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Biomedical subjects

C L Karp

Publications and source records attributed to C L Karp.

At least 37 records · Page 2Linked to original sources
PubMed1999

Mitogenesis in glioblastoma multiforme cell lines: a role for NGF and its TrkA receptors.

Neurotrophins have definitive roles in the growth/maintenance of neuronal populations, but their function in malignant gliomas is unknown. The ability for nerve growth factor (NGF) to serve as a mitogenic agent was investigated in several human glioblastoma multiforme (GBM) cell lines, including U251, U87, and U373. In a serum-free medium, the addition of NGF (200 ng/ml) to these cell lines increased cell counts over controls, after 3 days in culture by 9%, 16%, and 33%, respectively. Dose-dependent increases in cell counts and [3H]thymidine uptake were found in the more rigorously investigated U373 cell line. Proteins for both the high affinity NGF-specific tyrosine kinase binding site (p140TrkA; TrkA) and the low affinity neurotrophin (p75NTR) receptor were present in all three GBM cell lines. TrkA mRNA was identified in U373 (only cell line studied). NGF-stimulated proliferation was inhibited in a dose-dependent fashion by K252a, a blocker of Trk-induced receptor kinases. NGF, measured by ELISA, was detectable in all GBM cell lines even after 7 days of growth in serum-free medium. These data suggest that GBM cell growth can be enhanced by NGF acting via Trk receptor phosphorylation. Future studies of antiproliferative therapies should consider agents directed against intracellular Trk signaling cascades.

Carbazoles↗
PubMed1999

Effects of methylprednisolone and cyclosporine A on fungal growth in vitro.

PURPOSE: The management of corneal transplants after mycotic keratitis often poses a therapeutic dilemma. Clinicians are hesitant to use topical steroids because of their potential enhancement of fungal growth. This study seeks to evaluate the in vitro effects of methylprednisolone and cyclosporine A on the growth of various molds that often are responsible for keratomycoses. METHODS: Fusarium oxysporum, Fusarium solani, and Aspergillus fumigatus were grown in the presence of varying concentrations of methylprednisolone, cyclosporine A, and vehicle controls. Fungal growth was evaluated in a masked fashion based on the number of colonies and their morphologies. RESULTS: All tested concentrations of cyclosporine A (1%, 2%, 4%) had a statistically significant suppressive effect on the growth of F. oxysporum (p<0.001) and F. solani (p<0.001) compared with methylprednisolone and vehicle control solutions. A dose-dependent decrease in the number of colonies grown also was noted for F. oxysporum (p<0.001) and F. solani (p<0.001). In the case of A. fumigatus, cyclosporine A significantly decreased the colony size (p<0.015) in a dose-dependent fashion. CONCLUSIONS: Cyclosporine A appears to have an inhibitory effect on fungal growth in vitro. Cyclosporine A may be an important alternative to topical steroids for management of corneal transplants after mycotic keratitis.

Antifungal Agents↗
PubMed1999

Measles: immunosuppression, interleukin-12, and complement receptors.

Measles virus, the first pathogen recognized to cause immunosuppression, induces profound and prolonged abnormalities in cellular immune responses in infected hosts. The ability of measles virus to specifically ablate monocyte/macrophage and dendritic cell production of interleukin (IL)-12 provides a potentially unifying mechanism for many of these in vivo and in vitro abnormalities. Cross-linking of the cellular receptor for measles virus, the complement regulatory protein CD46, is sufficient to inhibit IL-12 production. CD46-mediated downregulation of IL-12 has turned out to be a specific instance of a more general pattern of tight inhibitory control over IL-12 production effected by complement and phagocytic receptors on antigen-presenting cells. Exploitation of these pathways by other intracellular pathogens is likely.

Animals↗
PubMed1999

Paecilomyces lilacinus fungemia in an adult bone marrow transplant recipient.

