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PubMed2001

Cytomegalovirus-specific cytolytic T-cell lines and clones generated against adenovirus-pp65-infected dendritic cells.

Cytomegalovirus (CMV) infection is a serious complication of allogeneic bone marrow transplantation (BMT). CMV disease can usually be prevented by passive immunization with donor-derived CMV-pp65-specific T-cell clones if provided early post-BMT. The classic method of generating CMV-specific T-cell clones requires donor-derived fibroblast lines infected with CMV as stimulators, thus limiting the availability of CMV immunotherapy to those patients for whom a donor skin biopsy can be obtained 6 to 8 weeks pretransplantation. To overcome this limitation we have used monocyte-derived dendritic cells (DCs) to induce donor anti-CMV cytotoxic T lymphocytes (CTLs). Matured, adeno-pp65-infected DCs were added at day 0 and at day 7 of a 2-week culture of donor peripheral blood mononuclear cells. DC-primed cultures were compared with cultures stimulated in an identical fashion with CMV-infected fibroblasts or with adeno-pp65-infected freshly isolated blood monocytes. Specific killing of CMV-infected fibroblasts was detected in all except the culture stimulated with pp65-infected monocytes. DCs infected after maturation elicited greater CTL activity than did DCs matured after infection. A series of 5 CD8+ clones from a fibroblast-stimulated culture and 7 CD8+ clones from a mature-DC-stimulated culture derived from a single HLA-A*0201+ individual were characterized. All 12 clones lysed autologous CMV-infected fibroblasts. All except 1 clone from the CMV-infected fibroblast arm (fibroblast arm) lysed vaccinia-pp65-infected B-lymphoblastoid cell lines (BLCLs); none lysed vaccinia-pp150-infected or noninfected BLCLs. Ten of 10 CD8+ clones tested were restricted by HLA-A*0201. Seven of the 12 clones were Vbeta6+ (2 from the fibroblast arm and 5 from the DC arm) with an identical Vbeta6.1-J1.4 sequence. Three clones from the fibroblast arm and 5 clones from the DC arm recognized the pp65 peptide NLVPMVATV (amino acids [aa], 495-503). These data show that CMV-specific T-cell clones with similar restriction patterns, T cell-receptor usage, and specificity can be generated using monocyte-derived pp65-infected-DC or CMV-infected-fibroblast stimulators. This approach should broaden the applicability of CMV-specific T-cell immunotherapy to a wider spectrum of patients by reducing the time required to generate CMV-specific T-cell clones.

Adenoviridae↗
PubMed1973

Leukocyte mean corpuscular volume in the differential diagnosis of acute leukemias.

The leukocyte mean corpuscular volume was measured in 61 cases of acute leukemia. The volume of blast cells allows a clear distinction between lymphoblastic and other varieties of acute leukemia. There seems to be good correlation between patients' age, leukocyte corpuscular volume, cytological and cytochemical findings. Furthermore, myeloblastic leukemias.Leukemic cells can be characterized by their volume, which is close to that of normal cells of the same line. This observation supports the clonal theory of their origin and concurs with the classical nomenclature which separates them into lymphoblastic, myeloblastic and monoblastic types.

Adolescent↗
PubMed2004

Primary immunodeficiency to pneumococcal infection due to a defect in Toll-like receptor signaling.

OBJECTIVE: The role of human Toll-like receptors (TLRs) in initiating protective immune responses in vivo is not well understood. We investigated the role of TLR signaling in defense against infection in a 3-year-old boy with a severe defect resulting in recurrent Streptococcus pneumoniae bacteremia. METHODS: After classic immunodeficiencies were ruled out, the patient's mononuclear cells, macrophages, and dendritic cells (DCs) were studied. TLR signaling responses to a range of TLR- and interleukin-1 receptor (IL-1R)-specific agonists were investigated pre- and posttranscriptionally by measuring NF-kappaB translocation and cytokine mRNA and protein expression. RESULTS: The patient's monocytic cells were profoundly deficient in cytokine production in response to a range of microbial-derived TLR agonists and to recombinant IL-1beta or IL-18. Lipopolysaccharide (LPS)-induced translocation of NF-kappaB p50 and p65 and the kinetics of LPS-induced cytokine mRNA transcription were normal except for IL-6 and IL-12p40, which were poorly transcribed. Despite deficient responses to TLR agonists by the patient's DCs and B cells, CD40L responses were normal. CONCLUSIONS: We describe a patient with deficient TLR-mediated cytokine production with intact interleukin receptor-associated kinase (IRAK)-4 expression, NF-kappaB translocation, and enhanced susceptibility to infection. This patient demonstrates that TLR signaling, in the presence of intact antibody responses, may be a nonredundant requirement for defense against pyogenic infections.

