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Biomedical subjects

N F Adkinson

Publications and source records attributed to N F Adkinson.

At least 145 records · Page 8Linked to original sources
PubMed1984

Peptide leukotriene release after antigen challenge in patients sensitive to ragweed.

Slow-reacting substance of anaphylaxis (composed of leukotrienes C, D, and E) is released in vitro by the interaction of antigen and IgE antibody on human mast cells and basophils. When we challenged ragweed-sensitive patients intranasally with pollen grains, their clinical response was significantly correlated with the release of the peptide leukotrienes (P less than 0.001). Nonallergic subjects had neither symptoms nor leukotriene release. The leukotrienes were released in a dose-dependent fashion, with a peak mean level of 827 +/- 234 pg per 0.1 ml of a 10-ml nasal wash. High-performance liquid chromatography revealed the presence of leukotrienes C, D, and E, suggesting that nasal cells or fluids had the ability to degrade leukotriene C enzymatically. The in vivo release of these potent inflammatory mediators after exposure to pollen suggests that leukotrienes may have an important role in human allergic reactions.

Adolescent↗
PubMed1984

Limitations of the radioimmunoprecipitation polyethylene glycol assay (RIPEGA) for detection of filarial antigens in serum.

The performance of the radioimmunoprecipitation polyethylene glycol assay (RIPEGA) was examined for quantitation of filarial antigens (Brugia malayi and Dirofilaria immitis) in serum from infected human and animal hosts and non-infected controls. Multiple PEG concentrations were employed to determine the level of non-specific binding (NSB) in non-exposed human sera (NEHS) containing no filarial antigen. The NSB observed when 3 different 125I-labeled IgG antibodies were added to 26 NEHS varied 3-fold and was correlated significantly with total serum IgM (r = 0.80, P less than 0.005, n = 24) but not with serum IgA (r = 0.37) or IgG (r = 0.45). NSB levels were significantly reduced when a Fab'2 fragment of the 125I-labeled antibody was used, but the correlation of NSB with total serum IgM remained significant (r = 0.57, P less than 0.01). The presence of rheumatoid factor in NEHS sera also significantly increased NSB by an average of 3-fold. These effects eliminated the assay's ability to detect in sera from infected hosts filarial antigen the presence of which could be readily demonstrated by an immunoradiometric assay. The RIPEGA's precision (intra-assay coefficient of variation (CV) = 21% at 35% Bmax) and reproducibility (inter-assay CV = 29% at 35% Bmax) are less satisfactory than many alternative immunoassays. In many cases, positive sera failed to dilute out in parallel with each other or with an antigen-spiked standard reference curve. We conclude that poor performance characteristics currently limit the utility of the RIPEGA for quantitating filarial antigen in human and animal serum.

Animals↗
PubMed1984

Risk factors for drug allergy.

Judging from available data on penicillin allergy there appear to be multiple definable risk factors for drug-induced immunopathology. The induction of a drug-specific immune response can be influenced by the age of the patient; underlying genetic or metabolic factors, which may restrict ability to initiate a drug-specific immune response; the chemical properties of the drug, largely its protein reactivity; and the dose and duration of treatment as well as the route of drug administration. The elicitation of drug-induced immunopathology is a function of the persistence of a drug-specific immune response; the frequency of drug treatment and its dose and duration; and probable constitutional factors that may determine in an important way the efficiency with which a drug-specific immune response can be translated into a systemic allergic reaction.

Age Factors↗
PubMed1984

Dose response of IgE and IgG antibodies during ragweed immunotherapy.