Paecilomyces lilacinus is a rare fungal pathogen in humans. We report a case of fungemia caused by P. lilacinus in a non-neutropenic adult, 120 days after bone marrow transplant. The patient's primary risk factor was the presence of an indwelling vascular catheter. Her initial clinical course was characterized by fever, chills, and rigors. Blood cultures from the central line and peripheral veins were positive, as was a peripheral specimen drawn after removal of the catheter. Two initial peripheral specimens were positive for P. lilacinus only by blind subculture and/or sustained incubation. She developed peripheral pulmonary nodules following the fungemia, thus raising the possibility of disseminated disease, but definitive diagnosis was confounded by Pseudomonas bacteremia. The nodules cleared and she recovered following removal of the central line and treatment with amphotericin B and 5-fluorocytosine, despite in vitro resistance to these antifungal drugs. This case underscores the increasing importance of P. lilacinus as a human pathogen capable of producing disease in immunocompetent, as well as in immunocompromised hosts. Also of note is that blood culture systems may require extended incubation or subcultures in order to detect fungi.

Adult↗
PubMed1998

Interleukin-13: central mediator of allergic asthma.

The worldwide incidence, morbidity, and mortality of allergic asthma are increasing. The pathophysiological features of allergic asthma are thought to result from the aberrant expansion of CD4(+) T cells producing the type 2 cytokines interleukin-4 (IL-4) and IL-5, although a necessary role for these cytokines in allergic asthma has not been demonstrable. The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma. IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.

Allergens↗
PubMed1998

Modulation of cell death by Bcl-XL through caspase interaction.

The caspases are cysteine proteases that have been implicated in the execution of programmed cell death in organisms ranging from nematodes to humans. Many members of the Bcl-2 family, including Bcl-XL, are potent inhibitors of programmed cell death and inhibit activation of caspases in cells. Here, we report a direct interaction between caspases and Bcl-XL. The loop domain of Bcl-XL is cleaved by caspases in vitro and in cells induced to undergo apoptotic death after Sindbis virus infection or interleukin 3 withdrawal. Mutation of the caspase cleavage site in Bcl-XL in conjunction with a mutation in the BH1 homology domain impairs the death-inhibitory activity of Bcl-XL, suggesting that interaction of Bcl-XL with caspases may be an important mechanism of inhibiting cell death. However, once Bcl-XL is cleaved, the C-terminal fragment of Bcl-XL potently induces apoptosis. Taken together, these findings indicate that the recognition/cleavage site of Bcl-XL may facilitate protection against cell death by acting at the level of caspase activation and that cleavage of Bcl-XL during the execution phase of cell death converts Bcl-XL from a protective to a lethal protein.

Apoptosis↗
PubMed1998

Potent suppression of IL-12 production from monocytes and dendritic cells during endotoxin tolerance.

Endotoxin tolerance, the down-regulation of a subset of endotoxin-driven responses after an initial exposure to endotoxin, may provide protection from the uncontrolled immunological activation of acute endotoxic shock. Recent data suggest, however, that the inhibition of monocyte/macrophage function associated with endotoxin tolerance can lead to an inability to respond appropriately to secondary infections in survivors of endotoxic shock. IL-12 production by antigen-presenting cells is central to the orchestration of both innate and acquired cell-mediated immune responses to many pathogens. IL-12 has also been shown to play an important role in pathological responses to endotoxin. We therefore examined the regulation of IL-12 during endotoxin tolerance. Priming doses of lipopolysaccharide ablate the IL-12 productive capacity of primary human monocytes. This suppression of IL-12 production is primarily transcriptional. Unlike the down-regulation of TNF-alpha under such conditions, the mechanism of IL-12 suppression during endotoxin tolerance is not dependent upon IL-10 or transforming growth factor-beta, nor is IL-12 production rescued by IFN-gamma or granulocyte-macrophage colony-stimulating factor. Of note, human dendritic cells also undergo endotoxin tolerance, with potent down-regulation of IL-12 production. Endotoxin tolerance-related suppression of IL-12 production provides a likely mechanism for the anergy seen during the immunological paralysis which follows septic shock.

Cells, Cultured↗
PubMed1998

The effect of acute infectious illnesses on plasma human immunodeficiency virus (HIV) type 1 load and the expression of serologic markers of immune activation among HIV-infected adults.

