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Biomedical subjects

R A Koene

Publications and source records attributed to R A Koene.

At least 91 records · Page 5Linked to original sources
PubMed1993

Lack of albuminuria in the early heterologous phase of anti-GBM nephritis in beige mice.

Passive anti-glomerular basement membrane (GBM) nephritis in the mouse is accompanied by acute massive albuminuria in the early heterologous phase. As we have previously shown, this albuminuria does not occur in the beige mutant of the C57BL/6J strain which is deficient for the leukocytic neutral proteinases elastase and cathepsin G. To address the question whether an intrinsic defect in the polymorphonuclear granulocyte (PMN) or local factors in the beige kidney are responsible for the lack of albuminuria in the beige mouse strain, we conducted reciprocal bone marrow transplantations (BMT) in beige and congenic control mice. Injection of anti-GBM antibody resulted in only slight albuminuria (89 +/- 47 micrograms/18 hours; N = 6) in normal (that is, non-irradiated, non-reconstituted) beige mice. By contrast, in beige mice, reconstituted with bone marrow (BM) from control mice, acute albuminuria developed (3032 +/- 1408 micrograms/18 hours; N = 8), to a degree comparable to that in non-irradiated control mice (4411 +/- 3405 micrograms/18 hours; N = 6, P < 0.01). Albuminuria in control mice, reconstituted with beige BM, was in the range of the normal beige mice (112 +/- 55 micrograms/18 hours; N = 9). Reconstitution with syngeneic bone marrow demonstrated that BMT by itself did not influence the level of albuminuria. All mice showed similar morphological lesions, with comparable influx of PMN in the glomeruli two hours after antibody injection. Elastase activities of PMN extracts in BMT groups were not different from those in donor mice. We conclude that the absence of albuminuria in beige mice is caused by an intrinsic defect in leukocytic neutral proteinase activity.

Albuminuria↗
PubMed1993

Angiotensin converting enzyme inhibition does not prevent the natriuretic effect of felodipine.

The mechanism of natriuresis with calcium entry blockers such as felodipine is largely unexplained. As these drugs prevent sodium retention following exogenous angiotensin II, the natriuretic effect of felodipine might be due to a similar interaction with endogenous angiotensin II. In such a case, angiotensin converting enzyme inhibition with ramipril should prevent natriuresis with felodipine. We tested this hypothesis in a randomized, double-blind, crossover study in 12 male volunteers by comparing intravenous felodipine after 1 week of oral ramipril with felodipine after placebo and with solvent after ramipril. Ramipril pretreatment reduced ACE activity to 11 +/- 1%, lowered the blood pressure, and increased renal blood flow. However, ramipril pretreatment did not prevent the pronounced increase in natriuresis and diuresis with felodipine. Fractional sodium excretion only tended to increase less during felodipine after ramipril than during felodipine after placebo (absolute changes of + 1.2 +/- 0.2 and + 1.7 +/- 0.2%, respectively; p = 0.07). Ramipril did not influence the felodipine-mediated blood pressure reduction and renal vasodilation. In conclusion, ACE inhibition has no significant effect on the natriuretic and hemodynamic effects of felodipine, suggesting that mechanisms other than interaction with endogenous angiotensin II are involved in these effects of calcium entry blockers.

Adult↗
PubMed1993

Proteolysis increases the Fc-mediated binding of murine IgG2b to human EBV-transformed B cells, but decreases the expression of Fc gamma RII and Fc epsilon RII.

We have previously described a polymorphic human Fc receptor for murine IgG2b (mIgG2b). This receptor was defined by the binding of (complexed) mIgG2b to monocytes and Epstein-Barr virus (EBV)-transformed B cells. Three per cent of normal individuals were high responders with respect to mIgG2b (mIgG2b-HR), whereas the other individuals were low responders for mIgG2b (mIgG2b-LR). In the present study we investigated the effect of proteolytic enzymes on the Fc-mediated binding of mIgG2b to EBV-B cells. Pronase, human leucocyte elastase and cathepsin G caused an increased binding (in an EA-rosetting assay) of mIgG2b to EBV-B cells from mIgG2b-HR, but not from mIgG2b-LR. Simultaneous immunofluorescence studies demonstrated that these proteolytic enzymes strongly reduced the expression of Fc gamma RII and Fc epsilon RII on these cells, whereas HLA class I or HLA class II molecules were not affected. These findings strongly suggest that binding of mIgG2b is not mediated by Fc gamma RII or Fc epsilon RII. We also studied the effect of proteolysis on mIgG2b-HR EBV-B cells from an HLA class II-negative individual. In this case EA-mIgG2b rosetting was decreased after proteolysis, suggesting that HLA class II molecules may have a role in protecting the binding site for mIgG2b against proteolytic destruction.

