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Biomedical subjects

K E Harris

Publications and source records attributed to K E Harris.

At least 73 records · Page 4Linked to original sources
PubMed1986

Human antibodies against formaldehyde-human serum albumin conjugates or human serum albumin in individuals exposed to formaldehyde.

Sera from patients undergoing hemodialysis with formaldehyde (F)-sterilized dialyzers were studied to determine if antibodies against F conjugated to human serum albumin (HSA) could be detected. F-human serum albumin (F-HSA) conjugates were prepared using ratios of F to HSA that did not precipitate the HSA. The F-HSA conjugates migrate differently electrophoretically than HSA with an increased negative charge of F-HSA as compared with HSA. The F-HSA was used in an ELISA. The results demonstrated that in certain sera, IgG, IgM, IgA and IgE antibodies against F-HSA could be measured. In the highest titered sera, it was shown that the IgG antibody was not directed against F alone or F-lysine but against an antigenic grouping of F-HSA. No correlation of either IgG or IgE antibodies with immune complex or allergic reactions was found in this series of dialysis patients. Some sera from dialysis patients had antibody activity against HSA. Sera from 2 physicians with rhinitis after F exposure had no antibody activity against F-HSA or HSA. Two nurses with a history of F-induced asthma had no IgG antibodies but did have IgE antibodies against F-HSA and HSA. This spectrum of immunologic responses is analogous to responses in dogs immunized with F or F dog albumin. We have not been able to identify anti HSA antibodies in patients reactive to other hapten-HSA compounds and it is suggested that anti HSA antibodies in F-exposed humans may relate to the F exposure.

Antibody Specificity↗
PubMed1986

Inhibition of rhesus monkey airway and cutaneous responses to platelet-activating factor (PAF) (AGEPC) with the anti-PAF agent SRI 63-072.

Previous studies with synthetic platelet-activating factor (PAF) (AGEPC) showed that aerosol challenges in rhesus monkeys resulted in airway responses simulating acute antigen-induced responses and immediate-type skin reactions [1]. The current studies evaluated whether an antagonist of PAF (SRI 63-072) could inhibit the airway and cutaneous reactivity to PAF. Under the conditions of these experiments, the antagonist partially inhibited PAF activity in both experimental systems. Inhibition of endpoint cutaneous reactivity to PAF may be a suitable system for comparing potency of pharmacologic antagonists in primate skin.

Aerosols↗
PubMed1986

Comparison of cutaneous and bronchial reactivity to leukotriene D4 in humans.

To establish whether a relationship exists between cutaneous and bronchial reactivity to leukotriene D4 (LTD4), endpoint cutaneous reactivity and bronchial reactivity were determined in six patients with asthma, six patients with seasonal allergic rhinitis, and six nonatopic men. In all subjects, increasing doses of LTD4 produced decreases in specific airway conductance (SGaw) and flow at 30% of vital capacity measured from a partial forced expiratory maneuver (V30P). Intracutaneous injections of LTD4 and histamine resulted in immediate wheal and erythema reactions in all patients. Serial 10-fold dilutions of LTD4 and histamine were injected to establish the lowest dose capable of producing a 4 mm wheal with erythema. Endpoint cutaneous reactivity to LTD4 ranged from 1 mumol to 100 pmol in controls and from 100 nmol to 1 fmol in patients with asthma, but statistically significant differences between groups were not apparent even with inclusion of six additional subjects. No meaningful correlations were found between the quantity of LTD4 producing the threshold cutaneous reaction and the dose of inhaled LTD4 that produced a 35% decrease in SGaw and 30% decrease in V30P. In contrast to the bronchi, where subjects in all three groups were 264 to 840 times more sensitive to LTD4 than to methacholine, 11/18 subjects (3/6 with asthma) were less sensitive to LTD4 than to histamine in terms of endpoint cutaneous reactivity. However, seven of 18 subjects who were more sensitive to LTD4 than to histamine had relative potencies ranging from 5 to 500,000.

Asthma↗
PubMed1985

Immunologic responses to intravenous streptokinase in dogs.

Streptokinase is used worldwide as a thrombolytic agent. Allergic reactions to streptokinase have been reported, but the immunologic mechanisms have not been well characterized. To develop a canine model of streptokinase immune responses analogous to human responses, four dogs received intravenous streptokinase infusions. Significant rises in IgG, IgA and IgM antibody levels occurred after streptokinase administration in three of four dogs; a fourth dog developed significant increases in IgG and IgA antibody levels. Two dogs developed immediate-type cutaneous hypersensitivity to streptokinase. One dog developed subacute dermatitis with eosinophilic infiltrates which was possibly a manifestation of an allergic reaction to streptokinase.

