conditions than in a heterogeneous environment (infected and uninfected patches).

Conclusion

Because filamentous fungi can be deadly competitors for insect larvae on ephemeral resources, social attraction of Drosophila larvae to fungal-infected sites leading to suppression of mould growth may reflect an adaptive behavioural response that increases insect larval fitness and can thus be discussed as an anti-competitor behaviour. These observations support the hypothesis that adverse environmental conditions operate in favour of social behaviour. In a search for the underlying mechanisms of communal behaviour in Drosophila, this study highlights the necessity of investigating the role of inter-kingdom competition as a potential driving force in the evolution of spatial behaviour in insects.
The Anatomy of Mucosal Immune Responses
Authors: GARSIDE PAUL , MILLINGTON OWAIN , SMITH KAREN M.
Published: January 2005

Abstract: It remains unclear how and where unresponsiveness to fed antigens is induced. This “oral tolerance” is probably necessary to prevent the array of immune effector mechanisms required to counteract pathogens of the mucosae from being misdirected against food antigens or commensal flora. It will obviously be important to dissect where, when, and how such immunological homoestasis is maintained in the gut, but it will also be necessary to determine whether similar inductive and effector mechanisms are required for the therapeutic applications of oral tolerance systemically. This may be influenced by anatomical and microenvironmental effects on the phenotype and/or activation state of the antigen‐presenting cell (APC), which presents orally delivered antigen. Fed antigen passes from the intestinal lumen either via the villus epithelium and M cells in the Peyer's patches (PP) or the mucosal lamina propria to the organized lymphoid tissues of the PP and mesenteric lymph nodes (MLN). In addition, there is evidence that mucosally administered antigen also gains access directly to peripheral lymphoid organs. Each of these sites contains distinctive populations of APCs and has unique local microenvironments that may influence the immune response in different ways. We propose that feeding antigen in high doses may induce clonal anergy, deletion, or altered differentiation because it gains direct access to resting APCs in the T cell areas of both the gut‐associated lymphoid tissues (GALT) and peripheral lymphoid organs, with presentation occurring in the absence of productive costimulation. By contrast, low doses of tolerizing antigen may be taken up and presented preferentially by APCs in the GALT, where the local environment may favor the induction of regulatory T cells. This is consistent with our own and others findings, using adoptive transfer of TcR tg T cells. These studies have shown that antigen‐specific CD4+ T cells are activated simultaneously in all peripheral and gut‐associated lymphoid organs after feeding high doses of proteins, but that this may be more restricted to local tissues when lower doses are used. Another level of anatomical control is imposed within lymphoid organs, where migration of T cells through distinct anatomical compartments can affect their differentiation. We find that, in contrast to orally primed T cells, orally tolerized T cells are unable to migrate into B cell follicles during their initial exposure to antigen. This affects their differentiation as upon subsequent challenge with antigen in adjuvant, tolerized T cells can be found in follicles but are unable to provide the B cell help that primed T cells can deliver. We hypothesize that the initial defective migration of tolerized T cells prevents them from receiving signals from antigen‐specific B cells in follicles and results in abortive differentiation. Thus, both gross and fine anatomical location of fed antigen presentation may be important in mucosal immunoregulation.
How the Gut Links Innate and Adaptive Immunity
Authors: RUMBO MARTIN , ANDERLE PASCALE , DIDIERLAURENT ARNAUD , SIERRO FRÉDÉRIC , DEBARD NATHALIE , SIRARD JEAN‐CLAUDE , FINKE DANIELA , KRAEHENBUHL JEAN‐PIERRE
Published: January 2005

