A seven-month-old infant with fever and neutrophilic leukocytosis.
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Diagnosis, Differential↗
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Suppression of cytokine production and cell adhesion molecule expression in human monocytic cell line THP-1 by Tripterygium wilfordii polysaccharide moiety.
Extracts of the vine-like plant Tripterygium wilfordii (TW) have been widely used in China as an immunosuppressant and anti-inflammatory drug for the treatments of rheumatoid arthritis, lupus erythematosus and other inflammatory disorders. In this study the molecular mechanisms of action of three TW extracts (ethanol, aqueous, polysaccharide) on the expression of inflammatory cytokines and adhesion molecules were investigated by RT-PCR and immunofluorescence binding techniques. The lipopolysaccharide (LPS)-mediated stimulatory effects of tumor necrosis factor-alpha (TNF-alpha) cytokine production and cell adhesion molecule (CD11c, CD18, CD14, CD54) expression in human monocytic THP-1 cells were modulated by treatments of the TW extracts or tacrolimus (FK506). The TW polysaccharide moiety exhibited more profound immunosuppressive properties than the aqueous and ethanol extracts. Biochemical characterization of the polysaccharide moiety revealed a major molecular weight of 22 kDa (viz. PSP22). The PSP22 was found to be a potential immunosuppressant that manifests the necessary immunomodulating properties.
CD18 Antigens↗
Role of leukocyte adhesion molecules during ex vivo kidney xenoperfusion.
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Animals↗
Primary membrane T cell immunodeficiencies.
Primary membrane T cell immunodeficiencies (ID) have recently been characterized. In this paper we describe the main findings about the leukocyte adhesion deficiencies (LAD), the ID with low expression of the T cell receptor/CD3 complex, and the Omenn's syndrome. LAD is a consequence of mutations in the beta-chain-encoding gene of the leukocyte adhesion proteins. Functional consequences mainly affect phagocytic cells which are incapable of transendothelial migration. Effector T lymphocyte functions are, however, also impaired, i.e., helper T cell activity and cytotoxicity. The latter defect may account for the inability of LAD patients to reject HLA nonidentical bone marrow. Low expression of the T cell receptor CD3 complex is a rare entity characterized by a profoundly diminished expression of the whole complex on all T cells. The basic defect has not yet been unravelled. Interestingly, such T cells differentiate normally and can be activated by some antigens while anti-CD3 and anti-CD2 antibodies are not efficient. In five patients with Omenn's syndrome (combined immunodeficiency with eosinophilia), oligoclonal T cells were detected in blood, skin, and gut. These T cells are also in vivo activated. Since in one family, one sibling presented with typical SCID, i.e., alymphocytosis, and another with the Omenn's syndrome, it is proposed that the latter syndrome may correspond to a form of leakiness of SCID as found in the mice SCID model.
Antigens, Differentiation, T-Lymphocyte↗
Ribosomal proteins sustain morphology, function and phenotype in acute myeloid leukemia blasts.
Translation of mRNA is a prerequisite for cell proliferation, differentiation and viability. We have studied the effect of ribosome protein factors (GPRE) on acute myeloid leukemia (AML) blast cells. Ribosomes were isolated from MPC-11 cells using ultra-centrifugation. GPRE were extracted using a high KCl procedure. Blast cells from six AML patients were grown in suspension cultures for 24 and 96 h. GPRE or granulocyte macrophage-colony stimulating factor (GM-CSF) were added at the start of the incubation. GPRE, but not GM-CSF, prevented chromatin condensation and fragmentation of blast cell nuclei in AML-M2, -M4 and -M5 and the loss of nucleoli in AML-M2 and -M5. The fraction of phagocytosing blast cells in AML-M1, -M2, -M4 and -M5 was increased by GPRE. GPRE stimulated opsonin-dependent and -independent attachment and internalisation of N. meningitidis. GPRE increased the fraction of blasts expressing CD11b and CD32 in AML-M2 and -M5. GPRE diminished the fraction of AML-M5 cells bearing CD35 and CD32. GPRE also decreased the fraction of CD11c-bearing AML-M2 and -M5 cells. GM-CSF potentiated effects of GPRE in AML-M1, -M2, -M4 and -M5. GPRE and GM-CSF in combination affected phagocytosis and surface antigen expression in blast cells that were not influenced by either factor alone. Neither GPRE nor GM-CSF induced terminal differentiation or DNA-synthesis. We conclude that GPRE affects AML blast cell morphology, function and surface molecule expression, possibly by inhibiting apoptosis. The effects of GPRE may be mediated by ribosomal proteins that regulate translation and modulate the subcellular distribution of mRNA species.
