bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokine requirements for the growth and development of mouse NK cells in vitro
Authors: Toomey Jennifer A , Gays Frances , Foster Don , Brooks Colin G 
Published: July 2003

Abstract
Natural killer (NK) cells arise from immature progenitors present in fetal tissues and adult bone marrow, but the factors responsible for driving the proliferation and differentiation of these progenitors are poorly understood. Mouse NK cells had previously been thought not to express interleukin (IL)-2Rα chains, but we show here that immature and mature mouse NK cells express IL-2Rα chain mRNA and that low levels of IL-2Rα chains can be detected on the surface of immature and mature NK cells provided they are cultured in the absence of IL-2. Despite their potential expression of high-affinity IL-2 receptors, immature NK cells only proliferate if IL-2 is present at extremely high concentrations. Surprisingly, IL-15 can also only support the growth of immature NK cells at high, presumably nonphysiological concentrations. Although NK cells express mRNA for the high-affinity IL-15Rα chain, they also express a variety of alternately spliced transcripts whose protein products could potentially disrupt signaling through IL-15 receptors. The requirement for high concentrations of IL-2 and IL-15 suggests that if these cytokines play any role in the proliferative expansion of NK cells in vivo, they act indirectly via other cells or in cooperation with other factors. In support of the latter possibility, we report that the recently described cytokine IL-21 can markedly enhance the proliferation of immature (and mature) NK cells in the presence of doses of IL-2 and IL-15 that by themselves have little growth-promoting activity.
Hypoxia reduces CD80 expression on monocytes but enhances their LPS-stimulated TNF-α secretion
Authors: Lahat Nitza , Rahat Michal A , Ballan Mouna , Weiss-Cerem Lea , Engelmayer Miri , Bitterman Haim 
Published: July 2003

Abstract
Monocytes/macrophages in ischemic tissues are involved in inflammation and suppression of adaptive immunity via secretion of proinflammatory cytokines and reduced ability to trigger T cells, respectively. We subjected human mononuclear cells and mouse macrophages to hypoxia and reoxygenation, the main constituents of ischemia and reperfusion, and added lipopolysaccharide (LPS) to simulate bacterial translocation, which frequently accompanies ischemia. We monitored the secretion of tumor necrosis factor α (TNF-α) and the surface expression of human leukocyte antigen-DR and the costimulatory molecules CD80 and CD86 on monocytes/macrophages. Hypoxia selectively reduced the surface expression of CD80 (P&lt;0.01), and synergistically with LPS, it enhanced TNF-α secretion (P&lt;0.003). Reoxygenation reversed both phenomena. In the mouse macrophage cell line RAW 264.7, hypoxia reduced the surface expression of CD80 and increased its concentrations in the supernatants (P&lt;0.01). Down-regulation of the mRNA coding for the membrane-anchored CD80 was observed, suggesting that hypoxia triggers alternative splicing to generate soluble CD80. Cumulatively, these results suggest that hypoxia simultaneously affects monocytes/macrophages to enhance inflammation and reduce their ability to initiate adaptive-immunity responses associated with ischemic injury.
Immunity in the eye: lessons in organ-specific responses
Authors: Ono Santa Jeremy 
Published: July 2003

Abstract
Fifty-five years have past since Sir Peter Medawar first demonstrated that the fate of allografts differs in the skin, brain, subcutaneous tissue, and anterior chamber of the eye. Indeed, these and other experiments performed at the University of Birmingham and University College London not only helped define key paradigms in transplantation biology but introduced the concept of immune privilege in the eye and in other tissues. In the ensuing years, the work from dozens of laboratories has confirmed that immune responses in eye, although sharing many features with immunity in other tissues, are atypical in many respects. This has been hypothesized to stem from the requirement in the eye to hold inflammation in check to preserve visual function. Indeed, inflammatory reactions in different regions of the eye can result in visual impairment and blindness, manifesting in diseases such as vernal keratoconjunctivitis, uveitis, corneal endotheliitis, Mooren’s ulcer, and pemphigoid. The investigation of the cell and molecular basis of the unique nature of immunity in the eye has revealed a remarkably complex network of interactions that controls inflammation while affording immunity. The most recent data generated in this field and the concepts arising from their interpretation were discussed at a symposium held at the University College London in late 2002. Here, we highlight some of the findings discussed at the meeting and introduce in-depth reviews published in this issue of the journal.
Expression of L-CCR in HEK 293 cells reveals functional responses to CCL2, CCL5, CCL7, and CCL8
Authors: Biber Knut , Zuurman Mike W , Homan Han , Boddeke Hendrikus W G M 
Published: July 2003