Bacteremia↗
PubMed1991

Demonstration of a 1,25-dihydroxyvitamin D3-responsive protein in human lymphocytes: immunologic crossreactivity and inverse regulation with the vitamin D receptor.

Using Western blot analysis with a monoclonal antibody recognizing a 17-amino acid epitope of the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]receptor, we have detected two crossreacting proteins in activated normal human lymphocytes. The smaller of the two proteins (50 kDa) was indistinguishable from the classical 1,25(OH)2D3 receptor and, similar to the classical 1,25(OH)2D3 receptor, was upregulated in a dose-dependent fashion by 1,25(OH)2D3. The larger crossreacting protein exhibited an electrophoretic mobility of 80 kDa, was localized in the cell cytosol, and appeared to be specific for activated lymphocytes since it was not detected in several other human cells including monocytes. More strikingly, the 80-kDa protein was downregulated in a dose-dependent fashion by 1,25(OH)2D3; this effect was independent of the mode of lymphocyte activation and specific for the 1,25(OH)2D3 metabolite of vitamin D3. However, two potent immunosuppressive agents, glucocorticoids and cyclosporin A, also inhibited the 80-kDa protein.

Blotting, Western↗
PubMed2001

Leukocyte receptor complex-encoded immunomodulatory receptors show differing specificity for alternative HLA-B27 structures.

We studied recognition of the disease-associated HLA-B27 allele by immunomodulatory receptors encoded within the leukocyte receptor complex. HLA class I are ligands for members of the killer Ig receptor (KIR) and Ig-like transcript (ILT)/LIR/LILR families (the new LILR nomenclature is described at www. gene.ucl.ac.uk/nomenclature/genefamily/lilr.html). Members of these families bound HLA-B27 in both classical and beta(2) microglobulin-independent forms. Classical complexes bound ILT2, ILT4, and LIR6 transfectants but not ILT1, ILT3, or ILT5. A free H chain form of HLA-B27 bound ILT4 and LIR6. Both forms of HLA-B27 bound KIR3DL1 transfectants. HLA-B27 free H chain bound CD14(+) cells in PBL from healthy controls, consistent with ILT4 expression on monocytes. Alternative recognition of different forms of HLA-B27 by KIR or ILT could influence their immunomodulatory function and may imply a role in inflammatory disease.

Antigens, CD↗
PubMed2007

Multiple NF-kappaB and IFN regulatory factor family transcription factors regulate CCL19 gene expression in human monocyte-derived dendritic cells.

CCL19 chemokine has a central role in dendritic cell (DC) biology regulating DC traffic and recruitment of naive T cells to the vicinity of activated DCs. In this study, we have analyzed the regulation of CCL19 gene expression in human monocyte-derived DCs. DCs infected with Salmonella enterica or Sendai virus produced CCL19 at late times of infection. The CCL19 promoter was identified as having two putative NF-kappaB binding sites and one IFN-stimulated response element (ISRE). Transcription factor binding experiments demonstrated that Salmonella or Sendai virus infection increased the binding of classical p50+p65 and alternative p52+RelB NF-kappaB proteins to both of the CCL19 promoter NF-kappaB elements. Interestingly, Salmonella or Sendai virus infection also increased the binding of multiple IFN regulatory factors (IRFs), STAT1, and STAT2, to the ISRE element. Enhanced binding of IRF1, IRF3, IRF7, and IRF9 to the CCL19 promoter ISRE site was detected in Salmonella or Sendai virus-infected cell extracts. The CCL19 promoter in a luciferase reporter construct was activated by the expression of NF-kappaB p50+p65 or p52+RelB dimers. IRF1, IRF3, and IRF7 proteins also activated CCL19 promoter in the presence of Sendai virus infection. CCL19 promoter constructs mutated at NF-kappaB and/or ISRE sites were only weakly activated. Ectopic expression of RIG-I (DeltaRIG-I, CARDIF) or TLR3/4 (TRIF, MyD88, IKKepsilon, or TBK1) signaling pathway components induced CCL19 promoter activity, suggesting that these pathways are important in CCL19 gene expression. Our experiments reveal that expression of the CCL19 gene is regulated by a combined action of several members of the NF-kappaB, IRF, and STAT family transcription factors.

