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Biomedical subjects

J B Klein

Publications and source records attributed to J B Klein.

At least 55 records · Page 3Linked to original sources
PubMed1993

Immunologic renal injury.

This review summarizes recent progress in the immunologic aspects of parenchymal renal disease. Progress in understanding basic immune mechanisms of glomerular injury is outlined, including the roles of chemoattractants, adhesion molecules, metalloproteinases, and cytokines. Current basic and clinical studies of focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, minimal-change nephropathy, and IgA nephropathy are summarized. Finally, research in glomerular involvement in systemic disorders, such as lupus nephritis, antineutrophil cytoplasmic antibody-associated syndromes, and human immunodeficiency virus-associated nephropathy, is reviewed.

Humans↗
PubMed1992

IFN-gamma enhances expression of formyl peptide receptors and guanine nucleotide-binding proteins by HL-60 granulocytes.

Exposure to IFN-gamma increases the respiratory burst of polymorphonuclear leukocytes stimulated by the chemoattractant FMLP. However, the mechanism by which IFN-gamma alters the response to FMLP is unclear. We addressed the hypothesis that IFN-gamma enhances the response to FMLP by regulating the expression of elements of the formyl peptide receptor transmembrane-signaling pathway. HL-60 granulocytes were used as a model of FMLP transmembrane signaling. Formyl peptide receptor number and affinity were studied in isolated plasma membranes prepared from control HL-60 cells (CM) and cells exposed to IFN-gamma 100 U/ml for 24 h (IFN-M). Formyl peptide receptors were significantly increased on IFN-M compared with CM (1473 +/- 300 vs 3209 +/- 924). FMLP stimulates increased guanine nucleotide-binding protein (G protein) activation in IFN-M as evidenced by enhanced guanosine 5'-[gamma-thio]triphosphate binding and GTPase activity. Gi sub-unit content was increased in IFN-M as measured by pertussis toxin-catalyzed ADP-ribosylation and immunoblotting with antibodies against alpha i2 and alpha i3 G protein subunits. Guanosine 5'-[gamma-thio]triphosphate equilibrium binding demonstrated an increased number of G proteins coupled to formyl peptide receptors on IFN-M. We conclude that IFN-gamma increases expression of both formyl peptide receptors and G proteins coupled to these receptors, thereby enhancing FMLP-stimulated transmembrane signaling. Regulation of transmembrane signaling element expression may be a significant mechanism by which IFN-gamma regulates cellular functions.

Cell Differentiation↗
PubMed1992

Interferon-gamma induces phosphorylation of multiple small-molecular-weight proteins in U937 cells.

This study examines the hypothesis that interferon-gamma (IFN-gamma) induces protein phosphorylation as part of the signal transduction pathway used to activate U937 cells. U937 cells labeled with 32Pi were treated with IFN-gamma, proteins were separated by two-dimensional polyacrylamide gel electrophoresis, and the pattern of protein phosphorylation was determined by autoradiography and computer-assisted two-dimensional densitometry. IFN-gamma (100 U/ml) induced phosphorylation of multiple proteins between 15 and 60 min, and the proteins were all dephosphorylated by 120 min. The pattern of proteins phosphorylated in the presence of ionomycin or PMA differed from that of IFN-gamma. Inhibition of protein kinase C activity by 1-(5-isoquinolinesulfonyl)2-methyl piperazine (H-7), inhibition of calcium-calmodulin-dependent protein kinase by N-(6-aminohexyl)-5-chloro-naphthalenesulfonamide (W-7), and inhibition of calcium redistribution by 8-(diethylamino)-octyl 3,4,5-trimethoxybenzoate hydrochloride (TMB-8) did not inhibit the majority of IFN-gamma-induced protein phosphorylation. These data indicate that IFN-gamma induces protein phosphorylation in U937 cells by activation of a kinase different from, or in addition to, protein kinase C or calcium-calmodulin-dependent kinase.