Abstract
It has become clear in the past years that chemokines and chemokine receptors are pivotal regulators of cellular communication and trafficking. In addition to the ∼20 chemokine receptors that have been cloned and described, various orphan receptors with a chemokine receptor-like structure are known. We have investigated the orphan mouse chemokine receptor (L-CCR) in HEK 293 cells, a receptor that was originally described in a mouse macrophage cell line. Cells expressing this receptor show pertussis toxin-sensitive chemotaxis and small intracellular calcium transients in response to the chemokines CCL2, CCL7, CCL8, and CCL5. Biotinylated CCL2 binds to L-CCR-expressing cells, and transfection experiments with an L-CCR–green fluorescent protein fusion protein showed L-CCR expression in the membranes of recombinant HEK 293 cells. Although radioligand binding was not detected, it is suggested that L-CCR is a functional chemokine receptor.
Pathways for the regulation of interferon-γ-inducible genes by iron in human monocytic cells
Authors: Oexle Horst , Kaser Arthur , Möst Johannes , Bellmann-Weiler Rosa , Werner Ernst R , Werner-Felmayer Gabriele , Weiss Günter 
Published: July 2003

Abstract
To elucidate iron-regulated interferon-γ (IFN-γ) effector functions, we investigated three IFN-γ-inducible genes [intercellular adhesion molecule-1 (ICAM-1), human leukocyte antigen (HLA)-DR, guanosine 5′-triphosphate-cyclohydrolase I (GTP-CH)] in primary human monocytes and the cell line THP-1. IFN-γ increased the surface expression of ICAM-1 and HLA-DR and stimulated GTP-CH activity. Addition of iron before cytokine stimulation resulted in a dose-dependent reduction of these pathways, and iron restriction by desferrioxamine (DFO) enhanced ICAM-1, HLA-DR, and GTP-CH expression. Iron neither affected IFN-γ binding to its receptor nor IFN-γ receptor surface expression. IFN-γ-inducible mRNA expression of ICAM-1, HLA-DR, and GTP-CH was reduced by iron and increased by DFO by a transcriptional mechanism. Moreover, ICAM-1 and to a lesser extent, GTP-CH and HLA-DR mRNA expression were regulated post-transcriptionally, as iron pretreatment resulted in shortening the mRNA half-life compared with cells treated with IFN-γ alone. Thus, iron perturbations regulate IFN-γ effector pathways by transcriptional and post-transcriptional mechanisms, indicating that iron rather interferes with IFN-γ signal-transduction processes.
Control of myeloid activity during retinal inflammation
Authors: Dick Andrew D , Carter Debra , Robertson Morag , Broderick Cathryn , Hughes Edward , Forrester John V , Liversidge Janet 
Published: July 2003