Abstract: Mucosal surfaces represent the main sites in which environmental microorganisms and antigens interact with the host. Sentinel cells, including epithelial cells, lumenal macrophages, and intraepithelial dendritic cells, continuously sense the environment and coordinate defenses for the protection of mucosal tissues. The mucosal epithelial cells are crucial actors in coordinating defenses. They sense the outside world and respond to environmental signals by releasing chemokines and cytokines that recruit inflammatory and immune cells to control potential infectious agents and to attract cells able to trigger immune responses. Among immune cells, dendritic cells (DC) play a key role in controlling adaptive immune responses, due to their capacity to internalize foreign materials and to present antigens to naive T and B lymphocytes, locally or in draining organized lymphoid tissues. Immune cells recruited in epithelial tissues can, in turn, act upon the epithelial cells and change their phenotype in a process referred to as epithelial metaplasia.
Compartmentalization of the Mucosal Immune Responses to Commensal Intestinal Bacteria
Authors: MACPHERSON ANDREW J. , UHR THERESE
Published: January 2005

Abstract: Mammals coexist with a luxuriant load of bacteria in the lower intestine (up to 1012 organisms/g of intestinal contents). Although these bacteria do not cause disease if they remain within the intestinal lumen, they contain abundant immunostimulatory molecules that trigger immunopathology if the bacteria penetrate the body in large numbers. The physical barrier consists only of a single epithelial cell layer with overlying mucus, but comparisons between animals kept in germ‐free conditions and those colonized with bacteria show that bacteria induce both mucosal B cells and some T cell subsets; these adaptations are assumed to function as an immune barrier against bacterial penetration, but the mechanisms are poorly understood. In mice with normal intestinal flora, but no pathogens, there is a secretory IgA response against bacterial membrane proteins and other cell wall components. Whereas induction of IgA against cholera toxin is highly T help dependent, secretory IgA against commensal bacteria is induced by both T independent and T dependent pathways. When animals are kept in clean conditions and free of pathogens, there is still a profound intestinal secretory IgA response against the commensal intestinal flora. However, T dependent serum IgG responses against commensal bacteria do not occur in immunocompetent animals unless they are deliberately injected intravenously with 104 to 106 organisms. In other words, unmanipulated pathogen‐free mice are systemically ignorant but not tolerant of their commensal flora despite the mucosal immune response to these organisms. In mice that are challenged with intestinal doses of commensal bacteria, small numbers of commensals penetrate the epithelial cell layer and survive within dendritic cells (DC). These commensal‐loaded DC induce IgA, but because they are confined within the mucosal immune system by the mesenteric lymph nodes, they do not induce systemic immune responses. In this way the mucosal immune responses to commensals are geographically and functionally separated from systemic immunity.
Isolated Lymphoid Follicles Can Function as Sites for Induction of Mucosal Immune Responses
Authors: LORENZ ROBIN G. , NEWBERRY RODNEY D.
Published: January 2005

Abstract: Isolated lymphoid follicles (ILFs) are organized lymphoid structures in the small intestine. ILFs were recently identified in the murine small intestine; however, the function of ILFs is unknown. To better understand ILFs and the role they play in the intestinal immune response, we have examined the composition of ILFs, the factors that are involved in the genesis of ILFs, and the ability of ILFs to support antigen‐specific immunoglobulin production. We found that ILFs contain predominantly B‐2 B lymphocytes, and CD4+ TCRβ+ T lymphocytes. Similar to the formation of Peyer's patches (PPs), lymphotoxin β receptor (LTβR)‐dependent events are required for ILF formation; however, the timing of these events and the cellular source of LT differ. ILF formation can occur de novo in response to luminal stimuli and requires LT‐sufficient B lymphocytes and TNF receptor I function for full maturation. The epithelium over ILFs resembles the PP follicle‐associated epithelium, as M cells are present and pathogens such as Yersinia can be bound and taken up into the underlying follicle. Total fecal IgA production is not augmented in animals possessing ILFs; however, the production of antigen‐specific IgA is increased in animals possessing ILFs orally challenged with Salmonella typhimurium. Similar to PPs, ILFs can support antigen‐specific IgA production following oral immunization. These findings support the concept that ILFs are formed in response to mucosal challenges, and may play a physiological role in the production of antigen‐specific intestinal IgA.
Uptake of Antigens from the Intestine by Dendritic Cells
Authors: MacPHERSON GORDON , MILLING SIMON , YRLID ULF , COUSINS LESLEY , TURNBULL EMMA , HUANG FANG‐PING
Published: January 2005