Base Sequence↗
PubMed2004

Nodal and extranodal tumor-forming accumulation of plasmacytoid monocytes/interferon-producing cells associated with myeloid disorders.

Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders. Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-alpha (IFN-alpha) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified. Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.

Adult↗
PubMed1997

Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high density lipoprotein-mediated reverse cholesterol transport.

Cultured macrophages and endothelial cells have been reported to secrete 27-oxygenated metabolites of cholesterol. This mechanism was compared with the classical high density lipoprotein (HDL)-dependent reverse cholesterol transport. Under standard conditions, macrophage preparations had considerably higher capacity to secrete 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid than had endothelial cells and fibroblasts. Western blotting showed that lung macrophages contained the most sterol 27-hydroxylase protein of the cells tested. The relative amounts of 3beta-hydroxy-5-cholestenoic acid produced by the macrophages were also highest. Macrophages derived from monocytes of patients with sterol 27-hydroxylase deficiency did not secrete 27-oxygenated products, demonstrating that sterol 27-hydroxylase is the critical enzyme for the conversion of cholesterol into the 27-oxygenated steroids. That sterol 27-hydroxylase is responsible not only for 27-hydroxylation of cholesterol but also for the further oxidation of this steroid into 3beta-hydroxy-5-cholestenoic acid was shown with use of tritium-labeled 27-hydroxycholesterol and an inhibitor of sterol 27-hydroxylase. Secretion of 27-oxygenated products by the cultured macrophages as well as the ratio between the alcohol and the acid appeared to be dependent upon total 27-hydroxylase activity, the availability of substrate cholesterol, and the presence of an acceptor for 27-hydroxycholesterol in the medium. With albumin as extracellular acceptor, the major secreted product was 3beta-hydroxy-5-cholestenoic acid. Under such conditions, secretion of labeled 27-oxygenated products was higher than that of labeled cholesterol from lung alveolar macrophages preloaded with [4-14C]cholesterol. With HDL as acceptor, 27-hydroxycholesterol was the major secreted product, and the total secretion of labeled 27-oxygenated products was only about 10% of that of labeled cholesterol. Thus, 27-hydroxycholesterol and cholesterol may compete for HDL-mediated efflux from the cells. The results support the contention that the sterol 27-hydroxylase-mediated elimination of cholesterol is more important in macrophages than in endothelial cells. This mechanism may be an alternative and/or a complement to the classical HDL-mediated reverse cholesterol transport in macrophages, in particular when the concentration of HDL is low.

Albumins↗
PubMed1991

The enhanced cellular uptake of very-low-density lipoprotein enriched in apolipoprotein E.

We have recently reported an increased clearance of plasma very-low-density lipoprotein (VLDL) after intravenous injection of apolipoprotein (apo) E in Watanabe heritable hyperlipidemic (WHHL) rabbits. In the present study, we have investigated the cellular uptake of VLDL enriched in apo E (VLDL-E) which had been incubated with purified rabbit apo E. VLDL-E was taken up approx. 2-fold more than VLDL in human skin fibroblast, human monocyte-derived macrophage and Hep G2 cell and its degradation was least in macrophage. To characterize the binding of VLDL-E, we performed a binding assay using hepatic endosome isolated from estradiol-treated rats and we observed both increased EDTA-sensitive and -resistant binding of VLDL-E on endosome. Ligand blotting of hepatic endosome demonstrated two major bands of LDL receptor (130 and 260 kDa protein) and a minor band of LDL receptor-related protein (580 kDa protein) with a ligand of VLDL-E. These results suggested that VLDL-E was endocytosed in liver through a similar pathway among three cell types, and enrichment of apo E in VLDL enhanced the uptake of VLDL not only via an EDTA-sensitive binding site (classical LDL receptor) but also via other binding sites including an EDTA-resistant binding site and an LDL receptor-related protein.