The effect of acute coinfections on plasma human immunodeficiency virus (HIV) load and immune activation markers was evaluated. Thirty-two HIV-infected persons were prospectively enrolled; 18 had pre-illness, acute, and follow-up specimens. Plasma HIV RNA levels were determined by reverse transcriptase-polymerase chain reaction, and serum levels of activation markers, including tumor necrosis factor (TNF)-alpha, soluble (s) TNF receptors (R)-I and -II, interleukin (IL)-2, IL-6, IL-10, sIL-2R, sCD4, and sCD8, were assessed by commercial ELISAs. Median plasma HIV load increased 7. 8-fold during illness (P=.001) and decreased 1.5-fold (P=.01) during convalescence (median, 15 days). Significant virus load reductions were limited to subjects with clinical recovery. By regression analysis, changes in plasma HIV RNA were significantly associated with changes in sTNFR-I, sTNFR-II, and sIL-2R. Increased HIV replication during acute coinfections is associated with in vivo immune activation, which underscores the need to prevent and promptly treat intercurrent illnesses.

Acute Disease↗
PubMed1998

Mapping of specific and promiscuous HLA-DR-restricted T-cell epitopes on the Plasmodium falciparum 27-kilodalton sexual stage-specific antigen.

We have characterized HLA-DR-restricted T-cell epitopes on the 27-kDa protein (Pfg27), a sexual stage-specific antigen, of the human malaria parasite Plasmodium falciparum in subjects with a history of malaria. Pfg27, expressed early in the sexual stages, is recognized by monoclonal antibodies capable of reducing the infectivity of gametocytes in mosquitoes. By using 16 Pfg27-specific CD4(+)-T-cell clones derived from three donors, seven different T-cell epitopes were identified. Among them, P11 (amino acids 191 to 210 of the Pfg27 sequence, IDVVDSYIIKPIPALPVTPD) was found to contain a previously described binding motif for multiple HLA-DR allotypes. Indeed, P11 was found to be promiscuous in that it could be recognized by T cells in the context of at least five different HLA-DR molecules. The cytokine profile of the clones was mixed. Seven of nine T-cell clones exhibited a Th0-like cytokine profile, producing high levels of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) upon stimulation with specific peptides and mitogens. The other two clones had a Th1-like cytokine profile with high expression of IFN-gamma and no IL-4. Identification of a promiscuous epitope in Pfg27 could play a significant role in the design of a subunit vaccine for suppressing malaria transmission.

Amino Acid Sequence↗
PubMed1998

Leptin regulates proinflammatory immune responses.

Obesity is associated with an increased incidence of infection, diabetes, and cardiovascular disease, which together account for most obesity-related morbidity and mortality. Decreased expression of leptin or of functional leptin receptors results in hyperphagia, decreased energy expenditure, and obesity. It is unclear, however, whether defective leptin-dependent signal transduction directly promotes any of the conditions that frequently complicate obesity. Abnormalities in tumor necrosis factor alpha expression have been noted in each of the above comorbid conditions, so leptin deficiency could promote these complications if leptin had immunoregulatory activity. Studies of rodents with genetic abnormalities in leptin or leptin receptors revealed obesity-related deficits in macrophage phagocytosis and the expression of proinflammatory cytokines both in vivo and in vitro. Exogenous leptin up-regulated both phagocytosis and the production of proinflammatory cytokines. These results identify an important and novel function for leptin: up-regulation of inflammatory immune responses, which may provide a common pathogenetic mechanism that contributes to several of the major complications of obesity.

Animals↗
PubMed1997

Inhibition of IL-12 production by thalidomide.

The immunomodulatory properties of thalidomide are currently being exploited therapeutically in conditions as diverse as erythema nodosum leprosum, chronic graft-vs-host disease, rheumatoid arthritis, and sarcoidosis. The relevant mechanism of action of thalidomide in these diseases remains unclear. The important role recently ascribed to IL-12, a cytokine critical to the development of cellular immune responses, in the pathogenesis of several of these conditions led us to examine whether thalidomide affects the production of IL-12. Thalidomide potently suppressed the production of IL-12 from human PBMC and primary human monocytes in a concentration-dependent manner. Thalidomide-induced inhibition of IL-12 production was additive to that induced by suboptimal inhibiting doses of dexamethasone, and occurred by a mechanism independent of known endogenous inhibitors of IL-12 production. These results suggest that thalidomide may have therapeutic utility in a wide range of immunologic disorders that are characterized by inappropriate cellular immune responses.