Abstract: The intestinal immune system responds to ingested antigens in a variety of ways, ranging from tolerance to full immunity. How T cells are instructed to make these differential responses is still unclear. Dendritic cells (DCs) sample enteric antigens in the lamina propria and Peyer's patches, and transport them within the patch or to mesenteric nodes where they are presented to lymphocytes. It is probable that DCs also transmit information that influences the outcome of T cell activation, but the nature of this information and the factors in the intestine that regulate DC behavior and properties are far from clear. We have developed a model in the rat that permits analysis of DCs actually in the process of migration from the intestine to mesenteric nodes. In this paper we will review those aspects of our research that relate to antigen uptake and discuss these in the context of other experimental systems.
Regulation of Tolerance in the Respiratory Tract: TIM‐1, Hygiene, and the Environment
Authors: UMETSU DALE T. , DeKRUYFF ROSEMARIE H.
Published: January 2005

Abstract: In this chapter we will discuss the regulation of immune responses in the respiratory mucosal system, rather than in the gastrointestinal mucosal system. However, because the lung and gastrointestinal tracts derive developbmentally from a common endoderm, immune mechanisms in the respiratory and gastrointestinal tracts are likely to be very similar. Therefore, concepts that are learned about the respiratory tract are likely to benefit the understanding of tolerance in the gastrointestinal tract. We will discuss the regulation of immune responses in asthma, the role of respiratory tolerance, mediated by dendritic cells and regulatory T cells in the lung. In addition, we will discuss a genetic approach to better understand respiratory tolerance and the discovery of the TIM gene family, which regulates the development of Th2 responses, asthma, and tolerance. Finally, we will discuss the association in humans of TIM‐1 and atopy, and the relationship between TIM1, hygiene, and the environment.
Bacterial Translocation in the Normal Human Appendix Parallels the Development of the Local Immune System
Authors: GEBBERS JAN‐OLAF , LAISSUE JEAN‐ALBERT
Published: January 2005

Abstract: Experimental modes and pathological conditions may result in bacterial translocation (BT), that is, the passage of indigenous bacteria colonizing the intestine through the intestinal mucosa to mesenteric lymph nodes. Yet no data are available on BT in the normal human gut. We determined the occurrence of BT and its extent in histologically normal, incidentally removed human vermiform appendices (VA) from individuals of different ages and correlated the findings with the development with age of associated lymphatic tissue. BT appears to pertain to normal antigen‐sampling processes of the GALT in the VA. It also parallels the development of the GALT and its maintenance during adulthood. In the first two weeks after birth, when bacterial colonization of the gut evolves and when the VA lacks the protection of secretory IgA, BT was not detected. Thereafter, BT occurs along with development of the local GALT, which is fully built up after the first year. A physiological uptake of, or invasion by, bacteria may be instrumental (1) for tolerance induction against the indigenous flora and (2) for the stimulation and normal development of the GALT.
The Presentation of Haptenated Proteins and Activation of T Cells in the Mesenteric Lymph Nodes by Dendritic Cells in the TNBS Colitis Rat
Authors: ISHIGURO YOH , SAKURABA HIROTAKE , YAMAGATA KAZUFUMI , MUNAKATA AKIHIRO
Published: January 2005