We studied the detailed dose-response relationship for ragweed (RW) antibody responses in 51 patients who received maximal-dose immunotherapy with crude RW extract. Serum RW-IgG and RW-IgE levels were determined by solid-phase radioimmunoassay at frequent intervals during initiation and maintenance of immunotherapy. Pretreatment RW-IgE ranged from 0.94 to 974 ng/ml (median 105); 45/51 patients had insignificant levels (less than 250 ng/ml) of RW-IgG. The maximal doses given ranged from 0.19 to 93.5 micrograms of RW antigen E per injection. All patients produced a significant IgG response (median peak 3462 ng/ml, range 689 to 24,395), and 46/51 had significant increases in IgE antibody (median peak 231 ng/ml, range 12 to 1528). A threshold dose was defined for each patient's IgG and IgE response as that dose level which initiated a persistent increment in immunoglobulin to greater than or equal to 25% of pretreatment levels. The median threshold dose for IgE was 0.13 micrograms of antigen E, which was achieved in a median time of 42 days. The threshold dose for IgG was significantly higher (median 0.56 micrograms of antigen E; p = 0.001) and occurred significantly later (median 79 days; p = 0.003). Despite variability over 3 orders of magnitude, the thresholds for IgE and IgG responses were significantly correlated for individual patients (r = 0.487; p = 0.002). The maximum RW-IgE response occurred in a median of 107 days, after which IgE antibodies declined in 46 of 49 patients. The maximal IgG response occurred significantly later (median 245 days; p less than 0.001) and then plateaued or declined modestly. The doses required to achieve maximal IgE and IgG responses were significantly correlated (r = 0.638; p less than 0.001). The maximum IgG response was positively correlated with the maximal dose of RW antigen E received (r = 0592; p less than 0.001). In 28 of the 51 patients, the incremental rise in total serum IgE was more than twice that observed for RW-IgE at the time of the maximum response, suggesting a nonspecific effect of RW immunotherapy on total serum IgE levels. This discrepancy could not be accounted for by environmental stimulation from other known allergens, as assessed by skin testing, or by pretreatment levels of RW-IgE or total IgE. These observations indicate that the human IgE antibody response during high-dose RW immunotherapy is more sensitive to both stimulation and suppression by continuous allergen administration than is the IgG response.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1984

Lack of cross-reactivity between aztreonam , a monobactam antibiotic, and penicillin in penicillin-allergic subjects.

Monobactam antibiotics are a new class of beta-lactam antibiotics. In contrast to penicillins or cephalosporins, monobactams possess a monocyclic beta-lactam structure. IgE or immediate hypersensitivity cross-reactivity between aztreonam (a monobactam) and penicillin was investigated, since this will be an important consideration when therapy is chosen. The maximum concentration of aztreonam reagents not giving false-positive skin tests was determined in normal subjects who were not allergic to penicillin. Subsequently, 41 subjects with IgE antibody to one or more penicillin moieties, as determined by positive skin reactions, were tested with the aztreonam reagents. Thirty-seven of these persons showed no reactivity while four showed equivocal tests. Repeat tests in those four persons were negative to the aztreonam reagents, while their penicillin tests remained unchanged. These in vivo data suggest that there is no cross-reactivity between IgE antibodies to penicillin and aztreonam and provide a basis for investigating the therapeutic use of monobactams in patients who are allergic to penicillin.

Adult↗
PubMed1984

Mechanisms of acute allergic reactions.

Acute allergic reactions range from mild conditions of local tissue swelling and pruritus to severe multisystem syndromes including asthma, urticaria and/or angioedema, gastrointestinal distress, and vascular collapse. Such reactions share a common pathophysiology characterized by vasodilation and postcapillary permeability, resulting in increased extravasation of fluid within minutes after exposure to an eliciting substance. Smooth muscle contraction of the respiratory or gastrointestinal tracts may also be involved. Most of these changes can be explained by the release of chemical mediators from circulating basophilic leukocytes and tissue mast cells. Human basophils and mast cells can be activated to release chemical mediators by several known pathways: crosslinking by allergens of specific immunoglobulin E antibodies attached to basophils and mast cells; anaphylatoxin formation following immune complex activation of the classical complement pathway; anaphylatoxin formed from direct activation of the alternative complement pathway by negatively charged surfaces; non-complement-, non-antibody-mediated direct histamine release; and idiosyncratic mechanisms involving physical exercise, psychological stress, or aspirin intolerance. Any or all of these mechanisms could be operative in patients experiencing acute allergic reactions at the commencement of hemodialysis.

Anaphylaxis↗
PubMed1984

Immunology of the monobactam aztreonam.

To assess the immunological cross-reactivity of the monobactam antibiotic aztreonam (AZ), rabbits were immunized with protein conjugates of benzylpenicillin, cephalothin (CEPH), and AZ. The resulting antibenzylpenicilloyl (BPO) and anti-CEPH rabbit antibodies showed negligible cross-reactivity with AZ conjugated to human serum albumin (AZ-HSA), whereas anti-AZ showed negligible cross-reactivity with BPO-HSA and CEPH-HSA. Unlike benzylpenicillin and CEPH, unconjugated AZ was as effective as AZ conjugated to epsilon aminocaproic acid (AZ-EACA) in inhibiting the binding of homologous antibody. Studies with various analogs of AZ confirmed that immunoglobulin G (IgG) anti-AZ was entirely side-chain specific. The inhibition of the binding of human IgE anti-penicilloyl to BPO-HSA was studied in the presence of AZ-EACA, BPO-formyl lysine, and CEPH-EACA. Whereas CEPH-EACA displayed 3% cross-reactivity with BPO-lysine, AZ-EACA showed little or no cross-reactivity (much less than 0.9%). To assess the immunogenicity of AZ in humans, IgE and IgG antibodies were measured in sera from 36 healthy male volunteers receiving 0.5 or 1 g intravenously or intramuscularly every 8 h for 7 days. None of the subjects had detectable preexisting IgE reactive with AZ or demonstrated an IgE response to antibiotic administration. Four subjects gave evidence for naturally occurring IgG cross-reactive with AZ, but only one subject demonstrated a rise in IgG levels after exposure to AZ. This anti-AZ IgG did not cross-react with BPO or CEPH conjugates of bovine thyroglobulin and was completely side-chain specific. These studies suggest that AZ displays very low immunological cross-reactivity with other beta-lactam antibiotics and may be only weakly immunogenic in humans.