Animals↗
PubMed2001

Highly efficient transduction of human monocyte-derived dendritic cells with subgroup B fiber-modified adenovirus vectors enhances transgene-encoded antigen presentation to cytotoxic T cells.

The efficiency of dendritic cells (DC) as immunotherapeutic vaccines critically depends on optimal delivery of target Ags. Although DC modified by subgroup C type 5 recombinant adenoviruses (rAd5) provide encouraging results, their clinical application is hampered by the need for high viral titers to achieve sufficient gene transfer, due to the lack of the Ad5 fiber receptor. We now demonstrate that rAd5 carrying subgroup B Ad fibers are up to 100-fold more potent than classical rAd5 for gene transfer and expression in human DC, rAd5 with a type 35 fiber (rAd5F35) being the most efficient vector. This improvement relates to a greater and faster virus entry and to an increased transgene expression especially following DC maturation. Furthermore, these new vectors possess enhanced synergistic effects with other activation signals to trigger DC maturation. Consequently, rAd5F35-infected DC engineered to express the gp100 melanoma-associated Ag largely exceed rAd5-infected DC in activating gp100-specific CTL. Finally, the DC infection pattern of rAd5F35 is fully conserved when DC are in the vicinity of primary skin-derived fibroblasts, suggesting this vector as a candidate for in vivo targeting of DC. Thus, subgroup B fiber-modified rAd5 constitute a major breakthrough in the exploitation of ex vivo rAd-targeted DC as clinically relevant vaccines and may also be suitable for in vivo genetic modification of DC.

Adenoviridae↗
PubMed1998

Prevalence of myeloperoxidase deficiency: population studies using Bayer-Technicon automated hematology.

The Bayer-Technicon hematological devices differentiate leukocytes by their peroxidase activity and their volume, displaying them as separate clusters. Peroxidase deficiencies are manifested by the irregular location of these clusters. This makes it possible to identify persons totally or partially lacking myeloperoxidase. The deficiency is quantified by the myeloperoxidase index, which is expressed for every routine analysis and for which normal values were determined. Values of the myeloperoxidase index confirm varying degrees of deficiency and prevalence. Family studies using these degrees show that the hereditary pattern must be more complicated than the classical autosomal-recessive mode. A bigenic mode is suggested. While about half of the totally deficient individuals detected were free of typical symptoms, in the other half we found infectious complications that were sometimes life-threatening. The hematological devices allow the identification of persons suffering from eosinoperoxidase deficiency and from MPO deficiency of the monocytes. The latter symptom seems to indicate immaturity of these cells and may lead to unexpected diagnosis of malignancy.

Female↗
PubMed1987

Reduced B-cell galactosyltransferase activity in rheumatoid arthritis.

Autosensitisation to IgG may be important in the pathogenesis of rheumatoid arthritis and could be related to reduced glycosylation of the oligosaccharides in the C gamma 2 region of serum IgG. The activity of galactosyltransferase, the enzyme that catalyses the addition of galactose to the oligosaccharide chains, was measured in the circulating B cells of seventeen patients with classic rheumatoid arthritis. It was significantly lower than that of a group of eleven controls (p less than 0.001) or of nine age-matched controls (p less than 0.001). In contrast, the enzyme activity of the T cells was within the range of that in nine age-matched controls, and enzyme activity in monocyte-rich mononuclear-cell populations was higher than in controls, possibly reflecting stimulation of the monocytes in rheumatoid arthritis. These findings suggest that galactosyltransferase may regulate the degree of glycosylation during IgG synthesis and could therefore be implicated in the rheumatoid inflammatory process.

Adult↗
PubMed1977

In vitro granulocyte adherence and in vivo margination: two associated complement-dependent functions. Studies based on the acute neutropenia of filtration leukophoresis.