Abstract: We described the role of dendritic cells (DCs) in aspects of T cell activation at the mesenteric lymph nodes (MLN) in trinitrobenzene sulfonic acid (TNBS)‐induced colitis. An antigenic‐immune response is induced at the MLN, and dendritic cells are the affected cell type. Cross‐linking and GRO/CINC‐1 have synergistic effects for DC maturation.
Genetic Selection for Resistance or Susceptibility to Oral Tolerance to Ovalbumin Affects General Mechanisms of Tolerance Induction in Mice
Authors: KAMPHORST ALICE O. , da SILVA MARIA F. S. , da SILVA ANTÔNIO C. , CARVALHO CLAUDIA R. , FARIA ANA MARIA C
Published: January 2005

Abstract: To study the genes involved in oral tolerance susceptibility, two strains of mice were genetically selected for susceptibility (TS) and resistance (TR) to oral tolerance to ovalbumin by bidirectional breeding. Herein we show that the genetic selection process is restricted neither to ovalbumin nor to oral tolerance. It affected oral tolerance to other proteins, such as casein, and tolerance induced the intravenous route.
Class II MHC‐Expressing Myofibroblasts Play a Role in the Immunopathogenesis Associated with Staphylococcal Enterotoxins
Authors: Barrera C A , Pinchuk I V , Saada J I , Suarez G , Bland D A , Beswick E , Adegboyega P A , Mifflin R C , Powell D W , Reyes V E
Published: January 2005

Abstract: Food poisoning due to staphylococcal enterotoxins (SEs) affects hundreds of thousands of people each year. Little is known about how SEs initiate immune responses and cause pathogenesis. Here, we demonstrate that cultured human intestinal myofibroblasts (IMFs) bind SEs in an MHC class II‐dependent fashion. IMFs respond to SE exposure with increased secretion of IL‐6, IL‐8, and TNF‐α. A significant proliferative T cell response was observed when MHC class II‐expressing IMFs were pulsed with SEA and cocultured with human CD4+ T cells. In conclusion, our findings support the hypothesis that IMFs may play an important role in pathology associated with staphlococcocal enterotoxigenic disease.
Intestinal Myofibroblasts and Immune Tolerance
Authors: SAADA J I , BARRERA C A , REYES V E , ADEGBOYEGA P A , SUAREZ G , TAMERISA R A , PANG K F , BLAND D A , MIFFLIN R C , DI MARI J F , POWELL D W
Published: January 2005

Abstract: Stromal cells, such as myofibroblasts and fibroblasts, represent a significant fraction of MHC class II‐positive cells in the normal human colonic lamina propria, suggesting they may play an important role in CD4+ T cell regulation in a tolerogenic environment. The aim of this study was to examine whether human colonic myofibroblasts (CMFs) phenotypically and functionally resemble conventional antigen‐presenting cells (APCs). Our results support the hypothesis that intestinal myofibroblasts are a novel, nonprofessional APC phenotype important in modulating mucosal T cell responses. Given their strategic location, we propose that intestinal myofibroblasts play a critical role in mediating tolerance to luminal antigens.
Genetic Selection for Susceptibility to Oral Tolerance Leads to a Profound Reduction of the Acute Inflammatory Response
Authors: da SILVA MARIA de FÁTIMA SARRO , da NÓBREGA ALBERTO , BARJA‐FIDALGO TEREZA CRISTINA , BRANDO‐LIMA ALINE C. , CUNHA FERNANDO , da SILVA ANTONIO CARLOS
Published: January 2005

Abstract: Strains of mice obtained by genetic selection to extremes of phenotype for susceptibility or resistance to oral tolerance were investigated for possible genetic correlations with acute inflammatory response using different models of inflammation. The results show a strong genetic association.
Immune Regulation in the Intestine: A Balancing Act between Effector and Regulatory T Cell Responses
Authors: POWRIE FIONA
Published: January 2005