Animals↗
PubMed1984

Platelet augmentation of IgE-dependent histamine release from human basophils and mast cells.

A factor(s) from human platelets enhances IgE-mediated histamine release from human basophils and mast cells. This effect is directly related to the platelet number; at physiological platelet/leukocyte ratios (40:1), the enhancement was 66 +/- 11%. Platelet stimulation by thrombin more than doubled the enhancement, to 172 +/- 10% at 40:1. Mast cell release was also enhanced by platelets although the magnitude was more limited (86 +/- 13% at 40:1 with thrombin). Direct basophil/platelet contact was unnecessary in that platelet supernatants were fully active; a direct platelet factor/basophil interaction is suggested, however, by the fact that basophils purified 100-fold with respect to other leukocytes were enhanced by the platelet factors. The appearance of platelet-enhancing activity is associated with the release of an alpha-granule marker (PF4) rather than with products of arachidonic acid metabolism (thromboxane B2). The platelet factor(s) responsible for these effects are not dialyzable, are heat stable and do not appear to be identical to PF4 or platelet-derived growth factor (PDGF). Since anti-IgE-stimulated basophils cause PF4 release and this correlates with the release of enhancing factor, we suggest that a pro-inflammatory feed forward relationship exists. Together with our previous data showing that platelets are activated in vivo during antigen challenge of allergic asthmatic subjects, these results suggest that platelets may be important in modulating IgE-mediated allergic reactions in man.

Basophils↗
PubMed1984

Serological methods in the diagnosis and management of human allergic disease.

The diagnosis and management of human allergic disease is aided by serological measurements involving the quantitation of total human serum IgE, allergen-specific IgE and allergen-specific IgG. Initially, a brief overview of immediate hypersensitivity reactions will be presented with a focus on the role of "reaginic" allergen-specific IgE antibody. The principles and design of immunoassay methods employed in the measurement of total serum IgE and allergen-specific human IgE will then be examined with a discussion of the pros and cons of different radioallergosorbent test (RAST) reporting schemes. Next, Hymenoptera venom will be used as a model allergen system for exploring the clinical utility, principles and design of immunoassays used to quantitate allergen-specific IgG antibody in human serum. Examples of the utility of specific IgG measurements will be provided with recent clinical data. Finally, an overview will be presented on more research-based techniques used in the study of human allergic responses such as cross-immunoelectrophoresis and immunoassays for leukotrienes, prostaglandins, platelet Factor 4 and cyclic AMP.

Allergens↗
PubMed1984

Arachidonic acid metabolism in purified human lung mast cells.

Arachidonic acid metabolism has been explored in preparations of purified human lung mast cells prelabeled with arachidonic acid (AA). Cells were of 83 to greater than 96% purity, and each experiment was performed with four to six different preparations of mast cells. After overnight culture of the purified cells in the presence of 3H-AA, followed by extensive washing in buffer, mast cell uptake of labeled AA was 61.4 +/- 14.8 pmol/10(6) cells with 21 +/- 2.4% of the label in phospholipids, 73 +/- 2.1% in neutral lipids, and 3.6 +/- 0.8% as free AA. Analysis of the distribution of radioactivity in phospholipid classes revealed 51.4 +/- 5.5% of the label in phosphatidylcholine, 14.5 +/- 1.6% in phosphatidylinositol, 12.0 +/- 3.0% in phosphatidylethanolamine, and 9.1 +/- 2.4% in sphingomyelin, with the rest in other phospholipid classes. Challenge of these cells with an optimal concentration of anti-IgE led to the release of 20 +/- 4.0% of cellular histamine and to a reduction in labeled phosphatidylcholine and phosphatidylinositol to 75.5 +/- 8.8% and 84.2 +/- 4.5% of the control levels, respectively, (p less than 0.05); anti-IgE challenge produced no statistically significant change in the quantities of other labeled phospholipids. Activation of human lung mast cells with anti-IgE led to the release of 3.4 +/- 1.3% of the cellular 3H as AA and AA metabolites (1.5 +/- 0.6% as unmetabolized AA) in conjunction with 16 +/- 4.3% of the cellular histamine. Although activation of human lung mast cells with ionophore A23187 caused 70 +/- 1.1% histamine release, a similar quantity of AA and AA metabolites was released (a total of 4.0 +/- 0.8% with 2.3 +/- 1.5% as unmetabolized AA). Analysis of the released metabolites by liquid scintillation spectrometry after high performance liquid chromatography separation showed that approximately equal amounts of metabolites were produced after mast cell activation with anti-IgE and ionophore A23187. In this series of experiments approximately equal amounts of cyclooxygenase and lipoxygenase products were generated.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Anti-Idiotypic↗
PubMed1983