Acute Disease↗
Expression, purification, and in vitro biological activities of recombinant bovine granulocyte-colony stimulating factor.
Neutrophils are essential components of the innate immune system and they play a critical role in the defense of host against bacterial and fungal infections. The colony stimulating factors are a class of glycoproteins that are required for proliferation, differentiation, and functional activation of hematopoietic progenitor cells. Granulocyte-colony stimulating factor (G-CSF) is a member of this regulatory family of cytokines that specifically stimulates proliferation and maturation of precursor cells in the bone marrow into fully differentiated and functional neutrophils. G-CSF also modulates the biological activities of mature neutrophils in circulation. A bovine G-CSF (bG-CSF) cDNA clone (previously isolated and sequenced in our laboratory) was expressed in Escherichia coli and the biological activities of the solubilized protein from purified inclusion bodies were examined. Flow cytometric analysis of membrane antigen density of neutrophils activated with bG-CSF revealed an upregulation in the expression of CD11a (>114%), CD11b (>148%), CD11c (>87%), and CD18 (>109%). Expression of L-selectin was decreased by more than 43%. There was no change, however, in the expression of CD14. These findings indicate that recombinant bG-CSF (rbG-CSF) expressed in E. coli is biologically active and exerts the same type of effects on neutrophils in vitro as those of human G-CSF (hG-CSF).
Animals↗
Modulating immune responses with dendritic cells: an attainable goal in veterinary medicine?
Dendritic cells (DCs) are antigen presenting cells that potently modulate immune responses with varying outcomes depending on the DC sub-population involved. To understand how DC sub-types arise, it is necessary to determine which factors influence their differentiation. At least three major sub-populations of DCs have been described in mice: CD4+/CD8- "myeloid" DCs, CD4-/CD8+ "lymphoid" DCs and Langerhans cell-derived DCs. Whilst somewhat comparable populations have been described in man, in most other species very little is known. The identification of cytokines which stimulate proliferation of DC precursors, and the observation that the cytokine environment influences the phenotype and the function of the DCs that subsequently develop, has provided a useful tool for evaluating these rare cells. We describe the influence of cytokines on the phenotype of DCs generated in the rat. Using bone marrow cells as the source of precursors we generated "myeloid-type" DCs from the adherent population using granulocyte-macrophage colony stimulating factor (GM-CSF), IL-4 and Flt-3L or "lymphoid-type" DCs from the non-adherent population using cytokines which included IL-7, IL-3, SCF and TNFalpha. In order to facilitate similar approaches to the study of equine DCs we have identified the nucleotide sequence encoding GM-CSF from the m-RNA of equine PBMC stimulated with Concanavalin A, amplified the cDNA by PCR and cloned it in eukaryotic and prokaryotic expression vectors. We report on the structure and function of this molecule.
Animals↗
Priming effect of met-enkephalin and beta-endorphin on chemiluminescence, chemotaxis and CD11b molecule expression on human neutrophils in vitro.
The opioid peptides are widely distributed throughout the body, and they are generated during stress and inflammatory reaction. Opioids are involved in the communication between the immune and neuroendocrine systems. In the present study we have investigated the ability of both met-enkephalin and beta-endorphin to stimulate and prime the human neutrophils for enhanced chemiluminescence (CL) and chemotaxis induced with fMLP, OZ or PMA. We have also tested the effect of beta-endorphin and met-enkephalin on CD11a, CD11b, CD18 and CD16 molecule expression on PMN in vitro. PMN from ten healthy donors were incubated in vitro with different concentrations of beta-endorphin or met-enkephalin, and the CL response was evaluated with luminometer. To assess the effect of opioid peptides on CD11a, CD11b, CD18 and CD16 molecule expression the whole blood samples were incubated with different concentrations of the opioids, then the white cells were labelled with respective PE-conjugated MoAb and evaluated by flow cytometry. We have shown that: (1) met-enkephalin and beta-endorphin at physiological concentrations relevant to that of in vivo (10(-8) and 10(-6) M) enhanced fMLP, PMA or OZ stimulated chemiluminescence and induced chemotactic response, (2) High concentrations of beta-endorphin (10(-3) M) or met-enkephalin (10(-5) M) decreased the CL response of PMN in vitro, (3) The opioid peptides at lower concentrations resulted in CD11b and CD18 molecule up-regulation on neutrophils. We may conclude that opioid peptides in physiological concentration are involved in neutrophil priming whereas in higher concentration exert immunosuppressive potency. Opioid peptides like inflammatory cytokines may prime the neutrophils inflammatory response.