Abstract: The immune system in the intestine must respond rapidly to invading pathogens without mounting sustained effector cell responses to the indigenous commensal bacteria. Results from this laboratory using the T cell transfer model of colitis suggest that specialized populations of regulatory T cells control the immune response in the intestine. Regulatory T (Tr) cell activity is enriched within the naturally arising CD4+ CD25+ Tr subset that has been shown to prevent a number of inflammatory diseases. CD4+ CD25+ Tr cells control intestinal inflammation induced by both innate and adaptive immune responses via IL‐10‐ and TGF‐β‐dependent mechanisms. Recent results have shown that CD4+ CD25+ Tr cells can cure established colitis, suggesting their utility for the treatment of inflammatory bowel disease.
IL‐10‐Producing T Regulatory Type 1 Cells and Oral Tolerance
Authors: BATTAGLIA MANUELA , GIANFRANI CARMEN , GREGORI SILVIA , RONCAROLOA MARIA‐GRAZIA
Published: January 2005

Abstract: Oral tolerance is mediated by multiple mechanisms such as anergy and/or active suppression of antigen‐specific effector T cells by T regulatory (Tr) cells. Among the CD4+ Tr cells, T regulatory type 1 cells (Tr1) have been shown to downmodulate immune responses through production of the immunosuppressive cytokines IL‐10 and TGF‐β. Human Tr1 cells can be induced to differentiate in vitro by IL‐10 1 IFN‐α or after stimulation by immature dendritic cells (DCs) or DCs rendered tolerogenic by exposure to immunomodulatory compounds. Murine Tr1 cells can be induced to differentiate in vitro by activating naive CD4+ T cells in the presence of high doses of IL‐10. Several protocols for induction of oral tolerance, including oral administration of the antigen with IL‐10, have been shown to induce antigen‐specific Tr1 cells that suppress undesired immune responses toward self‐antigens, allergens, and food antigens. Overall, these data demonstrate that IL‐10‐producing Tr1 cells play a central role in the induction of oral as well as systemic tolerance.
Natural Killer T Cells in Mucosal Homeostasis
Authors: KASER ARTHUR , NIEUWENHUIS EDWARD E. S. , STROBER WARREN , MAYER LLOYD , FUSS IVAN , COLGAN SEAN , BLUMBERG RICHARD S.
Published: January 2005

Abstract: The mucosal‐associated lymphoid tissues (MALT), including the gut‐associated lymphoid tissues, are a tightly regulated environment. In fact, it might be stated that on the basis of studies from animal models of inflammatory bowel disease (IBD), the major means of peripheral regulation of immune responses in the intestine is not necessarily from processes such as deletion or anergy, but more likely from the controls imposed upon responses due to the activities of a variety of regulatory subsets of cells. One type of regulatory cellular subset that has recently gained attention is the subset of T cells that are associated with CD1d‐restricted responses. Recently, CD1d‐restricted T cells have been increasingly appreciated to play a significant role in mucosal tissues of the intestine and lung, for example. Insights from these studies have clearly elevated these cells to particular importance in the regulation of a variety of infectious and inflammatory conditions, such as those associated with idiopathic IBD. In this review, we focus on recent observations on the characteristics of CD1d‐restricted pathways in mucosal compartments, after a brief introduction into the biology of CD1d and CD1d‐restricted T cells.
The Role of Transforming Growth Factor‐β in a Model of Oral Tolerance to the Diet Antigen Dextrin
Authors: OLMOS SOFÍA , MARQUEZ MARIA GABRIELA , LÓPEZ MARÍA C. , ROUX MARIA ESTELA
Published: January 2005

Abstract: In a model of immunodeficiency provoked by protein deficiency, cytosol fractions from gut IELS isolated from immunodeficient rats presenting oral tolerance to dextrin showed increased expression of TGF‐β to reduce the effect of higher levels of inflammatory cytokines.
Transforming Growth Factor‐β Regulates Susceptibility of Epithelial Apoptosis in Murine Model of Colitis
Authors: SAKURABA HIROTAKE , ISHIGURO YOH , YAMAGATA KAZUFUMI , TAGAWA YOH‐ICHI , IWAKURA YOICHIRO , SEKIKAWA KENJI , MUNAKATA AKIHIRO , NAKANE AKIO
Published: January 2005