Animals↗
PubMed1993

The human Fc receptor for mouse IgG2b on monocytes and EBV-B cells is functionally inhibited by anti-HLA class II antibodies.

We have recently described a polymorphic Fc receptor for murine IgG2b (mIgG2b), present on human monocytes and EBV-transformed B lymphocytes. The present study shows that anti-HLA class II monoclonal antibody (MoAb) completely inhibits both the (Fc receptor-dependent) T-cell proliferation, induced by mIgG2b anti-CD3 MoAb, and rosetting with mIgG2b-sensitized erythrocytes. This inhibition is also observed with F(ab')2 fragments of anti-HLA class II MoAb, and is therefore not Fc mediated. The Fc receptor for mIgG2b is also present on EBV-transformed B cells obtained from a patient with 'bare lymphocyte syndrome', that completely lack HLA class II antigens. Therefore, the Fc receptor for mIgG2b and HLA class II antigens are not identical. Since the low affinity receptor for IgE (Fc epsilon II; CD23) was reported to be associated at the cell surface with HLA class II antigens, we have compared both types of Fc receptor, and observed that human IgE strongly inhibits the mitogenic effect of murine IgE anti-CD3 but not of mIgG2b anti-CD3 MoAb. We conclude that the human Fc receptor for mIgG2b is strongly inhibited by anti-HLA class II MoAb, but is not identical to HLA class II or Fc epsilon RII.

Animals↗
PubMed1993

Endothelial cells promote anti-CD3-induced T-cell proliferation via cell-cell contact mediated by LFA-1 and CD2.

T-cell activation requires not only T-cell receptor (TCR) engagement and subsequent TCR/CD3 cross-linking, but also one or more secondary activation signals generated by accessory cells (AC). We investigated the accessory function of endothelial cells (EC) in an in vitro model for T-cell activation where the first cross-linking signal was delivered to peripheral human T lymphocytes by either immobilized anti-CD3 monoclonal antibody (MoAb) or by PHA. In a previous report, we showed that EC provided a potent costimulatory signal in this model system. We have now analysed the nature of the EC-derived costimulatory signal by testing whether EC could be substituted by cytokines, by studying the effect of EC fixation and by testing the involvement of a number of adhesion molecules. Our findings indicate that EC accessory function is mediated mainly by membrane-bound factors. The nature of these membrane-bound factors was analysed by studying the inhibitory properties of a series of MoAbs directed against several adhesion molecules. Antibodies directed against CD44, E-selectin, CD31, CD26, B7/BB1, VLA-4 or VCAM-1 were not inhibitory. However, an inhibition, was clearly observed with antibodies against LFA-1 and CD2. Remarkably, this inhibition was not found with MoAbs to their respective counterstructures ICAM-1 and LFA-3. In summary, we postulate that both LFA-1/ICAM-1, and CD2/LFA-3 interactions are involved in EC accessory function, although the role of the EC-associated adhesion partners is not fully understood.

Antibodies, Monoclonal↗
PubMed1993

Computer simulations in comparison with in vivo measurements of nifedipine-induced changes in renal allograft hemodynamics.

Analysis of Doppler spectrum waveforms is increasingly used in the differential diagnosis of human renal allograft dysfunction. The physiologic interpretation of changes in Doppler spectra obtained from renal allografts, however, remains a major problem. Computer simulation models of the renal circulation may provide insight into the physiologic mechanisms responsible for changes in Doppler spectrum characteristics. The results of measurements of renal allograft hemodynamics with both determinations of PAH clearance and Doppler spectrum analysis in 11 kidney allograft recipients were explained physiologically using a computer simulation model of kidney allograft hemodynamics. Using PAH clearance and blood pressure measurements a significant decrease in RVR was found (from 0.32 +/- 0.17 to 0.20 +/- 0.07 mm Hg x min/ml, P < 0.05) after administration of the vasodilatory drug nifedipine. The Doppler spectrum waveform obtained from interlobar renal arteries showed a decrease in the RI (from 0.60 +/- 0.04 to 0.56 +/- 0.06; P < 0.05) and Tmax (from 133 +/- 32 to 98 +/- 32 ms; P < 0.05). The user-designed simulation model of renal hemodynamics showed comparable changes of the waveform when, in the model, the analogs of blood pressure, impedance of the artery, and the impedance of the peripheral vascular bed were altered proportionally.