Animals↗
PubMed1985

Responses of human airways to inhaled chemicals.

A variety of complex pulmonary immunologic responses may follow the inhalation of reactive chemical haptens. Trimellitic anhydride (TMA) is an industrial chemical used as a plasticizer (and serves as a model of occupational immunologic lung disease). Sensitization to TMA can take several forms--IgE-mediated asthma and rhinitis, a late reaction in the lung which resembles hypersensitivity pneumonitis and an irritated airways syndrome. Antibody studies show that TMA can combine with bodily constituents to form new antigenic determinants (NADs) which are probably the most immunogenic form of the compound.

Antigen-Antibody Complex↗
PubMed1985

Creating an indoor environmental problem from a nonproblem: a need for cautious evaluation of antibodies against hapten-protein complexes.

An epidemic of illness in three schools in New York State occurred in early 1983. An epidemiological review of the problem led to the conclusion that some of the symptoms could have been explained by irritant reactions to boiler exhaust gases but that a major factor was likely public concern about environmental contamination and heightened awareness of common minor symptoms and of exacerbations of chronic illnesses. Diphenylmethane diisocyanate (MDI) from polyurethane insulation had previously been suspected as a potential cause. An earlier investigation had found low levels of anti MDI-human serum albumin in a small number of subjects who did not have typical symptoms of identified MDI or other hypersensitivity syndromes. Similar antibodies were found in two of nine unaffected children in Chicago, who served as a comparison group. The identification of these antibodies, however, was inappropriately used to support the idea of a school contaminated with MDI in spite of the absence of detectable MDI in the environment. The availability of highly sensitive immunoassays should not be inappropriately used to accelerate the fear of environmental toxins when there is no clinical correlation.

Air Pollutants↗
PubMed1985

Canine antibodies against formaldehyde-dog serum albumin conjugates: induction, measurement, and specificity.

Formaldehyde-dog serum albumin (F-DSA) conjugates were prepared as soluble haptenized proteins. The F-DSA reacted with rabbit anti-DSA. Change in electrophoretic migration of F-DSA as compared with DSA demonstrated conjugation. The more rapid migration toward the anode of F-DSA implied deletion of positive charges on DSA by conjugation with formaldehyde. F-DSA was antigenic for dogs when given intravenously as solution or subcutaneously in Freund's complete adjuvant. Intravenously administered formaldehyde resulted in an anti-F-DSA response, presumably caused by F-DSA forming in vivo. Canine IgG and IgA antibodies were measured by enzyme-linked immunosorbent assay. Canine anti-F-DSA has specificity for neither formaldehyde nor DSA alone, as determined by inhibition analysis, indicating that the antigenic determinant of F-DSA for dogs is a combination of formaldehyde and a new antigenic determinant formed on DSA. Immediate-type hypersensitivity occurred transiently in dogs immunized intravenously with formaldehyde or F-DSA. Finally, exposure of DSA to formaldehyde either in vivo or in vitro results in alteration of DSA molecules and an immune response to that altered DSA as well as to commercial DSA. Such results have previously been seen with formaldehyde in rabbits or with glutaraldehyde by other investigators.

Animals↗
PubMed1985

Parallel induction of IgE-mediated Ascaris antigen airway responses and increased carbachol airway reactivity in rhesus monkeys by infection with Ascaris suum.

In continuation of studies of four rhesus monkeys infected with Ascaris suum (J Lab Clin Med 101:864-872, 1983), we report the duration of IgE-mediated skin reactivity and airway responses to Ascaris antigen from 15 weeks to longer than 2.8 years. A second group of four rhesus monkeys was infected with A. suum ova after determination of the threshold of airway reactivity to carbachol. Evaluation of these animals confirmed the initial results of the first group of animals studied in relation to induction of skin and airway reactivity to Ascaris antigen. In addition, all animals developed increased airway reactivity, demonstrated by increased reactivity to lower concentrations of carbachol. We report this as a demonstration of induced IgE-mediated antigen airway responsiveness accompanied by induction of increased airway reactivity in a primate model. The increased airway reactivity does not appear related to the induction of IgE antibody.

Airway Resistance↗
PubMed1984

Antihypertensive efficacy of once daily MK-521, a new nonsulfhydryl angiotensin-converting enzyme inhibitor.