Abstract: Transforming growth factor (TGF)‐beta has a key role in intestinal homeostasis. Our present data suggest that TGF‐beta, which was constitutively expressed by lamina propria mononuclear cells and epithelium, affected epithelial cells. Abnormal suppression of TGF‐beta could enhance the sensitivity of epithelial cells to apoptosis associated with interferon‐gamma in DSS‐induced colitis.
Early Events in Antigen‐Specific Regulatory T Cell Induction via Nasal and Oral Mucosa
Authors: SAMSOM JANNEKE N. , HAUET‐BROERE FEMKE , UNGER WENDY W. J. , VAN BERKEL LISETTE A. , KRAAL GEORG
Published: January 2005

Abstract: Mucosal Tr prevent harmful immune responses to innocuous antigens that are encountered at the mucosae. This unique subset of Tr is adaptive, antigen specific, and suppresses irrespective of cytokine polarization. Here we study the earliest events of mucosal Tr induction and factors that control their differentiation from naive T cells.
Is Oral Tolerance Correlated with IgE Levels and Mast Cell Numbers?
Authors: DA SILVA ANTONIO CARLOS , SILVA MARIA F. S. , BIANCHI CRISTINA , RIBEIRO RICARDO C. , NÓBREGA ALBERTO , SANT'ANNA OSVALDO
Published: January 2005

Abstract: A triple genetic association between serum IgE levels, mast cell numbers, and susceptibility to oral tolerance was observed in mice genetically selected to extreme phenotypes of oral tolerance (susceptibility and resistance), suggesting a coadaptation of genes controlling these traits.
Gamma‐Delta T Cells as Orally Induced Suppressor Cells in Rats: In Vitro Characterization
Authors: WILDNER GERHILD , THURAU STEPHAN R. , DIEDRICHS‐MÖHRING MARIA
Published: January 2005

Abstract: Gamma‐delta T cells from orally tolerized rats adoptively transfer suppression of experimental autoimmune uveitis. In vivo and in vitro these regulatory cells specifically recognize retinal autoantigen peptide PDSAg and its mimotope B27PD, but not other mimicry peptides. Proliferation of γ/δ T cells was MHC class II and CD8 dependent.
Oral Glatiramer Acetate in Experimental Autoimmune Encephalomyelitis: Clinical and Immunological Studies
Authors: TEITELBAUM DVORA , AHARONI RINA , KLINGER ETY , KREITMAN RIVKA , RAYMOND EMANUEL , MALLEY ARTHUR , SHOFTI RONA , SELA MICHAEL , ARNON RUTH
Published: January 2005

Abstract: Glatiramer acetate (GA, Copaxone, copolymer 1) for injection is an approved drug for relapsing‐remitting multiple sclerosis. The clinical and immunological effects of GA were extensively studied in experimental autoimmune encephalomyelitis (EAE), the experimental animal model for MS. The effect of oral administration of GA was tested in both rodents and primates in acute as well as in chronic relapsing (CR) models of EAE. Oral GA was found to suppress acute EAE induced in rats, mice, and rhesus monkeys. The effect of GA was also tested in several models of CR‐EAE: proteolipid protein and myelin oligodendrocyte glycoprotein induced CR‐EAE in mice, CR‐EAE in Biozzi mice, and CR‐EAE in cynomolgus monkeys. In all the murine models, oral treatment with GA initiated at the peak of first relapse reduced the severity of disease and suppressed further relapses. Suppression of EAE with oral GA was associated with marked inhibition of spleen cell proliferation and Th1 cytokine (IL‐2 and IFN‐γ) response to the respective autoantigens. GA‐specific T cell lines of the Th2/3 type that inhibit EAE induction in vivo, similarly to those induced by injection of GA, could be isolated from spleens of GA‐fed mice and rats. Furthermore, as demonstrated previously for GA‐specific cells induced by the parenteral route, the orally induced GA‐specific cells accumulate in the CNS and secrete in situ Th2 cytokines in response to both GA and MBP as well as brain‐derived neurotrophic factor (BDNF). Although a clinical trial in MS with two doses of oral GA in enteric‐coated tablets did not show a significant effect either at the clinical or immunological level, the results presented here suggest that oral GA may still be developed into a therapeutic modality in MS.
Oral Insulin Therapy to Prevent Progression of Immune‐Mediated (Type 1) Diabetes
Authors: ERGUN‐LONGMIRE BERRIN , MARKER JOHN , ZEIDLER ADINA , RAPAPORT ROBERT , RASKIN PHILIP , BODE BRUCE , SCHATZ DESMOND , VARGAS ALFONSO , ROGERS DOUGLAS , SCHWARTZ SHERWYN , MALONE JOHN , KRISCHER JEFFREY , MACLAREN NOEL K.
Published: January 2005