Animals↗
Expression of authentic substance P receptors in murine and human dendritic cells.
Recent studies from our laboratory have shown that substance P can elicit transcription factor activation in dendritic cells. In the present study, we extend these findings by demonstrating the presence of authentic substance P (NK-1) receptors on both normal murine and human dendritic cells. Specifically, we demonstrate the presence of mRNA encoding NK-1 tachykinin receptors and have utilized specific antibodies to detect the expression of NK-1 receptor protein in dendritic cells by Western blot analysis and flow cytometry. These data provide a crucial first step in determining the potential of substance P to modulate dendritic cell function.
Amino Acid Sequence↗
Interferon-beta increases the stimulatory capacity of monocyte-derived dendritic cells to induce IL-13, IL-5 and IL-10 in autologous T-cells.
Dendritic cells (DCs) are key regulators of immune responses and have been associated with autoimmunity in animal models and human disease. The effects of interferon beta (IFN-beta), an immunomodulatory cytokine used in multiple sclerosis (MS) therapy, on DCs are not well understood. Monocyte-derived DCs at different stages of maturation were stimulated with IFN-beta and DC-phenotype and stimulatory function were measured. IFN-beta inhibited the development of DCs at early stages but enhanced DC maturation. Moreover, IFN-beta enhanced the capacity of DCs to stimulate autologous T-cells to secrete IL-13, IL-10 and IL-5. Thus, IFN-beta has both immunostimulatory and immunosuppressive effects on DCs depending on the stage of maturation.
Antigens, CD1↗
Dendritic cells and dendritic-like microglia in focal cortical ischemia of the mouse brain.
Intracerebral dendritic cells (DC) have recently been identified in neuroinflammation initiated peripherally by brain-targeted autoimmunity or infection. The present study detects DC in photochemically induced cortical ischemia of the mouse brain, a brain-intrinsic lesion model characterized by the lack of an overt T cell response. Concomitant to leukocyte infiltration of the infarcted area, cells expressing the pan-DC surface marker CD11c appeared at the lesion and persisted for weeks. These DC were located at the border zone of the infarct and remote from the lesion in degenerating corticothalamic fibre tracts and subcortical nuclei. All CD11c+ brain cells displayed a uniform CD11b+/CD8alpha-/CD205- surface phenotype, indicating a myeloid origin, and were immature DC based on their MHC class II+/CD40-/CD80+/CD86+/- profile. By expressing high levels of CD45, most DC from ischemic brain seemed to be blood-derived while a minority were CD45(low), thus corresponding to resident microglia. Consistently, round-shaped CD11c+ cells were found at the lesion whereas CD11c+ cells at subcortical sites were ramified like parenchymal microglia. These findings evidence a recruitment of myeloid DC to ischemic brain lesions and suggest that reactive microglia in remote areas transform into dendritic-like cells. Brain-infiltrating DC and their microglial counterparts may play a role in the inflammatory response to cerebral ischemia independently of T cells.
Animals↗
Mechanisms of recovery from experimental allergic encephalomyelitis induced with myelin basic protein peptide 68-86 in Lewis rats: a role for dendritic cells in inducing apoptosis of CD4+ T cells.
Spontaneous remission of experimental allergic encephalomyelitis (EAE) is usually associated with prominent apoptosis. The mechanisms behind apoptosis are unknown. We examined the functions of dendritic cells (DC) from Lewis rats with EAE induced by immunization with myelin basic protein peptide 68-86 (MBP68 - - 86). Recovery from EAE was associated with three major functional changes of freshly prepared DC: (1) elevated proliferation, (2) increased nitric oxide (NO) production, and (3) augmented IFN-gamma secretion. In Freund's complete adjuvant (FCA)-immunized control rats, no increase of proliferation, NO production or IFN-gamma secretion was observed on day 21 post-immunization (p.i.), i.e., recovery from EAE. In vitro effects of IFN-gamma, TNF-alpha, TGF-beta1, IL-4 and IL-10 on DC were examined. IFN-gamma enhanced proliferation and NO production by DC, while TNF-alpha and IL-4 induced only slight DC proliferation. DC from recovering EAE rats (day 21 p.i.) suppressed MBP68 - - 86-induced T cell proliferation compared to DC obtained at other time points in EAE and FCA-immunized rats. DC-derived NO induced apoptosis of CD4+ T cells, thereby inhibiting autoreactive T cell responses. Besides IFN-gamma stimulation, NO production by DC was mainly induced in an antigen-dependent manner when DC were co-cultured with T cells. The results suggest that spontaneous recovery from EAE is associated with augmented DC functions. Overproduction of NO by DC results in apoptosis of autoreactive CD4+ T cells, thereby decreasing autoreactive T cell reactivities. The existence of such a NO negative feedback loop may contribute to remission of EAE.