Blood Proteins↗
PubMed1991

Modulation of transmembrane signalling in HL-60 granulocytes by tumour necrosis factor-alpha.

Differentiated HL-60 granulocytes were used to study the mechanism by which tumour necrosis factor-alpha (TNF) enhances responses to N-formyl-methionyl-leucylphenylalanine (FMLP). Cultivation of differentiated HL-60 cells with 100 units of TNF/ml for 24 h resulted in a 3-fold increase in superoxide release and 4-fold increase in prostaglandin E2 production on stimulation with 1 microM-FMLP. On the other hand, cultivation with TNF failed to increase phorbol diester stimulation of superoxide release. Formyl-peptide-receptor expression determined on isolated membranes from cells cultivated with TNF (TNF-M) was increased by 50% compared with membranes from control cells (NM). Similarly, FMLP binding to intact HL-60 cells was increased by cultivation with TNF. Guanine-nucleotide-binding proteins (G-protein) levels were not different between TNF-M and NM, as determined by pertussis-toxin-catalysed ADP-ribosylation and by immunoblotting with antisera recognizing alpha i2 subunit. Binding of guanosine 5'-[gamma-thio]triphosphate and GTP hydrolysis stimulated by FMLP were enhanced by about 50% in TNF-M. The efficiency of G-protein activation by formyl-peptide receptors did not differ between TNF-M and NM. TNF regulates expression of formyl-peptide receptors independently of G-protein levels. The regulation of receptor expression is one mechanism by which TNF enhances cell responses to formylated peptides.

Adenosine Diphosphate Ribose↗
PubMed1991

Interferon-gamma enhances superoxide production by HL-60 cells stimulated with multiple agonists.

The production of superoxide anion (O2-) by phagocytic cells plays an important role in host defenses and inflammatory processes. Interferon-gamma (IFN-gamma) primes neutrophils for increased O2- release stimulated by various agonists. This study examines if myeloid differentiated HL-60 cells also serve as a model for IFN-gamma-induced priming, and examines mechanism by which this priming occurs. IFN-gamma enhanced HL-60 cell superoxide production in response to F-Met-Leu-Phe (FMLP) in a concentration-dependent manner. Following a 4-h exposure, an increase in O2- production was seen with IFN-gamma at 0.1 U/ml, with optimal priming at 100 U/ml. The time course of priming by 100 U/ml IFN-gamma showed that at least a 1-h exposure was required, and a maximal effect was seen at 24 h. Priming after a 4-h exposure to 100 U/ml IFN-gamma was completely inhibited by 1 micrograms/ml cycloheximide. HL-60 cells cultivated with 100 U/ml IFN-gamma produced increased O2- when exposed to 25 mM NaF (containing AIF4) or 10 nM phorbol myristate acetate, agonists that trigger the respiratory burst independent of receptor stimulation. These results indicate that IFN-gamma primes the HL-60 cell respiratory burst in a concentration and time-dependent manner similar to its effect on neutrophils. The data are consistent with the hypothesis that IFN-gamma primes HL-60 cells, in part, by stimulating synthesis of proteins that participate in NADPH oxidase activation distal to the FMLP receptor.

Antigens, Surface↗
PubMed1991

Priming of the HL-60 cell respiratory burst response by tumor necrosis factor-alpha.

The ability of tumor necrosis factor-alpha (TNF) to prime Me2SO-differentiated HL-60 cell respiratory burst activity to N-formylmethionyleucylphenylalanine (f-Met-Leu-Phe) was determined. Cultivation of differentiated HL-60 cells with TNF induced a time- and dose-dependent increase in superoxide production following stimulation with f-Met-Leu-Phe. An increase in the respiratory burst response could be detected as early as 1 h, and was maximally enhanced at 24 h. TNF enhanced superoxide production by increasing the initial rate of production without altering the time over which HL-60 cells produced superoxide following f-Met-Leu-Phe stimulation. The dose-response to f-Met-Leu-Phe in TNF-primed cells demonstrated the same half-maximal and maximal concentrations of f-Met-Leu-Phe as seen in untreated cells. Inhibition of protein synthesis by cycloheximide prevented the primary effect of TNF. We conclude that differentiated HL-60 cells can be used to examine the mechanisms by which TNF primes the neutrophil oxidative burst response.

