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Biomedical subjects

P H Plotz

Publications and source records attributed to P H Plotz.

At least 91 records · Page 5Linked to original sources
PubMed1983

Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up.

From 1969 to 1975, 53 patients with lupus nephritis took part in randomized trials comparing prednisone, oral azathioprine plus low-dose prednisone, and oral cyclophosphamide plus low-dose prednisone. After a mean follow-up of 85 months, cyclophosphamide appears marginally superior to prednisone for maintaining renal function (p = 0.03) and preventing end-stage renal failure (p = 0.07). Chronic change shown by renal biopsy assessed by a chronicity index was found useful in predicting renal function outcomes and response to immunosuppressive therapy. Three of 21 patients with a low chronicity index and 9 of 10 patients with a high chronicity index doubled their serum creatinine (p less than 0.00003). The probability of renal functional deterioration was not different among the treatments studied. However, in 14 patients with an intermediate chronicity index, 1 of 11 patients treated with azathioprine or cyclophosphamide doubled the serum creatinine level whereas all 3 patients treated with prednisone have progressed to end-stage renal failure (p = 0.005). The study suggests that single-drug oral immunosuppressive treatment combined with prednisone is most beneficial in lupus patients with intermediate chronic change shown by renal biopsy.

Administration, Oral↗
PubMed1983

Reticuloendothelial system fc receptor function in rheumatoid arthritis.

Patients with systemic lupus erythematosus (SLE) have abnormal reticuloendothelial system (RES) IgG Fc receptor function which is correlated with disease activity and levels of immune complexes (IC). We studied RES function, IC levels, clinical and laboratory manifestations in 43 patients with RA. The articular index was abnormal in 42 patients (range of 6 to 153). Thirty were seropositive; 31 had an elevated erythrocyte sedimentation rate. Extraarticular manifestations included nodules (25), anemia (19), Sjögren's syndrome (6), vasculitis (4), and Felty's syndrome (2). Medication included corticosteroids (32), nonsteroidal antiinflammatory drugs (33), slow acting antirheumatic drugs (18), and cytotoxics (2). Thirty-three patients had IC (30 by the Clq binding assay, 21 by the Raji cell assay); 13 patients had normal RES function (t 1/2-24-60 min; upper 95% confidence limit in normals = 62 min). Thirty had prolonged clearance times (65-210 min, mean 106 min). In contrast to SLE, clearance times were not found to be correlated with IC levels, or clinical or laboratory measures of disease activity. Defective RES immune clearance may not be an important determinant in the pathogenesis of immunologic tissue damage in rheumatoid arthritis.

Adult↗
PubMed1983

Bacterial endocarditis complicating systemic lupus erythematosus.

Culture proven bacterial endocarditis occurred in 6 of 571 patients with systemic lupus erythematosus (SLE) admitted to the National Institutes of Health (NIH). Although 4 of the patients had a murmur noted on examination prior to developing endocarditis, only one of the 6 had a recognized valvular abnormality. Bacterial endocarditis followed dental procedures in 2 of the 6 patients; no precipitating events were recorded in the remaining 4. M-mode and 2-D echocardiography of 20 unselected SLE patients did not reveal previously unrecognized cardiac disease. There was an unexpectedly high frequency of bacterial endocarditis among SLE patients relative to all other connective tissue disease patients seen at the NIH.

Adult↗
PubMed1982

Stable, soluble, model immune complexes made with a versatile multivalent affinity-labeling antigen.

We describe here the synthesis of a family of multivalent affinity-labeling antigens based on the soluble carbohydrate polymer Ficoll. Ficoll was derivatized successively with chloroacetate, ethylenediamine, and glutaric anhydride and finally esterified with 2,4-dinitrophenol. Prior to esterification, the polymer could also be derivatized with tyramine to allow trace iodination and with the monosaccharides galactose or mannose. The numbers of substituent groups could be controlled at several points in the synthesis. The resulting multiple dinitrophenyl esters on a Ficoll or glycosylated Ficoll polymer specifically cross-linked anti-dinitrophenyl antibodies to form covalently cross-linked antigen-antibody complexes. The glycosylated Ficolls were particularly made for studies of the influence of antigen structure on the behavior of immune complexes. The intermediates in the synthesis are suitable for other derivatizations as well. These model immune complexes are stable and soluble, they can be separated by size, and they overcome some of the limitations on the study of complexes imposed by previous techniques of preparing them.

Affinity Labels↗
PubMed1982

A serial study of splenic reticuloendothelial system Fc receptor functional activity in systemic lupus erythematosus.

