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Biomedical subjects

L W Heck

Publications and source records attributed to L W Heck.

At least 19 recordsLinked to original sources
PubMed1998

T cell receptor peptide vaccination in rheumatoid arthritis: a placebo-controlled trial using a combination of Vbeta3, Vbeta14, and Vbeta17 peptides.

OBJECTIVE: Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of Vbeta3, Vbeta14, and Vbeta17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). METHODS: A double-blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (Vbeta3, Vbeta14, and Vbeta17) in IFA. A total of 99 patients with active RA received either 90 microg (n = 31) or 300 microg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. RESULTS: Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-microg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-microg and the 300-microg dosage groups at week 24 after the fourth injection. CONCLUSION: IR501 therapeutic vaccine therapy was safe and well tolerated, immunogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.

Adult↗
PubMed1998

Nondepleting humanized anti-CD4 monoclonal antibody in patients with refractory rheumatoid arthritis.

OBJECTIVE: To investigate the safety, tolerability, pharmacokinetics, and immunologic activity of single intravenous infusions (0.2-10 mg/kg) of Orthoclone OKTcdr4a, a nondepleting humanized anti-CD4 monoclonal antibody (Mab) in patients with rheumatoid arthritis. METHODS: Eighteen patients were treated with a single intravenous dose of Mab. Three patients each received 0.2, 0.5, 1.0, 2.0, 5.0, or 10.0 mg/kg of OKTcdr4a. RESULTS: No patient had a significant change in CD4+ T cells in peripheral blood after treatment. No human antimurine antibodies were detected. At > or = 1.0 mg/kg dose level, CD4 receptor saturation was > or = 95% 24 h after infusion. At 5.0 mg/kg, CD4 receptor occupancy was a mean of 88% at 6 days after infusion. At 10 mg/kg, CD4 receptor occupancy was still a mean of 79% 2 weeks after infusion. No significant infusion related adverse events occurred. Two subjects had headaches at the time of drug administration. Two subjects were hospitalized for infections (pneumonia, Day 45; cellulitis, Day 14), which resolved with antibiotic therapy. CONCLUSION: OKTcdr4a was well tolerated at the doses used and saturation of CD4 receptors in peripheral blood could be routinely obtained for over one week with a single infusion of Mab.

Adult↗
PubMed1997

Human neutrophils do not degrade major basement membrane components during chemotactic migration.

At sites of inflammation, circulating neutrophils (PMNs) migrate through microvessel walls into the subendothelial interstitium. While endothelial passage is mediated by adhesion proteins, including those of the integrin, selectin and immunoglobulin superfamily classes, the mechanisms used to cross the subendothelial basement membrane (BM) are unclear. Studies examining tumour cell invasion and lymphocyte extravasation suggest several possible mechanisms, including proteolysis. Different cells, however, may use different mechanisms to effect passage. To examine neutrophil-basement membrane interactions in more detail, human PMNs were embedded within reconstituted BM (Matrigel) and used in migration assays. The integrity of the gel following migration was assessed by assaying for the release of incorporated radiolabelled products and by-immunoblotting for specific matrix molecule epitopes. PMNs migrated through Matrigel in response to the chemotactic peptide FMLP. Degradation products of laminin, heparan sulphate proteoglycan or of gelatin, however, were not detected. In contrast, phorbol ester, which triggers activation without migration, released approximately 40% of incorporated HSPG, 30% of gelatin and 20% of laminin as intact molecules or degraded fragments. Electron microscopy of migrating cells demonstrated pseudopodia associated with channels within the Matrigel. Although the serine proteinase inhibitor DFP, plasma and a specific anti-neutrophil elastase IgG blocked degradation, these agents failed to inhibit migration. Migration was inhibited, however, when the Matrigel concentration was increased to 10 mg/ml. Thus, although PMNs will degrade matrix components they do not do so during migration, and proteolytic remodelling of the BM is not a pre-requisite for neutrophil passage.

Basement Membrane↗
PubMed1997

Nodular scleritis: case report involving immunosuppressive therapy.

BACKGROUND: Scleritis is a chronic inflammation of the scleral coat of the eye. Although the clinical manifestations of scleritis can follow a benign clinical course, the more serious forms may lead to vision loss and even enucleation of the eye. METHODS: A case is presented of a 57-year-old woman with a diagnosis of nodular scleritis and attendant ocular manifestations. RESULTS: Scleritis affects females slightly more frequently than males, and is most commonly found in patients who are 40 to 60 years of age. Patients who are symptomatic in only one eye typically have bilateral involvement within 5 years. More importantly, 50% of patients with scleritis have an underlying systemic disorder, which makes a detailed medical history and complete physical examination a crucial part of the treatment regimen. CONCLUSION: Recognizing the disease and determining the possible underlying systemic etiologies as early as possible will elucidate the appropriate treatment options and help suppress the potentially devastating effects of scleritis.