Cell Differentiation↗
PubMed1991

Clinical, serologic, and immunogenetic studies in patients with dermatomyositis.

Dermatomyositis is a disease of unknown etiology characterized by progressive, symmetrical, proximal muscle weakness with accompanying compatible cutaneous findings. Thirty-nine patients with dermatomyositis from the Louisville, Kentucky area were enrolled in this study. Patients were grouped into those with or without a malignancy. Ten patients (26%) either had or have had a malignancy. Twenty-five Caucasian patients were HLA typed for the A, B, DR and DQ locus antigens, of whom 5 had an associated malignancy and 20 did not have a malignancy. We found that no single antigen had a significantly increased or decreased frequency as compared with our control population for the entire group, or for any clinical subset we examined. Serologic testing revealed 4 patients with anti-Mi-2 antibodies and 1 patient with anti-PM-SCL antibodies. No patient had a positive anti-Jo-1 antibody in this group. The results of serologic tests in this group did not correlate with any clinical subset or HLA antigen. Our findings were in agreement with the previous reports in which approximately 25% of patients with DM have an associated malignancy. Our findings also support the notion that untargeted malignancy searches are not warranted. Contrary to previous reports we did not observe an inverse relationship between cancer and pulmonary disease in the dermatomyositis patient. This study does not indicate that there are any HLA associations or clinical associations, other than age, that distinguish patients with dermatomyositis as running a greater risk of developing malignancy.

Dermatomyositis↗
PubMed1990

Role of intracellular calcium concentration and protein kinase C activation in IFN-gamma stimulation of U937 cells.

IFN-gamma enhances many monocyte functions, including oxidative metabolism and Ag presentation. IFN-gamma has been reported to increase the intracellular concentration of calcium ([Ca2+]i) and modulate protein kinase C activity in murine macrophages, but the signal transduction pathways induced by IFN-gamma in human cells and their functional significance are poorly understood. Our study examined the hypothesis that an increases in [Ca2+]i and protein kinase C activation are required for functional responses to IFN-gamma. The U937 cell line was used as a model of an IFN-gamma responsive cell. IFN-gamma caused a rapid and concentration-dependent increase in [Ca2+]i, which was partly inhibited by calcium-free medium, diltiazem, and TMB-8. IFN-gamma induced a fourfold increase in the concentration of inositol 1,4,5-trisphosphate. Induction of HLA-DR, Fc gamma R, CR3, and Mo3e Ag expression by IFN-gamma was blocked by concentrations of TMB-8 that inhibited an increase in [Ca2+]i, but not by protein kinase C inhibition by H-7 or inhibition of calmodulin with W-7. Ionomycin did not enhance Ag expression and PMA induced the expression of only the Mo3e Ag. We conclude that IFN-gamma induces antigenic expression on human U937 cells by a mechanism dependent on, but not limited to, an increase in intracellular calcium, which is likely due to inositol 1,4,5-trisphosphate generation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1990

Bacterial lipopolysaccharide enhances polymorphonuclear leukocyte function independent of changes in intracellular calcium.

Bacterial lipopolysaccharide (LPS) enhanced expression of C3bi receptors (CR3), phagocytosis of opsonized bacteria, and subsequent hydrogen peroxide (H2O2) production by human polymorphonuclear leukocytes (PMNs). The role of changes in intracellular calcium concentration ([Ca2+]i) in LPS-induced priming was examined by determining the effect of modulators of intracellular calcium on enhanced PMN function, determining the ability of calcium ionophores to reproduce the effects of LPS, and measuring PMN [Ca2+]i following addition of LPS. Inhibition of intracellular calcium-dependent processes with TMB-8 or quin-2 blocked all three measures of LPS-induced priming. LPS did not stimulate an increase in [Ca2+]i, and calcium ionophores failed to reproduce the effect of LPS. Maintenance of [Ca2+]i is necessary for LPS priming, but an increase in [Ca2+]i is not a component of the signal transduction pathway leading to PMN priming by LPS.