Abstract: Repeated ingestion of insulin has been suggested as an immune tolerization therapy to prevent immune‐mediated (type 1) diabetes. We performed a placebo‐controlled, two‐dose, oral insulin tolerance trial in newly diagnosed (< 2 years) diabetic patients who had required insulin replacement for less than 4 weeks and were found to have cytoplasmic islet cell autoantibodies (ICAs). No oral hypoglycemic agents were permitted during the trial. Endogenous insulin reserves were estimated at six‐month intervals by plasma C‐peptide responses to a mixed meal. Positive ICAs were found in 262 (31%) of the 846 patients screened. Of the 197 who agreed to participate, 187 could be followed for 6 to 36 months. Endogenous insulin retention was dependent upon initial stimulated C‐peptide response, age at diabetes onset, and numbers of specific islet cell autoantibodies found. Oral insulin improved plasma C‐peptide responses in patients diagnosed at ages greater than 20 years, best seen at the low (1 mg/day) over the high (10 mg/day) insulin dose (P= .003 and P= .01, respectively). In patients diagnosed before age 20 years, the 1 mg dose was ineffective, whereas the 10 mg dose actually accelerated C‐peptide loss (P= .003). There were no adverse effects. If confirmed, these findings suggest that diabetic patients over age 20 years with ICA evidence of late‐onset immune‐mediated diabetes should be considered for oral insulin at 1 mg/day to better retain endogenous insulin secretion.
Noise and Microflora Behavior
Authors: LORENZO MÁXIMO , SÁNCHEZ PABLO , REWALD ENRIQUE
Published: January 2005

Abstract: Noise is ubiquitous, and in any discussion about regulation of immune diversity, oral tolerance, commensal microflora, and “health” homeostasis, stochastic resonance should not be omitted. It also may have a role in immune receptor regulation, transplant tolerance, and host reaction against intruders. It would be in line with nature's tendency to adapt to available network patterns.
Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry
Authors: Chung Ki Young , Shia Jinru , Kemeny Nancy E. , Shah Manish , Schwartz Gary K. , Tse Archie , Hamilton Audrey , Pan Dorothy , Schrag Deborah , Schwartz Lawrence , Klimstra David S. , Fridman Daniel , Kelsen David P. , Saltz Leonard B.
Published: January 2005

Purpose

To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC).

Patients and Methods

Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria.

Results

Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%).

Conclusion

Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.
Suppression of ps20 Expression in the Rat Uterus by Tamoxifen and Estrogens
Authors: Hung Huynh
Published: January 2005