Animals↗
Regulation of expression of the LFA-1 and p150,95 leukocyte integrins: involvement of the CD11a and CD11c gene promoters.
Human Lymphocyte Associated Antigen-1 (LFA-1, CD11a/CD18, alpha L/beta 2) and p150,95 (CD11c/CD18, alpha X/beta 2) are cell surface alpha/beta heterodimers that, together with Mac-1 (CD11b/CD18, alpha M/beta 2) comprise the leukocyte-restricted beta 2 subfamily of integrins. LFA-1 is the only integrin expressed on all leukocyte lineages while p150,95 is exclusively expressed on cells of the myeloid lineage and on activated B lymphocytes and natural killer cells. The expression of the leukocyte integrins is regulated during cell activation and differentiation by transcriptional mechanisms. To dissect the molecular basis for the tissue-restricted and developmentally regulated expression of LFA-1 and p150,95, the promoter regions of their corresponding alpha subunits (CD11a and CD11c) were isolated and functionally characterized. Both promoters lack TATA and CAAT boxes, but exhibit initiator-like sequences at their major transcriptional start sites. Transient expression of CD11a- and CD11c-based reporter gene constructs have demonstrated the involvement of both promoters in the tissue-specific expression of LFA-1 and p150,95. Furthermore, a combination of DNAse I protection experiments and mobility band shift assays have revealed the existence of numerous DNA-protein interactions at the proximal region of both promoters, some of which overlap with consensus binding sequences for known transcription factors and correlate with the pattern of expression of both integrins.
Base Sequence↗
Expression of polymorphonuclear leukocyte adhesion molecules and its clinical significance in patients treated with percutaneous transluminal coronary angioplasty.
OBJECTIVES: This study evaluated the role of neutrophil adhesion molecules LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) and p150,95 (CD11c/CD18) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Several recent studies have suggested that cell adhesion molecules on both neutrophils and vascular endothelial cells play an important role in the process of tissue inflammation. METHODS: Thirty-eight patients (30 men, 8 women; mean [+/-SE] age 56 +/- 5 years, range 38 to 76) with single-vessel coronary artery disease of the left anterior descending artery underwent coronary angioplasty. Peripheral blood was sampled at baseline before, immediately after and 12, 24, 48 and 144 h after PTCA. The expression of CD18, CD11a, CD11b and CD11c on the surface of polymorphonuclear leukocytes was examined by flow cytometry with monoclonal antibodies. RESULTS: In patients without subsequent restenosis, there was no change in mean channel fluorescence intensity (MFI) of CD18 at each sampling time. However, in the patients with restenosis, the MFI of CD18 significantly increased at 48 h after PTCA (from 57 +/- 6 to 73 +/- 8, p = 0.0008). The MFI of CD11b increased slightly at 48 h after PTCA in patients without restenosis (from 584 +/- 121 to 735 +/- 114, p = 0.037). In patients with restenosis, the MFI of CD11b was slightly increased at 24 h after PTCA (from 586 +/- 122 to 768 +/- 214, p = 0.018) and significantly increased at 48 h after PTCA (to 1,534 +/- 268, p = 0.0006). The expression of CD11a and CD11c did not change at any sampling points after PTCA in either of the two patient groups. Percent change in the expression of CD18 at 48 h after PTCA (from baseline) and that of CD11b were correlated (r = 0.73, p = 0.0008) in patients with restenosis. CONCLUSIONS: Inflammatory stimuli within the coronary vessels associated with coronary angioplasty may upregulate Mac-1 expression on the surface of polymorphonuclear leukocytes. This process may be more marked in patients who experience later restenosis. Thus, activation of neutrophil adhesion molecule Mac-1 at 48 h after PTCA may have value as a predictor of subsequent restenosis.