Aminoquinolines↗
PubMed1989

Otolaryngologic problems in cardiac transplant patients.

Cardiac transplantation is now a well-accepted treatment for selected patients who have end-stage heart disease. Of the 38 patients who underwent cardiac transplants at our center from August 1984 through August 1987, 27 received consultation for otolaryngologic problems. Eleven patients had sinonasal complications; 8 had laryngotracheal complications; 4 had otologic complications; 2 had oropharyngeal complications; and 2 had a combination of more than one of the above complications. Of these otolaryngologic disorders, 63% were infectious in etiology. Development of otolaryngologic infections generally did not correlate with either higher doses of maintenance immunosuppression or with treatment of an acute rejection episode, which requires increased immunosuppression. Otolaryngologists should be aware of the sinonasal, laryngotracheal, oropharyngeal, and otologic disorders that can occur in cardiac transplant patients.

Heart Transplantation↗
PubMed1988

Use of OKT3 monoclonal antibody in the treatment of acute cardiac allograft rejection.

OKT3 is a murine monoclonal antibody that recognizes the T3 surface antigen present on mature T cells, and it has been used to successfully treat renal allograft rejection. We report our experience with OKT3 in the treatment of cardiac allograft rejection. Eight patients with endomyocardial biopsy evidence of moderate or severe rejection were given fourteen daily intravenous treatments of OKT3. Six of the eight patients had complete recovery following OKT3 therapy; one required additional steroid therapy for recurrence and one patient failed to respond. Five of the six patients with a complete response have experienced no further rejection (mean follow-up 437 days). Adverse reactions to OKT3 were common early in the treatment course, but were well tolerated. We concluded that OKT3 is a safe and effective treatment of cardiac allograft rejection and that a majority of patients experience long-term rejection-free periods.

Acute Disease↗
PubMed1988

Cutaneous mast cell quantity in pruritic and nonpruritic hemodialysis patients.

Pruritus remains a significant complication of end-stage renal disease. Its cause in hemodialysis patients is not known. It has been postulated that increased numbers of mast cells occur in these patients and may account for the presence of pruritus. Our objective was to determine if there is a difference in the number of cutaneous mast cells between pruritic and nonpruritic patients. A 3-mm punch biopsy specimen was obtained from pruritic (n = 7) and nonpruritic (n = 6) hemodialysis patients. We observed no significant difference in the quantity of cutaneous mast cells in pruritic and nonpruritic hemodialysis patients. We conclude that the etiology of pruritus in hemodialysis patients is not related to an increase in the number of cutaneous mast cells.

Aged↗
PubMed1988

Infant orthotopic cardiac transplantation.