A serial study of reticuloendothelial system splenic Fc receptor function was undertaken in 13 patients with systemic lupus erythematosus (SLE). Fc receptor function was assessed by measuring the clearance half times of IgG-sensitized 51Cr-labeled autologous erythrocytes from the circulation. Prolonged clearance half times were initially detected in all patients, and the magnitude of the clearance defect was significantly correlated with disease activity (P less than 0.01, Spearman rank correlation) and immune complex levels (P less than 0.01). Clinical course and changes in receptor functional activity over time were found to be significantly correlated. Clearance half-times tended to return to normal in all 11 patients who clinically improved. The clearance half-time remained unchanged in 1 patient whose disease activity was stable, and it worsened in 1 patient whose illness flared. Levels of immune complexes also changed concordantly with clearance half-times and disease activity. These studies underscore the interrelationship between the presence of circulating immune complexes, defects in Fc receptor function that might lead to prolonged circulation of these complexes, and disease activity in SLE.

Adult↗
PubMed1982

Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis.

Forty-one patients with systemic lupus erythematosus and glomerulonephritis were studied in a randomized drug trial. Thirteen patients received prednisone only (Group 1), 16 received oral cyclophosphamide and oral azathioprine (1 mg/kg body weight . d of each initially) (Group 2), and 12 were given boluses of intravenous cyclophosphamide (0.5 to 1.0 g/m2 body surface area every 3 months) (Group 3). The mean observation period was 42 months (range 1 to 6.5 years). Renal function deteriorated in four of 12 patients in Group 1 and three of 27 patients in Groups 2 and 3 (p = 0.114). By life-table analysis, 86% of the entire group survived 5 years after entry to the study. Marked hypertension, fluctuating changes in serum creatinine, erratic changes in levels of antibody to DNA, reduced C3 levels, increasing proteinuria or sustained hematuria, and flares of extrarenal disease activity occurred more commonly in Group 1. Infectious complications were not commoner in Groups 2 and 3. We conclude that any marginal benefits produced by the programs tested cannot be shown in this class of patients without markedly increasing the sample size. Our current studies involve more vigorous treatment of patients with more acute disease and less treatment during prolonged periods of relatively good health.

Administration, Oral↗
PubMed1981

Acute effects of aspirin and acetaminophen on renal function.

The renal effects of aspirin and acetaminophen are minor. With a major overdose of acetaminophen, uncommonly renal failure may occur that cannot be ascribed to hepatic failure; its mechanism is unknown. Aspirin may cause a transient shedding of renal tubular cells, alterations in urate excretion, inhibition of spironolactone action, and, in certain clinical settings, a reversible decline in renal function manifested as a fall in glomerular filtration that may be accompanied by mild water, sodium, and potassium retention. Active systemic lupus erythematosus, advanced cirrhosis, and chronic renal insufficiency seem to predispose patients to the effects on renal function, and there is direct or indirect evidence in those conditions that prostaglandin synthesis is an important part of the body's attempt to preserve renal blood flow. Study of these effects has provided new insight into the way in which the kidneys may use prostaglandins to preserve renal function when it is threatened.

Acetaminophen↗
PubMed1981

Influence of antigen on immune complex behavior in mice.

To explore the possibility that the behavior of immune complexes can, under some circumstances, be directed by the antigen, we have studied the behavior of complexes of identical size made with the glycoproteins, orosomucoid (OR), and ceruloplasmin: or with their desialylated derivatives, asialo-orosomucoid (ASOR) and asialo-ceruloplasmin. Such desialylated proteins are rapidly removed from the circulation by a hepatic cell receptor for galactose, the sugar exposed upon removal of sialic acid. Mixtures of 125I-goat anti-ASOR with either ASOR or OR and mixtures of 125I-rabbit anti-OR with either ASOR or OR form complexes identically. The complexes were separated by density gradient centrifugation and injected intravenously into C3H mice. Blood clearance and hepatic uptake of the OR complexes and ASOR complexes were markedly different. T 1/2 for the goat OR complexes exceeded 300 min, whereas that for the ASOR complexes was 15 min. More detailed studies using rabbit complexes of various sizes revealed that light rabbit complexes behaved similarly to the goat complexes. The light rabbit OR complexes were cleared slowly, with only 18% found in the liver at 60 min, whereas the light rabbit ASOR complexes were cleared much more rapidly, with 62% found within the liver by 30 min. This rapid clearance was completely suppressed by a prior injection of a blocking dose of ASOR, which implies uptake by a galactose-mediated mechanism on hepatocytes. As the size of the rabbit complexes increased, so did the rate of Fc receptor-mediated clearance. Heavy rabbit OR complexes were cleared more rapidly than light OR complexes but not so rapidly as heavy ASOR complexes. The clearance and hepatic uptake of the heavy OR complexes were markedly suppressed by a prior injection of heat-aggregated gamma globulin, a known Fc receptor-blocking agent (45% hepatic uptake without and 6% with aggregated gamma globulin). The heavy rabbit ASOR complexes exhibited inhibition of blood clearance and hepatic uptake by both galactose receptor-blocking and Fc receptor-blocking agents. A blocking dose of ASOR reduced the hepatic uptake at 30 min from 75 to 49%, and heat-aggregated gamma globulin reduced it from 75 to 39%, which suggests that these heavy complexes were removed from the circulation by receptors both for the immunoglobulin and for the antigen. Cell separation studies and autoradiographs confirmed that those complexes cleared primarily by galactose-mediated mechanism were within hepatocytes, and those cleared by Fc receptors were within the nonparenchymal cells of the liver. It seems probable, therefore, the some antigen-antibody complexes may be removed from the circulation via receptors not only for immunoglobulin but also for antigen.