To study mechanisms and mediators regulating the distribution of intravascular granulocytes between circulating and marginated pools, a human model with extreme transient margination, the neutropenia of continuous flow filtration leukophoresis, was analyzed. Studies in animals demonstrated the existence of a complement (C)-derived granulocytopenia-inducing factor. Thus, autologous plasma, exposed to nylon fibers (NF) of the filtration system, produced an acute selective decrement of circulating granulocytes and monocytes. This phenomenon was blocked by decomplementing plasma, by pretreatment of plasma with EDTA or hydrazine, and by preheating at 56 degrees C, but did occur after recombination of heat-inactivated and hydrazine-treated plasma before NF exposure. Preheating plasma at 50 degrees C did not inhibit the neutropenic response, suggesting involvement of the classical pathway of C activation. Ultrafiltration studies indicated that the NF-provoked neutropenia-inducing factor has a mol wt in the range of 10,000-30,000, and is heat stable (56 degrees C). To analyze the hypothesis that C- induced neutrophil margination might be consequent to increased cell adhesiveness to endothelial surfaces, the role of C in promoting granulocyte adherence was evaluated in vitro. Measured with a plastic Petridish assay, granulocyte adherence was significantly reduced in heat- inactivated (56 degrees C) and hydrazine-treated plasma, but adherence promoting capacity was restored by mixing the two plasmas, or by adding purified C3 to hydrazine-treated plasma. After exposure to activated C, neutrophils showed significantly increased adhesiveness which was maintained when cells were resuspended in heat-inactivated plasma, but progressively lost when resuspended in fresh plasma. On the basis of these results we conclude that granulocyte adhesiveness in vitro and margination in vivo are closely associated, C-dependent phenomena.

Agranulocytosis↗
PubMed1999

The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles.

Interleukin 1beta (IL-1beta), a secretory protein lacking a signal peptide, does not follow the classical endoplasmic reticulum-to-Golgi pathway of secretion. Here we provide the evidence for a "leaderless" secretory route that uses regulated exocytosis of preterminal endocytic vesicles to transport cytosolic IL-1beta out of the cell. Indeed, although most of the IL-1beta precursor (proIL-1beta) localizes in the cytosol of activated human monocytes, a fraction is contained within vesicles that cofractionate with late endosomes and early lysosomes on Percoll density gradients and display ultrastructural features and markers typical of these organelles. The observation of organelles positive for both IL-1beta and the endolysosomal hydrolase cathepsin D or for both IL-1beta and the lysosomal marker Lamp-1 further suggests that they belong to the preterminal endocytic compartment. In addition, similarly to lysosomal hydrolases, secretion of IL-1beta is induced by acidotropic drugs. Treatment of monocytes with the sulfonylurea glibenclamide inhibits both IL-1beta secretion and vesicular accumulation, suggesting that this drug prevents the translocation of proIL-1beta from the cytosol into the vesicles. A high concentration of extracellular ATP and hypotonic medium increase secretion of IL-1beta but deplete the vesicular proIL-1beta content, indicating that exocytosis of proIL-1beta-containing vesicles is regulated by ATP and osmotic conditions.

Adenosine Triphosphate↗
PubMed2003

Ca2+-independent protein kinase Cs mediate heterologous desensitization of leukocyte chemokine receptors by opioid receptors.

Heterologous desensitization of chemokine receptors by opioids has been considered to contribute to their immunosuppressive effects. Previous studies show that Met-enkephalin, an endogenous opioid, down-regulates chemotaxis of selected chemokine receptors via phosphorylation. In the present study, we further investigated the molecular mechanism of such cross-regulation. Our data showed that preincubation with Met-enkephalin inhibited both MIP-1 alpha-mediated chemotaxis and Ca(2+) flux of monocytes in a dose-dependent manner. The inhibitory effects were maximal using nanomolar concentrations of activating chemokines, a concentration found in physiological conditions. A decrease both in chemokine receptor affinity and in coupling efficiency between receptors and G protein were observed, which directly contributed to the desensitization effects. However, comparing with chemokines such as MIP-1 alpha and MCP-1, opioids did not elicit a calcium flux, failed to induce MIP-1 alpha receptors internalization, and mediated a less potent heterologous desensitization. We hypothesized that these differences might originate from the involvement of different protein kinase C (PKC) isotypes. In our studies, opioid-mediated down-regulation of MIP-1 alpha receptors could be blocked by the general PKC inhibitor calphostin C, but not by the calcium-dependent classic PKC inhibitor Go6976. Western blotting analysis and immunofluorescent staining further showed that only calcium-independent PKCs were activated upon opioid stimulation. Thus, opioids achieve desensitization of chemokine receptors via a unique pathway, involving only calcium-independent PKC isotypes.