Chronic Disease↗
PubMed1996

Health outcome improvements in patients with systemic lupus erythematosus using two telephone counseling interventions.

OBJECTIVE: To examine the effectiveness of two telephone intervention strategies for improving the health outcomes of patients with systemic lupus erythematosus (SLE). METHODS: Fifty-eight SLE patients were randomly assigned to receive a 6-month telephone counseling intervention using either a treatment counseling (TC) or symptom monitoring (SM) strategy. Health outcomes were assessed using the Fatigue Severity Scale (FSS) and the Arthritis Impact Measurement Scales 2 (AIMS2). RESULTS: At the 6-month followup, the mean AIMS2 Physical Function scale and AIMS2 Social Support scale scores were significantly improved (P < 0.05) for the TC group compared to the SM groups. The mean FSS score, AIMS2 Affect score, and AIMS2 Pain score were significantly improved (P < 0.05) for both groups. CONCLUSIONS: Telephone interventions, especially using the TC approach, can be effective for improving the functional status of persons with SLE.

Activities of Daily Living↗
PubMed1996

V beta 17 T cell receptor peptide vaccination in rheumatoid arthritis: results of phase I dose escalation study.

OBJECTIVE: To determine whether modulation of activated T cells occurs in patients with rheumatoid arthritis (RA) after immunization with T cell receptor (TCR) V beta 17 peptides, a phase I trial was initiated to investigate the safety and feasibility of TCR peptide immunization as a therapeutic approach in RA. METHODS: 15 patients with moderate to severe RA were given an intramuscular injection of one of 4 doses (10, 30, 100, and 300 micrograms) of the V beta 17 peptide vaccination, followed by a booster injection of the same dose of vaccine 3 weeks later. Patients were followed for 48 weeks. RESULTS: The product was well tolerated and no serious adverse events attributable to the vaccine were observed. This was an uncontrolled phase I trial, however; decreases in patients joint scores were observed at all followup visits starting at 4 weeks after primary immunization. Activated V beta 17 T cells (IL-2R+) in peripheral blood were decreased (> or = 20%) in 3/5 patients in the 100 micrograms group after initial measurement at Week 2 and 3/4 patients in the 300 micrograms group 3 weeks after immunization. Lymphocyte proliferation in response to the V beta 17 peptide was detected at 6 weeks or later after primary inoculation in 6/15 patients (40%) immunized. CONCLUSION: Further controlled studies are required to assess the biologic and clinical efficacy of this treatment approach.

Adult↗
PubMed1996

Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis.

OBJECTIVE: To determine the safety and pharmacokinetics of recombinant human tumor necrosis factor receptor (p80) fusion protein (rhTNFR:Fc) administered as a single intravenous (iv) loading dose followed by subcutaneous (sc) maintenance injections twice weekly for one month in patients with refractory rheumatoid arthritis (RA). METHODS: Four dose groups were evaluated with 4 patients with RA per group: 3 received active drug and one received placebo injection. After each dose group completed 4 weeks of treatment, the patient who received placebo was allowed to receive the active drug for one month. After these 16 patients completed the study, 3 additional patients received the highest dose and 3 additional patients received the lowest dose in an open label study to obtain more safety data (total of 22 patients treated). RESULTS: There were no serious adverse effects. Drug related events include mild injection site reactions in 4 patients that did not necessitate discontinuation of the drug. There was no clearcut dose response among the treatment groups. At Week 4, there was 45% mean improvement in total pain and total joint scores in patients receiving active drug (n = 12), compared to 22% mean improvement in patients receiving placebo (n = 4). C-reactive protein (CRP) levels decreased substantially in patients treated with drug compared to placebo, 30 vs 13%, respectively. The decrease in CRP was most pronounced in the highest dose group. CONCLUSION: This initial experience with rhTNFR:Fc fusion protein in RA justifies further evaluation of this agent in a larger placebo controlled trial.

Adult↗
PubMed1995

Development of an observation method for assessing pain behaviors in children with juvenile rheumatoid arthritis.

OBJECTIVE: To develop an observation method for assessing pain behaviors in children with juvenile rheumatoid arthritis (JRA). METHODS: Thirty children with JRA performed a standardized sequence of activities for video recording, and correlations between the pain behaviors observed on the videotapes and established measures of pain, depression, and functional disability were determined. RESULTS: Pain behaviors were reliably observed (kappa coefficients 0.53-0.79). Total pain behaviors were significantly correlated with subjective reports of pain (r = 0.50) and disability levels (r = 0.64). These behaviors were not significantly associated with children's depression ratings (r = 23). CONCLUSION: The results indicate that the behavioral observation method provides a reliable and valid measure of pain associated with JRA. Measurement of pain behaviors may be especially useful in treatment outcome studies because these behaviors are relatively independent of depression.