Dirofilaria immitis: performance and standardization of specific antibody immunoassays for filariasis.

The factors associated with the development, optimization, and validation of immunoassays for the detection of parasite-specific antibody in filariasis infections were investigated using the dog heartworm, Dirofilaria immitis as a model. We examined two assays, the Protein A solid-phase radioimmunoassay (SPRIA) and enzyme-linked immunosorbent assay (ELISA), for quantitation of specific antibody to the parasite in canine serum. Precision, reproducibility, and parallelism were examined using response-error relationships and precision profile analyses. A staphylococcal Protein A saturation analysis was applied to the standardization of IgG anti-parasite antibody reference sera in weight per volume units (microgram/ml). Using the mean minimal detectable dose + 3 SD and an intraassay precision profile less than 10% coefficient of variation (CV) as criteria for assay sensitivity, the SPRIA and ELISA displayed comparable positive thresholds of 1 microgram/ml IgG anti-parasite antibody/ml of serum. Both assays demonstrated good reproducibility (less than 15% interassay CV) and parallelism (less than 20% interdilutional CV) over their working ranges (SPRIA: 1-40 micrograms/ml; ELISA: 1-5 micrograms/ml). Specificity of each assay was enhanced by preadsorption of cross-reacting antibodies in canine serum (i.e., specific for Toxocara canis antigens) with solid-phase antigen prior to assay. Methods for comparing different immunoassay designs are considered in relation to the variables that influence the assays' performance characteristics.

Adsorption↗
PubMed1983

Immunologic observations during desensitization and maintenance of clinical tolerance to penicillin.

A nurse anesthetist who had experienced four systemic allergic reactions attributed to penicillin exposure was safely and successfully desensitized to penicillin despite predominantly minor determinant allergy (benzyl penicilloate skin test was positive at 1:100,000 dilution of standard 10 mM solution). Because of unavoidable occupational exposure to penicillin, daily oral doses of penicillin were continued after hospital discharge in an effort to maintain clinical tolerance. Immunologic measurements throughout the long-term desensitization effort provided some evidence that in this patient, drug-induced mast cell desensitization is an ongoing dynamic process that is dose dependent and that skin mast cell reactivity recovers slowly over a period of many weeks after the short-term high-dose desensitization protocol. A dose-dependent state of clinical tolerance to inadvertent penicillin exposure has been safely maintained in this patient for 18 mo.

Desensitization, Immunologic↗
PubMed1983

Oxidant- and lipid-induced pulmonary vasoconstriction mediated by arachidonic acid metabolites.

In experiments using isolated rabbit lungs perfused with Krebs-Henseleit buffer in a nonrecirculating manner, we found that administration of an organic peroxide, tert-butyl hydroperoxide (t-bu-OOH), or Intralipid, an esterified mixture of unsaturated fatty acids, caused a marked vasopressor response which was associated with increased levels of thromboxane in the effluent perfusate. The vasopressor response to t-bu-OOH was greater in the lungs of vitamin E-deficient animals, and this could be correlated with an attenuated ability to increase prostacyclin production in these lungs. Conversely, administration of Intralipid to normal lungs caused marked increases in prostacyclin and a smaller pressor response. The magnitude of the pressor response was strongly correlated with the ratio of thromboxane B2 to the prostacyclin metabolite. No release of these mediators was associated with pulmonary vasoconstriction caused by administration of angiotensin II. The pressor response could be completely blocked by administration of indomethacin. We propose that this activation of the cyclooxygenase pathway of arachidonic acid metabolism may be important in the pathophysiology of oxidant lung damage.

6-Ketoprostaglandin F1 alpha↗