Calcium↗
PubMed2000

Effect of interleukin-7 on the in vitro development and maturation of monocyte derived human dendritic cells.

We have compared the cell phenotype and functional properties of monocyte/macrophage derived dendritic cells (DCs) obtained by culture of human adherent peripheral blood mononuclear cells (PBMCs) in medium containing granulocyte macrophage colony stimulating factor (GM-CSF) either alone (GM-CSF-DCs), or in combination with interleukin (IL)-4 (IL4-DCs) or IL-7 (IL7-DCs). The cell surface phenotype of GM-CSF-DCs and IL-7-DCs was characterized by a high expression of major histocompatibility complex (MHC) class I and II, CD80, CD86 and CD40. In contrast to 'classical' IL-4-DCs, these two types of DCs expressed CD14 and a CD21-like molecule detected by two out of four CD21-specific monoclonal antibodies (MoAb) tested. The same pattern of reactivity with CD21 specific antibodies was observed in freshly isolated adherent PBMCs but not in B lymphocytes. This reactivity was upregulated by IL-7 in a dose dependent manner. Lipopolysaccharide (LPS) treatment induced the upregulation of CD40, CD80, CD86 and the T-cell stimulatory capacity in IL-4-DCs and, to a lesser extent, in the IL-7-DCs whereas GM-CSF-DCs responded very poorly to such treatment. Our data indicate that, together with GM-CSF, the IL-7 drives macrophage precursors to a differentiation stage that is close to but distinct from the phenotype of IL-4-DCs. Comparison of DC development in the presence of IL-7 or IL-4 may help in dissecting signalling pathways that regulate the expression of functionally relevant DC markers.

Antigens, CD↗
PubMed1997

In vitro and in vivo biocompatibility of substituted cellulose and synthetic membranes.

Regenerated cellulosic membranes are held as bioincompatible due to their high complement - and leukopenia - inducing properties. Adherence of polymorphonuclear neutrophils and monocyte purified from normal human blood to the three membranes were evaluated in an in vitro recirculation circuit in the presence or absence of fresh, autologous plasma after recirculation in an in vitro circuit using minimodules with each of the three membranes. In in vivo studies, 9 patients were treated with conventional haemodialysis for 2 weeks with each membrane and 1 week for wash-out using haemodialysers with the following surface: 1.95 m2 for benzyl-cellulose, 1.8 m2 for acetate-cellulose and low-flux polysulfone. Measurement of leukopenia, plasma C3a des Arg and elastase-alpha1 proteinase inhibitor complex levels as well as urea, creatinine, phosphate and uric acid clearances was performed. Plasma-free neutrophils adhered maximally to acetate-cellulose (65% remaining in the circulation), while there was no significant difference between low-flux polysulfone and benzyl-cellulose (80% circulating neutrophils, at 15 min, p<0.001 vs acetate cellulose). In the presence of fresh plasma, as source of complement, the differences between acetate cellulose vs polysulfone and benzyl-cellulose were even more evident, suggesting the role of complement-activated products in neutrophil adherence. A similar trend was observed for monocyte adherence with the three membranes in the absence or presence of plasma. In vivo studies showed that the nadir of leukopenia was at 15 and 30 min with acetate-cellulose (79%) and benzyl-cellulose (50%) (p<0.05 acetate- vs benzyl-cellulose) and at 15 min with polysulfone (24%) (p<0.01 vs acetate- and benzyl-cellulose). Plasma C3a des Arg levels arose to 2037 +/- 120 ng/ml, 1216 + 434 ng/ml and 46 +/- 55 ng/ml with acetate-, benzyl-cellulose and polysulfone, respectively. No pre- vs post-dialysis increase in the intracellular content of TNF-alpha was detected with any of three membranes. Clearance values of urea, creatinine and uric acid were superimposable for all the three membranes. However, benzyl cellulose had a significantly higher clearance for phosphorus (normalized for surface area) (p<0.01 vs acetate-cellulose, 0.001 vs polysulfone). These results implicate that synthetic modification of the cellulose polymer as for the benzyl-cellulose significantly reduces the in vitro adherence, delays the in vivo activation of "classic" biocompatibility parameters and notably improves the removal of inorganic phosphorus.

Aged↗