Abstract
Combating myeloid cell-mediated destruction of the retina during inflammation or neurodegeneration is dependent on the integrity of homeostatic mechanisms within the tissue that may suppress T cell activation and their subsequent cytokine responses, modulate infiltrating macrophage activation, and facilitate healthy tissue repair. Success is dependent on response of the resident myeloid-cell populations [microglia (MG)] to activation signals, commonly cytokines, and the control of infiltrating macrophage activation during inflammation, both of which appear highly programmed in normal and inflamed retina. The evidence that tissue CD200 constitutively provides down-regulatory signals to myeloid-derived cells via cognate CD200-CD200 receptor (R) interaction supports inherent tissue control of myeloid cell activation. In the retina, there is extensive neuronal and endothelial expression of CD200. Retinal MG in CD200 knockout mice display normal morphology but unlike the wild-type mice, are present in increased numbers and express nitric oxide synthase 2, a macrophage activation marker, inferring that loss of CD200 or absent CD200R ligation results in “classical” activation of myeloid cells. Thus, when mice lack CD200, they show increased susceptibility to and accelerated onset of tissue-specific autoimmunity.
The immune privilege of corneal grafts
Authors: Niederkorn Jerry Y 
Published: July 2003

Abstract
Keratoplasty is the oldest and one of the most successful forms of solid tissue transplantation. In the United States, over 33,000 corneal transplants are performed each year. Unlike other forms of tissue transplantation, keratoplasties are routinely performed without the aid of tissue typing or systemic immunosuppressive drugs. In spite of this, 90% of the first-time corneal transplants will succeed–a condition that demonstrates the immune privilege of keratoplasties. The avascular nature of the corneal allograft bed led many to suspect that corneal grafts were sequestered from the immune apparatus. Although pleasing in its simplicity, this explanation has given way to a more comprehensive hypothesis that embodies multiple, interdependent mechanisms, which promote the long-term survival of corneal allografts. These mechanisms conspire to interrupt the transmission of immunogenic stimuli to peripheral lymphoid tissues; induce the generation of a deviated immune response; and neutralize immune effector elements at the host-graft interface. This paradigm is analogous to a three-legged stool. Disassembly of any one of the three components results in the collapse of immune privilege. Strategies to re-establish corneal immune privilege may have clinical application for high-risk hosts who have rejected previous corneal allografts.
Corneal immunity is mediated by heterogeneous population of antigen-presenting cells
Authors: Hamrah Pedram , Huq Syed O , Liu Ying , Zhang Qiang , Dana M Reza 
Published: July 2003

Abstract
Corneal antigen-presenting cells (APC), including dendritic cells (DC), were thought to reside exclusively in the peripheral cornea. Here, we present recent data from our group demonstrating that the central cornea is indeed endowed with a heterogeneous population of epithelial and stromal DC, which function as APC. Although the corneal periphery contains mature and immature resident bone marrow-derived CD11c+ DC, the central cornea is endowed exclusively with immature and precursor DC, both in the epithelium and the stroma, wherein Langerhans cells and monocytic DC reside, respectively. During inflammation, a majority of resident DC undergo maturation by overexpressing major histocompatibility complex class II and B7 (CD80/CD86) costimulatory molecules. In addition to the DC, macrophages are present in the posterior corneal stroma. In transplantation, donor-derived DC are able to migrate to host cervical lymph nodes and activate host T cells via the direct pathway when allografts are placed in inflamed host beds. These data revise the tenet that the cornea is immune-privileged as a result of lack of resident lymphoreticular cells and suggest that the cornea is capable of diverse cellular mechanisms for antigen presentation.
Chemokine receptor expression and chemotactic responsiveness of human monocytes after influenza A virus infection
Authors: Salentin Robert , Gemsa Diethard , Sprenger Hans , Kaufmann Andreas 
Published: July 2003