Adolescent↗
PubMed1994

Radioimmunometric quantification of surface lactoferrin in blood mononuclear cells.

A radioimmunometric method was developed for the quantification of lactoferrin molecules natively bound to blood monocyte and lymphocyte surfaces and the estimation of the surface lactoferrin-binding capacity of these cells after their incubation with exogenous lactoferrin. Values of surface lactoferrin obtained were greatest for monocyte-rich isolates (9,168 +/- 1,713 molecules/cell; n = 19). The values of monocyte surface lactoferrin for males were similar to those of premenopausal females (8,980 +/- 2,378 (n = 8) and 9,427 +/- 2,606 molecules/cell (n = 11), respectively), but males had slightly lower values of monocyte surface lactoferrin binding capacity than did premenopausal females (10,447 +/- 2,478 molecules/cell versus 15,958 +/- 3,731 molecules/cell, respectively; p > 0.05). Expressed as saturation of the monocyte surface lactoferrin binding capacity, values of 97.2% +/- 22.6% for males and 76.6% +/- 14.3% for females were calculated. Intermediate values of surface lactoferrin were found in B-lymphocyte-rich isolates from five patients with B-cell chronic lymphocytic leukemia. In T-lymphocyte-rich preparations, there were low levels of native lactoferrin expression (154 +/- 63 molecules of lactoferrin/cell; 3 isolates). The present technique should permit additional quantitative studies of mononuclear cell surface lactoferrin to determine the role of lactoferrin surface binding and analyses of factors that modulate this binding.

Adult↗
PubMed1993

Degradation of human articular cartilage by neutrophils in synovial fluid.

OBJECTIVE: To determine whether surface-adherent immunoglobulins are capable of mediating synovial fluid (SF) neutrophil degradation of proteoglycan and collagen in intact, normal human articular cartilage, and to define the respective roles of neutrophil serine proteases and metalloproteases in degrading these cartilage constituents. METHODS: Pellet explants of normal human articular cartilage pretreated with bovine serum albumin (BSA) or IgG were incubated with polymorphonuclear cells suspended in SF (PMN-SF), or with supernatants derived from neutrophils stimulated with surface-associated IgG. Proteoglycan degradation was measured by assaying release of 35S-proteoglycan fragments from cartilage explants prelabeled with 35S-sulfate. Collagen degradation was measured by assaying hydroxyproline content in the PMN-SF preparations or neutrophil supernatants following their incubation with unlabeled explants. RESULTS: Significant release of both 35S fragments and hydroxyproline was noted following incubation of PMN-SF with IgG-treated pellets, compared with pellets treated with BSA. IgG preparations derived from pooled normal serum or rheumatoid arthritis SF were equally efficacious in mediating PMN degradation of cartilage collagens. Explant release of 35S fragments during incubation with PMN supernatant was completely inhibited when serine proteases were inactivated by diisopropyl fluorophosphate (DFP); however, release of 35S fragments was enhanced when metalloprotease activity was present in the supernatant. Release of hydroxyproline during incubation of explants with PMN supernatant was comparable in the presence of DFP or EDTA, but was markedly enhanced when both serine and metalloprotease activity were present in the supernatant. CONCLUSION: Neutrophils in SF are capable of degrading both proteoglycans and collagens in intact human articular cartilage. Degradation of these cartilage constituents is facilitated by immunoglobulins adherent to the cartilage surface and by the synergistic action of PMN serine and metalloproteases released during activation of neutrophils with surface-associated immunoglobulin.

Arthritis, Rheumatoid↗
PubMed1993

Laminin cleavage by activated human neutrophils yields proteolytic fragments with selective migratory properties.

We studied the interactions between human neutrophils, as well as the purified human neutrophil serine proteases elastase (HNE) and cathepsin G (HNCG), and laminin. Our results show that intact laminin and two proteolytic fragments generated by HNE bind to neutrophils and stimulate cell migration. Domain-specific antilaminin monoclonal antibodies, rotary shadowing electron microscopy, and Western blotting mapped the two promigratory fragments on the laminin cross to the apical three-armed region and long arm, respectively. In contrast, a fragment derived from the terminal ends of short arms neither bound to neutrophils nor stimulated migration. When neutrophils embedded in a reconstituted basement membrane gel were activated with phorbol myristate acetate, several stable, proteolytic laminin fragments were released into supernatants. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting showed that these fragments appeared identical to those generated after digestion of soluble laminin with HNE and HNCG. Furthermore, release of laminin fragments by embedded neutrophils was inhibited by diisopropyl fluorophosphate, and duplicated by incubating the basement membrane gel with purified HNE and HNCG. Our findings therefore suggest that neutrophils, through release of HNE and HNCG, are capable of digesting basement membrane laminin in vivo. In addition, the release of laminin fragments from damaged basement membranes may promote neutrophil migration and thereby accelerate inflammatory processes.