Administration, Oral↗
PubMed1993

Antigen-specificity of antibodies bound to glomeruli of mice with systemic lupus erythematosus-like syndromes.

BACKGROUND: MRL/l mice with diffuse proliferative glomerulonephritis, and graft-versus-host (GVH) mice with membranous glomerulonephritis, are both regarded as models for human systemic lupus erythematosus. In these two models, the specificity of the nephritogenic antibodies was analyzed. EXPERIMENTAL DESIGN: The nephritogenic antibodies were eluted from isolated glomeruli with an acid buffer. The antibodies were purified from these eluates on protein-A sepharose under high salt conditions to exclude the presence of antigens potentially bound to the antibodies. The specificities of the antibodies were analyzed towards components of the glomerular basement membrane (GBM), nuclear antigens and brush border of proximal epithelial cells in the indirect immunofluorescence (IF), enzyme linked immunosorbent assay, and Crithidia luciliae assay. Furthermore, we studied the glomerular binding by IF and immunoelectron microscopy after intravenous injection of the eluted antibodies into control mice. RESULTS: Glomerular eluates of both MRL/l and GVH mice showed nuclear staining and linear to homogeneous binding to GBM and tubular basement membrane in IF on normal mouse kidney. In enzyme linked immunosorbent assay, both eluates reacted not only with DNA, but also with histones and laminin, an important component of the GBM, however not with brush border. Reactivity with dsDNA was also found in the Crithidia luciliae assay for both eluates. In vivo binding was determined by injection of eluates into control MRL/n and F1 hybrid mice. The GVH eluate showed linear to homogeneous binding to the GBM 1.5 hour after injection which changed into a granular, membraneous pattern after 5 days, as determined by IF and immunoelectron microscopy. The MRL/l eluate also demonstrated linear to homogeneous binding to the GBM 1.5 hour after intravenous injection, that had decreased after 5 days, but did not change into a granular pattern. CONCLUSIONS: In these two models of systemic lupus erythematosus nephritis not only antibodies to DNA and histones, but also antibodies to laminin are involved in the induction of murine systemic lupus erythematosus nephritis. The latter antibody specificity has not been identified before in renal or glomerular eluates obtained from diseased MRL/l mice.

Animals↗
PubMed1993

Angiotensin-converting enzyme inhibition and the combination of a beta blocker and a diuretic are equally effective in lowering proteinuria in patients with glomerulonephritis.

In this study we compared the antihypertensive and antiproteinuric efficacies of an angiotensin-converting enzyme inhibitor and of conventional treatment consisting of a beta blocker and a diuretic in 13 patients with biopsy-proven glomerulonephritis and a proteinuria of more than 2 g/24 h. Ten of these 13 patients were normotensive. None had diabetes mellitus. In a randomized cross-over design with two treatment periods of 6 weeks, each preceded by a washout period of 4 weeks, patients were treated with benazepril (20 mg o.d.) and the combination of metoprolol (200 mg o.d.) and chlorthalidone (25 mg o.d.). At the end of the treatment periods with benazepril or metoprolol/chlorthalidone mean arterial pressure was lowered to a similar degree by 7.4 (mean, 95% confidence interval 2.0-12.7) and 9.7 (5.7-13.7) mmHg respectively. Both treatment modalities caused similar reductions in proteinuria, being 3.4 g/24 h (mean, 95% confidence interval 2.1-4.8) on benazepril and 3.2 (1.2-5.1) g/24 h on metoprolol/chlorthalidone. Glomerular filtration rate and renal plasma flow were slightly less during metoprolol/chlorthalidone treatment. Subgroup analysis of normotensive patients gave similar results. In conclusion, in these patients with glomerular disease angiotensin-converting enzyme inhibition was not more effective than the conventional treatment with the combination of a beta blocker and a diuretic in reducing blood pressure and proteinuria. Both treatments reduced proteinuria not only in hypertensive, but also in normotensive patients.

Adult↗
PubMed1993

Erythropoietin: mechanisms of action and indications for treatment.

We review data concerning site and regulation of erythropoietin (EPO) production, its effects on target tissue, routes of administration and clinical applications. In the anaemia of chronic renal failure (ACRF) treatment with recombinant human erythropoietin (r-Hu-EPO) has been shown to be effective in both improvement of the anaemia and increase in quality of life. In the anaemia of chronic disease (ACD), associated with various malignant, infectious and inflammatory disorders, many investigators have demonstrated an inappropriately low EPO response to anaemia. Therapeutic trials in patients with ACD mostly lacked sufficient numbers of patients for evaluation of the effects. The results obtained from some studies in AIDS and rheumatoid arthritis and the effect on the number of units of autologous blood obtained from patients planned for elective surgery are encouraging, however. Adverse reactions of r-Hu-EPO treatment are mainly confined to the ACRF population and include hypertension, shunt thrombosis and pain at the injection site. The exact mechanism of action of EPO is not yet fully understood. Large scale clinical trials are required to establish its effects on both the anaemia and quality of life in anaemias other than ACRF.