Infant orthotopic cardiac transplantation has been recently applied to various forms of congenital heart disease with encouraging short-term results. Between June 1986 and September 1987 we evaluated 16 infants for orthotopic cardiac transplantation. Fourteen had hypoplastic left heart syndrome, one had endocardial fibroelastosis with aortic atresia, and one had anomalous pulmonary arterial origin of the left main coronary. Eight families accepted the treatment program and eight families refused (two because of associated anomalies and six on philosophical grounds). Of the eight patients who were candidates for orthotopic cardiac transplantation, one died 6 hours after diagnosis, one was allowed to die after 60 days because of acquired neurologic complications, and another had congenital cytomegalic virus infection. The remaining five patients (four with hypoplastic left heart syndrome, one with anomalous pulmonary arterial origin of the left main coronary) had orthotopic cardiac transplantation. The operation was performed with absorbable polydioxanone suture with deep hypothermia and circulatory arrest in four neonates for hypoplastic left heart syndrome (average time 47 minutes) and bicaval cannulation and continuous bypass in one 11-month-old infant for anomalous origin of the left main coronary. In-house retrieval was used in all. One neonate died of complications as a result of pretransplant donor heart dysfunction and size discrepancy, whereas the remaining three neonates and one infant survived and are home 23 months, 12 months, and 8 months (the patients with hypoplastic left heart syndrome) and 17 months (the patient with anomalous origin of the left main coronary) postoperatively. Triple-drug immunosuppression included cyclosporine, azathioprine, and prednisone. Rejection was diagnosed by clinical evaluation of child activity and monocyte cell cycle analysis from peripheral blood samples without myocardial biopsies. Routine echocardiograms, electrocardiograms, and chest x-ray films were not helpful. Six episodes of rejection were successfully treated in four patients. Twelve-month postoperative catherization in one patient (hypoplastic left heart syndrome) showed appropriate graft growth, no aortic or pulmonary anastomotic strictures, normal right and left ventricular function, and no coronary artery disease. We conclude that infant orthotopic cardiac transplantation is an acceptable procedure for severe forms of untreatable congenital heart disease. The excellent short-term results warrant continued application of orthotopic cardiac transplantation.

Acute Kidney Injury↗
PubMed1988

Clinical, serologic and immunogenetic studies in patients with chronic cutaneous (discoid) lupus erythematosus who have verrucous and/or hypertrophic skin lesions.

Verrucous and/or hypertrophic lesions occasionally occur in patients with lupus erythematosus. It has been suggested that these patients have skin disease which is characterized by chronicity and resistance to therapy other than intralesional corticosteroids. We studied 8 patients with chronic cutaneous (discoid) lupus erythematosus and 1 patient with papulosquamous subacute cutaneous lupus erythematosus with verrucous and/or hypertrophic lesions. Serologic, immunogenetic, and clinical data were gathered to confirm the distinctiveness of this subset and to seek specific laboratory correlates.

Adrenal Cortex Hormones↗
PubMed1987

Potential mechanisms of cytosolic calcium modulation in interferon-gamma treated U937 cells.

Interferon-gamma (IFN-gamma) at a concentration of 50 U/ml increased internal Ca2+ in the monocyte-like cell line U937 by about 100% within 3 min of addition, as determined by indo-1 fluorescence. This IFN-gamma-induced increase was reduced to 30-40% of basal (Ca2+) by the addition of diltiazem (1 microM) or incubation in Ca2+-free buffer. Ai crude membrane preparation obtained by differential centrifugation of sonicated U937 cells possessed Ca2+-ATPase activity (10 nmol ATP hydrolyzed/min/mg protein at 30 C) and sequestered Ca2+ to a level of 8 nmol/mg protein in 30 min. Addition of inositol trisphophate (IP3) (10 microM) after accumulation of Ca2+ resulted in release of a portion of the sequestered Ca2+ within 30 s, which was then resequestered. Although mitochondrial contamination was indicated by partial inhibition of Ca2+ uptake by oligomycin A, this mitochondrial inhibitor had no effect on the IP3-induced Ca2+ release. These results suggest that the increase in U937 cell cytoplasmic Ca2+ induced by IFN-gamma results from both intracellular redistribution of Ca2+, probably via polyphosphoinositide metabolism, and the entry of extracellular Ca2+ through slow channels.

Biological Transport, Active↗
PubMed1987

Clinical orthotopic cardiac transplantation.

The results of orthotopic cardiac transplantation have improved dramatically since the early experiences in the late 1960s. After almost 20 years of research and experience and the introduction of cyclosporine, 1 and 5 year survival rates are now 80 percent and 60 percent, respectively. The number of potential recipients far exceeds that of available donors, which is the limiting factor in cardiac transplantation. Complications related to immunosuppressive therapy remain significant, and despite decreased length of hospitalization, costs remain high. The majority of patients have good functional rehabilitation and are free of cardiac symptoms. Moreover, orthotopic cardiac transplantation has finally become a therapeutic treatment of end-stage heart disease.

Age Factors↗