Abstract
Chemokines and their receptors play an important role in site-directed migration and activation of leukocytes. To understand how viral infections may impair this function, we analyzed chemokine receptor expression and responsiveness of human monocytes after infection with influenza A virus. Whereas treatment with infectious virus induced a rapid down-regulation of the CCL2/monocyte chemoattractant protein-1 (MCP-1)-specific receptor CCR2, inactivated virus did not significantly alter CCR2 surface expression. In parallel, the response to CCL2/MCP-1 was lost after infection with active virus: Neither a CCL2/MCP-1-induced shift of intracellular calcium concentrations nor the chemotactic response to CCL2/MCP-1 was detectable. In striking contrast, the presence of CCR1 and CCR5 on the cell surface remained unchanged or was even slightly up-regulated after viral infection. However, the remaining expression of CCR1 and CCR5 correlated reciprocally with an ongoing unresponsiveness to the CCR1 and CCR5 agonists CCL3/macrophage-inflammatory protein-1α (MIP-1α), CCL4/MIP-1β, and CCL5/regulated on activation, normal T expressed and secreted (RANTES), all chemokines binding to these two receptors. The CCL3/MIP-1α-induced shifts of intracellular calcium concentrations declined gradually to almost undetectable levels, and most conspiciuously, the chemotactic response to CCL3/MIP-1α, CCL4/MIP-1β, and CCL5/RANTES was lost after infection with active influenza virus. Inactivated virus particles did not significantly alter the responsiveness induced by CCR1 and CCR5 agonists. Despite the inability of chemokine receptors to elicit migration, phosphorylation of protein kinase B was not altered in virus-infected monocytes. Thus, influenza A virus infection rapidly abolishes the functional responsiveness of monocytes and prevents an adequate response of the infected cells to chemokine stimulation.
Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation
Authors: Streilein J Wayne 
Published: July 2003

Abstract
The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and γδ T cells create an antigen-presentation environment that leads to CD4+ and CD8+ α/β T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.
DLX genes as targets of ALL-1: DLX 2,3,4 down-regulation in t(4;11) acute lymphoblastic leukemias
Authors: Ferrari Nicoletta , Palmisano Giulio L , Paleari Laura , Basso Giuseppe , Mangioni Manuela , Fidanza Vincenzo , Albini Adriana , Croce Carlo M , Levi Giovanni , Brigati Claudio 
Published: July 2003

Abstract
Dlx genes constitute a gene family thought to be essential in morphogenesis and development. We show here that in vertebrate cells, Dlx genes appear to be part of a regulatory cascade initiated by acute lymphoblastic leukemia (ALL)-1, a master regulator gene whose disruption is implicated in several human acute leukemias. The expression of Dlx2, Dlx3, Dlx5, Dlx6, and Dlx7 was absent in All-1 −/− mouse embryonic stem cells and reduced in All-1 +/− cells. In leukemic patients affected by the t(4;11)(q21;q23) chromosomal abnormality, the expression of DLX2, DLX3, and DLX4 was virtually abrogated. Our data indicate that Dlx genes are downstream targets of ALL-1 and could be considered as important tools for the study of the early leukemic cell phenotype.
Analysis of the maturation process of dendritic cells deficient for TNF and lymphotoxin-α reveals an essential role for TNF
Authors: Ritter Uwe , Meissner Anja , Ott Jessica , Körner Heinrich 
Published: July 2003

Abstract
Dendritic cells (DCs) generated from bone marrow (BM) precursor cells of C57BL/6 (B6.WT) mice and cultured in the presence of granulocyte macrophage-colony stimulating factor differentiate to mature BM-DCs spontaneously. These mature DCs are characterized by high levels of major histocompatibility complex (MHC) class II, CD40, and CD86 on their surface. To analyze the involvement of tumor necrosis factor (TNF) and the related cytokine lymphotoxin (LT)α in DC maturation, we studied the development of DCs from the BM of B6.TNF−/−, B6.LTα−/−, and B6.TNF/LTα−/− mice and compared it to B6.WT mice. Although the development of BM precursor cells to the level of immature DCs (CD11c+, MHC class IIlow, CD40low, and CD86low) was equivalent in all genotypes, B6.TNF−/− and B6.TNF/LTα−/− cells showed an impaired capacity to differentiate to mature DCs. In contrast, mature BM-DCs generated from LTα-negative, immature DCs developed like B6.WT cells. Further studies revealed that once matured, the phenotype of all tested genotypes was comparable. They expressed high levels of CD40 and CD86, were exclusively positive for the chemokine receptor (CCR)7 but negative for CCR5 and CCR2, and were able to enter the paracortex of draining lymph nodes. The limited maturation of TNF-deficient BM-DCs could be restored by mixing TNF-negative with TNF-positive Ly5.1 BM cells, and maturation of B6.WT DCs could be blocked with an anti-TNF monoclonal antibody. The substitution of B6.TNF−/− BM cells with recombinant TNF revealed promotion or suppression of BM-DC maturation depending on the point of time of TNF addition.
Mannose receptor contribution to Candida albicans phagocytosis by murine E-clone J774 macrophages
Authors: Porcaro Isabelle , Vidal Michel , Jouvert Sylvie , Stahl Philip D , Giaimis Jean 
Published: July 2003