Adult↗
In-vivo delivery of therapeutic proteins by genetically-modified cells: comparison of organoids and human serum albumin alginate-coated beads.
We have designed a self-assembling multimeric soluble CD4 molecule by inserting the C-terminal fragment of the alpha chain of human C4-binding protein (C4bp alpha) at the C-terminal end of human soluble CD4 genes. This CD4-C4bp alpha fusion protein (sMulti-CD4) and two other reference molecules, a fusion protein of human serum albumin (HSA) and the first two domains of CD4 (HSA-CD4) and monomeric soluble CD4 (sMono-CD4), were delivered in vivo by genetically modified 293 cells. These cells were implanted in mice as organoids and also encapsulated in HSA alginate-coated beads. sMulti-CD4 showed an apparent molecular weight of about 300-350 kDa, in accordance with a possible heptamer formula. sMulti-CD4 produced either in cell culture or in vivo in mice appeared to be a better invitro inhibitor of HIV infection than sMono-CD4. Plasma levels of sMulti-CD4, HSA-CD4, and sMono-CD4 reached approximately 2,300, 2,700, and 170 ng/mL, respectively, 13 weeks after in-vivo organoid implantation, which had formed tumours at that time. This suggests that the plasma half-life of sMulti-CD4 is much longer than that of sMono-CD4. The 293 xenogeneic cells encapsulated in HSA alginate-coated beads remained alive and kept secreting sMono-CD4 or HSA-CD4 continuously at significant levels for 18 weeks in nude mice, without tumour formation. When implanted in immunocompetent Balb/c mice, they were rejected two to three weeks after implantation. In contrast, encapsulated BL4 hybridoma cells remained alive and kept secreting BL4 anti-CD4 mAb for at least four weeks in Balb/c mice. These results suggest the clinical potential of the C4bp-multimerizing system, which could improve both the biological activity and the poor in-vivo pharmacokinetic performance of a monomeric functional protein like soluble CD4. These data also show that a systemic delivery of therapeutic proteins, including immunoglobulins, can be obtained by the in-vivo implantation of engineered allogeneic cells encapsulated in HSA alginate-coated beads.
Alginates↗
Migration of CD18-deficient neutrophils in vitro: evidence for a CD18-independent pathway induced by IL-8.
Neutrophils isolated from a child with severe leukocyte adhesion deficiency 1 (LAD1) had a complete absence of expression of the CD11/CD18 beta2 integrin family of adhesion molecules, and were shown to be deficient in the in vitro adhesion and migration properties. However, we found that interleukin-8 (IL8), a potent chemoattractant for neutrophils, and sputum sol phase induced these LAD1 neutrophils to migrate through an endothelial cell layer in vitro, and confirmed that this migration was CD18-independent. These findings add to evidence of CD18-independent mechanisms of neutrophil recruitment, in particular neutrophil infiltration into the lungs, where IL8 may be an important recruitment factor.
Antibodies↗
Directed differentiation of dendritic cells from mouse embryonic stem cells.
Dendritic cells (DCs) are uniquely capable of presenting antigen to naive T cells, either eliciting immunity [1] or ensuring self-tolerance [2]. This property identifies DCs as potential candidates for enhancing responses to foreign [3] and tumour antigens [4], and as targets for immune intervention in the treatment of autoimmunity and allograft rejection [1]. Realisation of their therapeutic potential would be greatly facilitated by a fuller understanding of the function of DC-specific genes, a goal that has frequently proven elusive because of the paucity of stable lines of DCs that retain their unique properties, and the inherent resistance of primary DCs to genetic modification. Protocols for the genetic manipulation of embryonic stem (ES) cells are, by contrast, well established [5], as is their capacity to differentiate into a wide variety of cell types in vitro, including many of hematopoietic origin [6]. Here, we report the establishment, from mouse ES cells, of long-term cultures of immature DCs that share many characteristics with macrophages, but acquire, upon maturation, the allostimulatory capacity and surface phenotype of classical DCs, including expression of CD11c, major histocompatibility complex (MHC) class II and co-stimulatory molecules. This novel source should prove valuable for the generation of primary, untransformed DCs in which candidate genes have been overexpressed or functionally ablated, while providing insights into the earliest stages of DC ontogeny.
Animals↗