Antibodies, Monoclonal↗
PubMed1997

Central cloudy corneal dystrophy of Francois. A clinicopathologic study.

Central cloudy corneal dystrophy of Francois was first described in 1955 by J. Francois; its pathophysiology remains unknown. An 80-year-old woman with bilateral central cloudy corneal dystrophy of Francois was examined after having undergone a combined penetrating keratoplasty and cataract extraction. The corneal button was obtained. Light microscopy revealed stromal staining for acid mucopolysaccharide. Transmission electron microscopy revealed extracellular vacuoles, some of which had fibrillogranular material and electron-dense deposits. Fibrillogranular material was present in and around some keratocytes. Numerous endothelial vacuoles contained light-staining fibrillogranular material and round electron-dense granules. Our findings suggest that the opacities in patients with central cloudy corneal dystrophy of Francois are due to the extracellular accumulation of mucopolysaccharide and lipidlike material. Further studies are needed to elucidate the nature of these deposits.

Aged↗
PubMed1997

Kupffer cell depletion abolishes induction of interleukin-10 and permits sustained overexpression of tumor necrosis factor alpha messenger RNA in the regenerating rat liver.

Tumor necrosis factor alpha (TNF), initiates a cytokine cascade that promotes hepatocyte proliferation after 70% partial hepatectomy (PH) but the mechanisms regulating TNF production after PH are unknown. We previously reported that gadolinium chloride (GdCl), an agent that depletes the liver of phagocytically active Kupffer cells, enhances hepatic expression of TNF messenger RNA (mRNA) and promotes liver regeneration after subsequent PH. This suggests that GdCl interferes with Kupffer cell mechanisms that normally constrain TNF production after PH. To evaluate this, the pre- and post-PH expression of TNF, TNF-inducible cytokines (interleukin [IL]-1, IL-6) and cytokines (transforming growth factor [TGF] beta 1 and IL-10) that down-regulate TNF were compared in controls and GdCl-treated rats. In controls, TNF, IL-1, IL-6, and IL-10 increase within 3 hours after PH, whereas TGF-beta 1 is induced much later (> 24 hours after PH). GdCl causes sustained overexpression of TNF mRNA and transient overexpression of circulating TNF protein after PH; both TNF-inducible cytokines are also relatively overexpressed. Cytokines that down-regulate TNF are effected differentially by GdCl. Regenerative induction of IL-10 is abolished but TGF-beta 1 induction is unaltered. Because IL-10 is known to shorten the half-life of TNF mRNA, these results suggest that Kupffer cell production of IL-10 is an important mechanism that down-regulates TNF production during liver regeneration.

Animals↗
PubMed1997

Inhibition of human interleukin-12 production by pentoxifylline.

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.

Cell Culture Techniques↗
PubMed1997

Interleukin-4 receptor blockade prevents airway responses induced by antigen challenge in mice.

The functional role of interleukin (IL)-4 in the development of airway hyperresponsiveness (AHR) and pulmonary eosinophilia in response to sensitization and challenge of mice with sheep red blood cells (SRBC) was examined. Control- and SRBC-sensitized A/J mice were treated with an antibody to the murine IL-4 receptor (anti-IL-4R) 3 days before intratracheal challenge with the antigen or vehicle only. Blockade of IL-4R significantly reduced antigen-induced AHR and prevented increases in goblet cells and bronchoalveolar lavage (BAL) eosinophils. Treatment with anti-IL-4R did not affect antigen-induced increases in lung mRNA and BAL protein levels of IL-5 and interferon-gamma or IL-4 mRNA but did significantly increase IL-4 protein levels. Antigen-induced AHR was not reduced by treatment with antibodies to the adhesion molecules, vascular cell adhesion molecule-1 and very late activation antigen-4. Administration of IL-4 over a 7-day period did not increase airway reactivity or induce any changes in BAL cell numbers in naive mice. These results demonstrate that IL-4 is necessary for in vivo development of antigen-induced AHR, goblet cell metaplasia, and pulmonary eosinophilia.

Animals↗