Animals↗
PubMed1981

An abnormality of immune complex kinetics in murine lupus.

In order to understand better the role of immune complex metabolism in the pathogenesis of autoimmune diseases, we have investigated the early stages of immune complex uptake by the liver, the major organ responsible for clearance of soluble complexes in the mouse. Livers were perfused in situ via the portal vein over 3 to 5 min with trace amounts of radiolabeled soluble model immune complexes. In 4 nonautoimmune strains (BALB/c, DBA/2, CAF1, NZW) 60 to 72% of the model complexes perfused were taken up and remained in the liver after 20 min of continuous perfusion with oxygenated Krebs-Henseleit buffer. In NZB and NZB/W F1 female mice at ages 0.5 to 11 mo, 66 to 78% of the model complexes remined in the liver. However, when a dose of heat-aggregated human gamma-globulin sufficient to saturate the reticuloendothelial system was perfused 7 min after radiolabeled complexes, 15.2 +/- 7.2% (mean +/- SD) of the complexes were displaced in the nonautoimmune strains. In contrast, 32.6 +/- 10.5% of the complexes were displaced from the liver in NZB and NZB/W F1 female mice (p < 0.001). Thus, although hepatic uptake of immune complexes in autoimmune mice appears to be normal or even enhanced, there may be impaired phagocytosis by the hepatic RES or weaker binding of complexes to the surface of the Kupffer cells. Such surface-bound immune complexes remaining accessible to the circulation may contribute to the autoimmune process.

Aging↗
PubMed1980

The specificity of uptake of model immune complexes and other protein aggregates by the murine reticuloendothelial system.

We have studied the selectivity of the murine reticuloendothelial system in recognizing and removing from the blood model immune complexes and several aggregated proteins. Although both IgG anti-DNP model immune complexes and micro-aggregated albumin exhibited rapid hepatic uptake, which is saturable, they did not cross-inhibit each other. Aggregates of ovalbumin, a glycoprotein rich in mannose (a sugar recognized by Kupffer cells), had no effect on the uptake by the liver of either IgG immune complexes or micro-aggregated albumin. The finding that transferrin aggregates were not taken up by the liver at all suggests that aggregation alone is not sufficient to overcome the lack of a specific hepatic receptor for that protein. Thus, several mechanisms exist whereby aggregated proteins can be cleared from the blood by the reticuloendothelial system, an observation consistent with the selective failure of reticuloendothelial function found in several human diseases.

Animals↗
PubMed1979

Complement fixation by model immune complexes free in solution and bound onto cell surfaces.

Immunoglobin (IgG) molecules with anti-2,4-dinitrophenyl activity were covalently cross-linked by using three cross-linking reagents. The resulting oligomers were separated into monomer, dimer, trimer, and heavy fractions. These stable assemblages of IgG molecules were capable of fixing dilute whole guinea pig complement in solution. When oligomers were further aggregated noncovalently into larger complexes, all were able to fix complement. Radioiodinated oligomers were attached to 2,4,6,-trinitrophenylsulfonic acid treated sheep red blood cells (N3ph-SRBC), and the number of bound molecules was determined from the cell-associated radioactivity. Complement-mediated lysis of N3ph-SRBC was then assayed over a range of levels of bound protein and at increasing concentrations of complement. The lytic efficiencies of all oligomers increased with the number of bound molecules, with complement concentration, with hapten density on N3ph-SRBC, and with oligomer size. The results suggest that two adjacent IgG molecules may not serve as a unit signal for triggering the complement cascade, but instead, initiation occurs with increasing efficiency as the size of cell-bound IgG clusters increases.

Animals↗
PubMed1979

Defective reticuloendothelial system Fc-receptor function in systemic lupus erythematosus.

To determine whether reticuloendothelial-system immunospecific Fc-receptor function is abnormal in patients with systemic lupus erythematosus, we studied the clearance of IgG-sensitized 51Cr-labeled erythrocytes by these splenic macrophage membrane receptors in 15 untreated patients. Fc-specific clearance rates were strikingly abnormal in 13 of 15 patients (half-times ranging from 80 to 2256 minutes, P less than 0.001 as compared to controls). Abnormal clearances correlated with immune-complex levels (as measured by the C1q-binding assay) and with disease activity. C1q-binding activity and anti-DNA titers also correlated with disease activity. The correlations of C3, C4, CH50 and factor B with abnormal clearance and disease activity were weaker or nonexistent. The significant correlations among clearance, disease activity and C1q-binding activity suggest that the defect in Fc-receptor function may lead to the prolonged circulation of immune complexes, thereby contributing to tissue deposition and damage.

Adult↗