Anemia↗
PubMed1992

Removal of monocytes from cell suspensions with anti-CD14 antibody and carbonyl-iron, using Fc gamma R-dependent accessory function as a sensitive measure of monocyte presence.

Human (Fc gamma RI-positive) monocytes are required as accessory cells when T cell proliferation is induced by murine IgG2a anti-CD3 monoclonal antibodies (mAbs). This T cell proliferation assay provides a sensitive method for detecting the presence of monocytes (less than 1% of monocytes can be detected), and we have used it to monitor the effectiveness of different procedures for the removal of monocytes from peripheral blood mononuclear cells. Counterflow centrifugation, phagocytosis of carbonyl-iron, adherence to plastic, monocyte depletion with magnetic beads (Dynabeads M450), and panning with anti-CD14 antibodies each strongly reduced the number of monocytes. However, none of these methods, when used on their own, were capable of completely abolishing the mitogenic response to murine IgG2a anti-CD3 mAb. A virtually complete depletion of monocytes was obtained when the panning procedure using anti-CD14 antibodies was combined with phagocytosis of carbonyl-iron. Importantly, this method could also be used with cryopreserved cells. We have applied this improved method for the removal of monocytes, to study T cell proliferation induced by murine IgG2b anti-CD3 mAb. We were able to demonstrate with this model that cells other than monocytes were able to provide accessory function.

Antigen-Presenting Cells↗
PubMed1992

A nephritogenic rat monoclonal antibody to mouse aminopeptidase A. Induction of massive albuminuria after a single intravenous injection.

Antibodies directed against antigens present on renal epithelial cells can cause membranous glomerulonephritis in experimental animals, which closely resembles the human form of this disease. However, most antibodies produced so far fail to cause the persistent and severe proteinuria that is seen in humans. In our search for new antibodies of this kind, we have now produced a monoclonal antibody (mAb) against mouse aminopeptidase A, a hydrolase that is present in the mouse kidney. The mAb (ASD-4) was prepared by fusion of mouse myeloma cells with splenocytes of Lou rats immunized with brush border (BB) membranes from mouse kidneys. ASD-4 is of the IgG1 subclass and reacts with a 140-kD protein as demonstrated by immunoprecipitation on radiolabeled BB membranes. In indirect immunofluorescence and immunoelectronmicroscopy of normal mouse kidneys, ASD-4 was diffusely present on the BB of the S1 and S2 segments of the proximal tubules, and on the cell membranes of the glomerular visceral epithelia. It also bound to cell membranes of nonglomerular endothelia, smooth muscle cells of arteries, and juxtaglomerular cells. After injection of ASD-4 into normal mice, an immediate homogeneous binding to the capillary wall was seen that gradually changed into a fine granular pattern after 1 d. This glomerular binding was followed by binding to the BB and basolateral membranes of the convoluted proximal tubules. Immediately after injection of ASD-4, a dose-dependent albuminuria occurred that lasted for at least 16 d. ASD-4 is thus a new rat mAb against a well-defined renal epithelial antigen that causes not only membranous glomerulonephritis after a single injection in the mouse, but also severe albuminuria.

Albuminuria↗
PubMed1992

Post-transplant haemoglobin levels and host kidney status.

Erythrocytosis after renal transplantation has been ascribed to inappropriate production of erythropoietin by the recipient's native kidneys. In a retrospective analysis we examined the effect of pre-transplant bilateral nephrectomy on post-transplant haemoglobin level (Hb) and haematocrit (Ht) in 370 renal transplant patients. Hb and Ht were significantly higher in the 341 patients with host kidneys in situ compared with the 29 patients who had undergone bilateral nephrectomy (Hb, 8.5 +/- 1.2 mmol/l vs 7.8 +/- 1.3 mmol/l, P = 0.005; Ht, 41 +/- 6% vs 38 +/- 7%, P = 0.02). Moreover, a very high Hb and/or Ht (defined as a value above the 80th percentile of the whole group) occurred more frequently in patients with host kidneys in situ (20.5% vs 3.5%, P = 0.02). It thus appears that host kidneys significantly contribute to the unexpectedly high haemoglobin levels occurring after renal transplantation.

Adult↗