Using differential display methodology, we isolated a tamoxifen-regulated cDNA. This cDNA was identical to the ps20 cDNA isolated from urogenital sinus mesenchymal cells. ps20 expression was detected in various female rat tissues, with the highest expression in lung and heart. ps20 transcripts were low during estrus and proestrus, but high during the diestrous stage of the estrous cycle coincident with estrogen-induced uterine cell proliferation. Treatment of ovary-intact or ovariectomized rats with estrogens or tamoxifen resulted in increased uterine weight and decreased ps20 expression. Uterine involution associated with ovariectomy or antiestrogen treatment led to up-regulation of ps20. Antibody against rat ps20 recognized the native rat ps20 in conditioned medium of primary rat uterine cells and stable ps20-transfected MCF-7 cells with molecular masses of approximately 24, 27, and 29 kDa. In primary rat uterine cells, ps20 secretion was enhanced by ICI 182,780, but was inhibited by estrogens and tamoxifen. Immunohistochemistry revealed that ps20 was localized to smooth muscle and luminal epithelial cells as well as the glandular population of uterine tissue. Conditioned medium derived from ps20-transfected MCF-7 cells, but not Escherichia coli recombinant ps20, exhibited mild growth suppression on PC-3 cells. The data indicate that ps20 expression is negatively regulated by estrogens and tamoxifen and suggest that ps20 may function as a mediator of local growth.
Regulation of T Cell-Mediated Hepatic Inflammation by Adiponectin and Leptin
Authors: Sennello Joseph A. , Fayad Raja , Morris Alison M. , Eckel Robert H. , Asilmaz Esra , Montez Jason , Friedman Jeffrey M. , Dinarello Charles A. , Fantuzzi Giamila
Published: January 2005

Concanavalin A-induced hepatotoxicity was compared in lipodystrophic aP2-nSREBP-1c transgenic mice (LD mice) lacking adipose tissue, obese leptin-deficient ob/ob mice, and lean wild-type (WT) mice. Serum leptin and adiponectin were low in LD mice, whereas ob/ob mice had undetectable leptin, but high adiponectin. Protection from hepatotoxicity was observed in ob/ob, but not in LD mice, despite low cytokine levels and reduced T cell activation and hepatic natural killer T cells in both groups. Administration of adiponectin protected LD mice from hepatotoxicity without altering cytokine levels. In contrast, administration of leptin heightened disease susceptibility by restoring cytokine production. Neutralization of TNFα protected LD mice from liver damage. Increased in vivo susceptibility to the hepatotoxic effect of TNFα was observed in LD mice. In vitro, adiponectin protected primary hepatocytes from TNFα-induced death, whereas leptin had no protective effect. In conclusion, although leptin increases susceptibility to hepatotoxicity by regulating cytokine production and T cell activation, adiponectin protects hepatocytes from TNFα-induced death.
Quantitative estimation of the effects of bile salt surfactant systems on insulin stability and permeability in the rat intestine using a mass balance model
Authors: Lane Majella E , O'Driscoll Caitriona M , Corrigan Owen I
Published: January 2005

The oral delivery of peptides and proteins is compromised by chemical and proteolytic instability as well as by permeability limitations. The aim of this study was to delineate the relative contributions of simple bile salt and bile salt:fatty acid mixed micellar systems to protein stability vs permeability enhancement in the rat intestine. Insulin disappearance from the rat intestine was evaluated when administered in simple micellar systems of sodium cholate (NaC), sodium taurocholate (NaTC) and sodium glycocholate (NaGC), and in mixed micellar systems of these bile salts and linoleic acid (LA). In-vitro stability studies were used to evaluate the extent of insulin degradation in the different micellar systems. After correction for insulin degradation in all systems a mass balance model was used to estimate the fractions of insulin absorbed for all systems. Mass balance estimates for the extent of insulin absorption in control perfusion systems were consistent with previously reported predictions of the model for ileal insulin absorption. Mass balance estimates for NaGC suggested no significant effects on the fraction of insulin absorbed relative to control. However, insulin absorption was estimated to occur to a significantly greater extent for NaTC simple micellar systems and was coincident with increased permeability of the hydrophilic marker molecule PEG 4000. The mass balance model estimated higher fractions of insulin absorbed for all mixed micellar systems in line with enhanced plasma insulin levels and higher PEG 4000 permeabilities for these systems.