Adult↗
PubMed1993

New approaches to the therapy of autoimmune diseases: rheumatoid arthritis as a paradigm.

Several therapeutic agents currently are used to treat rheumatoid arthritis (RA). However, there is no compelling evidence that any of these agents substantially alters the long-term destructive course of RA. Advances in biotechnology have led to a better understanding of mechanisms that underlie autoimmune diseases such as RA. Although the etiology of RA remains unknown, there now is considerable insight regarding the immune and inflammatory pathways that ultimately lead to cartilage and bone destruction. Therapies with monoclonal antibodies directed against cell surface constituents, fusion toxins against cell activation markers, and cytokine inhibitors all have been shown to be safe and possibly efficacious in early open trials in RA. They now are being more rigorously tested in double-blind, placebo-controlled trials. Early experience with these biologic agents in humans, as well as data obtained from the use of these agents in animal models of autoimmune disease, are reviewed. In addition, experimental studies with "blocking peptides" and immunization with autoreactive T cell receptor peptides will be reviewed, and implications for therapy in RA will be discussed.

Antibodies, Monoclonal↗
PubMed1992

Additive enhancement of neutrophil collagenase activity by HOCl and cathepsin G.

Using preparations of latent collagenase derived from neutrophil specific granule extracts, the relative effects of cathepsin G and HOCl on activation of neutrophil collagenase were determined using a quantitative collagenase assay. Enhancement of collagenase activity by cathepsin G and physiologically relevant concentrations of HOCl were comparable, but HOCl mediated collagenase activation was reversible in the presence of HOCl scavenger. Collagenase activity in preparations treated with cathepsin G and HOCL simultaneously or sequentially was significantly greater than activity in preparations treated with HOCl or cathepsin G alone. The results indicated additive, yet independent enhancing effects of HOCl and cathepsin G on activity of neutrophil collagenase.

Cathepsin G↗
PubMed1991

Inhibition of 5-lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis.

We studied the effect of tenidap sodium, a new antiinflammatory/antirheumatic drug (120 mg/day for 7 days), on eicosanoid production and neutrophil degranulation in patients with rheumatoid arthritis. Endogenous prostaglandin E2 levels and ex vivo production of leukotriene B4 (LTB4) were measured in synovial fluid samples obtained at baseline and 1 week later. We measured peripheral blood polymorphonuclear cell (PMN) degranulation following surface-bound IgG stimulation, a possible 5-lipoxygenase product-mediated event, by determining lactoferrin and elastase release into the culture fluid. We found decreased levels of endogenous prostaglandin E2 as measured by radioimmunoassay, and decreased ex vivo production of LTB4 by PMN as measured by high performance liquid chromatography, in synovial fluid samples from patients who took tenidap. Release of the granule proteins lactoferrin and elastase was decreased in PMN obtained from patients receiving tenidap, as well as in the PMN incubated in vitro with tenidap. Improvement in clinical measures paralleled the biochemical changes. The unique 5-lipoxygenase inhibitory property of tenidap, as measured by LTB4 production and degranulation, suggests that it may have clinical activity which differentiates it from nonsteroidal antiinflammatory drugs.

Aged↗
PubMed1991

Tenidap, in contrast to several available nonsteroidal antiinflammatory drugs, potently inhibits the release of activated neutrophil collagenase.

Neutrophils contain a collagenase that is stored in a latent form within the specific granule. With cellular activation, the latent enzyme is activated in association with the production of a variety of oxidants, including hypochlorous acid. We evaluated 4 nonsteroidal antiinflammatory drugs (NSAIDs) currently on the market and the new antiinflammatory/antirheumatic drug tenidap for their effects on the release of activated collagenase. In contrast to the 4 NSAIDs, tenidap profoundly inhibited the release of activated collagenase. This inhibition was predominantly due to interference with activation of the latent enzyme, rather than interference with enzyme release. The inhibition of collagenase activation was associated with a profound reduction in myeloperoxidase activity and in hypochlorous acid production. These observations demonstrate that tenidap has properties that set it apart from conventional NSAIDs and suggest that it may be a particularly useful agent in the treatment of inflammatory rheumatic disorders.

Anti-Inflammatory Agents, Non-Steroidal↗