Abstract
Mannoproteins, as the main constituents of the outer layer of yeast cell walls, are able to interact with phagocytic cells in an opsonin-independent manner through the mannose receptor (MR) and to induce yeast ingestion by the professional phagocytes. Moreover, the MR also mediates endocytosis of soluble ligands through clathrin-coated pits. Here, we studied some aspects of the interaction between the MR and Candida albicans using murine E-clone macrophages and the consequences on MR trafficking. Using a pull-down assay involving mixture E-clone macrophage detergent lysate with mannosylated Sepharose beads and glutaraldehyde-fixed, heat-killed (HK) C. albicans, we found that binding of solubilized MR to mannosylated particles occurred with characteristics similar to the receptor’s cell-surface mannose-binding activity. We then demonstrated that MR expressed on E-clone macrophages contributed to phagocytosis of unopsonized, HK C. albicans and that yeast phagocytosis induced a decrease in MR endocytic activity without concomitant degradation of the receptor in the time lapse studied.
High expression of p21Waf1 in sarcoid granulomas: a putative role for long-lasting inflammation
Authors: Xaus Jordi , Besalduch Núria , Comalada Mònica , Marcoval Joaquim , Pujol Ramón , Mañá Juan , Celada Antonio 
Published: July 2003

Abstract
In sarcoid granulomas, apoptotic events are reduced, which explains their characteristic long-lasting inflammation. We have described that interferon-γ (IFN-γ) inhibits apoptosis in macrophages through the expression of p21Waf1. Here, we explore the molecular mechanisms involved in the inhibition of apoptosis in sarcoid granulomas. We analyzed skin biopsies from 19 sarcoidosis patients and 16 controls. Total RNA was subjected to semiquantitative reverse transcriptase-polymerase chain reaction analysis. There was no difference found in the expression of proapoptotic (Bax and Bcl-Xs) or antiapoptotic (Bcl-2 and Bcl-XL) genes nor in the expression of the tumor suppressor gene p53. Furthermore, the expression of IFN-γ and the cdk inhibitors p21Waf1 and p27Kip1 were analyzed. IFN-γ was detected in 37% of the sarcoidosis patients, and controls were negative (P&lt;0.02). In addition, a higher proportion of patients expressing p21Waf1 (58%) versus controls (12%) was found (P&lt;0.005). There was a significant correlation between the expression of IFN-γ and p21Waf1 (r=0.69) and between p21Waf1 and fibronectin (r=0.65). Finally, using immunohistochemistry, high p21Waf1 reactivity was observed inside the granuloma. We conclude that the high levels of p21Waf1 in sarcoidosis may explain the absence of apoptosis in the granuloma and the persistence of inflammation.
Study of the MIB-1 Labeling Index as a Predictor of Tumor Progression in Pilocytic Astrocytomas in Children and Adolescents
Authors: Bowers Daniel C. , Gargan Lynn , Kapur Payal , Reisch Joan S. , Mulne Arlynn F. , Shapiro Kenneth N. , Elterman Roy D. , Winick Naomi J. , Margraf Linda R. 
Published: July 2003

Purpose: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs. Patients and Methods: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis. Results: One hundred forty-one children were identified (mean ± SD age, 7.6 ± 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P = .035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P = .001 for all). Tumors in the optic pathways were associated with a shorter PFS (P = .001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P = .001 and .019, respectively). Conclusion: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.