The effects of the new nonsulfhydryl-containing oral converting-enzyme inhibitor MK-521 on blood pressure, heart rate, angiotensin-converting enzyme activity, plasma renin activity and plasma aldosterone concentration were assessed in 10 hypertensive patients. After a 2-week no-treatment period, patients received placebo and then 14 days each: MK-521 20 mg once daily, hydrochlorothiazide 50 mg once daily and the latter 2 in combination. During the last day of each treatment, the mean (+/- standard deviation) time-averaged (1- to 12-hour) standing diastolic blood pressure decreased from 106 +/- 8 (placebo) to 95 +/- 10 mm Hg with MK-521, 95 +/- 13 mm Hg with hydrochlorothiazide (p less than 0.05 vs placebo) and 88 +/- 11 mm Hg with the combination (p less than 0.05 vs all other treatments). The antihypertensive effect of MK-521 was maintained 24 hours after dosing. Heart rate did not change significantly after MK-521 treatment. MK-521 caused a marked suppression of converting enzyme activity for over 24 hours; plasma renin activity increased significantly after each active treatment and MK-521 significantly decreased the hydrochlorothiazide-induced elevation of plasma aldosterone concentration. In this short-term trial, MK-521 was well tolerated.

Adult↗
PubMed1984

Initial evaluation of the non-sulfhydryl-containing converting enzyme inhibitor MK-521 in hypertensive humans.

MK-521 is a new orally active, nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Single doses of 2.5, 5.0, 10.0, and 20.0 mg were administered to nine hypertensive patients alternating with placebo. All doses of MK-521 caused profound suppression of ACE activity for more than 24 h and decreased standing diastolic blood pressure for more than 12 h without changes in pulse rate. Although there was no further reduction in blood pressure with doses above 5.0 mg, the duration of action was prolonged for more than 24 h with the higher doses. Serum MK-521 concentrations increased with dosage, and ACE was inhibited maximally at concentrations above 10 ng/ml. In this initial study, MK-521 was well tolerated and proved to be a potent and long-acting antihypertensive agent.

Adult↗
PubMed1984

Airway responses to sequential challenges with platelet-activating factor and leukotriene D4 in rhesus monkeys.

Leukotriene D4 and synthetic platelet-activating factor have been shown to qualitatively reproduce an antigen-induced airway response in rhesus monkeys at concentrations several hundred times less than histamine. In normal rhesus monkeys, challenges with concentrations of leukotriene D4 or platelet-activating factor, established as subthreshold doses (not producing a response), result in abnormal pulmonary function parameters when followed by a second challenge of a subthreshold dose. Results were similar with any sequence of leukotriene D4 and platelet-activating factor combination. This was not a result of additive effects of agonists, because previous experiments have shown that log or 0.5 log increases over the subthreshold dose are necessary for a response. Our results may suggest that these mediators that possess remarkable biologic activity might sensitize the lower airway for response to stimulation with the same or other mediators.

Aerosols↗
PubMed1983

Immunologic and respiratory responses to airway challenges of dogs with toluene diisocyanate.

Dogs received biweekly or monthly aerosol immunization with single doses of toluene diisocyanate (TDI) that were cumulative doses analogous to human chronic exposure at 0.02 ppm. The three dogs developed systemic immune responses to TDI-dog serum albumin (DSA). The immune responses included IgG, IgA, and IgM antibody responses and development of lymphocyte reactivity. IgA titers approached IgG titers and both were persistent, whereas IgM titers were low and of short duration. IgE antibody titers demonstrated by endpoint cutaneous titration appeared but fluctuated and became negative in spite of continued aerosol exposure of TDI. Immediate-type airway responses occurred after TDI aerosolization. Some limited responses that showed only abnormalities of selected pulmonary function parameters were clearly not immunologically mediated because they occurred with initial exposure. Other immediate-type airway responses occurred that qualitatively simulated IgE-mediated, antigen-induced airway responses in dogs. There was a statistically significant correlation (p = 0.0268) between these latter airway responses and immediate-type skin reactivity. This study demonstrates that this dog model simulates the complexity of airway responses to TDI in man but may provide a laboratory system for evaluation of immunologic or other proposed mechanisms of TDI asthma.

Animals↗
PubMed1983

Antibodies against toluene diisocyanate protein conjugates. Three methods of measurement.

With the use of canine antisera against toluene diisocyanate (TDI)-dog serum albumin (DSA), techniques for measuring antibody against TDI-DSA were evaluated. The use of an ammonium sulfate precipitation assay showed suggestive evidence of antibody binding but high levels of TDI-DSA precipitation in the absence of antibody limit any usefulness of this technique. Double-antibody co-precipitation techniques will measure total antibody or Ig class antibody against 125I-TDI-DSA. These techniques are quantitative. The polystyrene tube radioimmunoassay is a highly sensitive method of detecting and quantitatively estimating IgG antibody. The enzyme linked immunosorbent assay is a rapidly adaptable method for the quantitative estimation of IgG, IgA, and IgM against TDI-homologous proteins. All these techniques were compared and results are demonstrated by using the same serum sample for analysis.

Ammonium Sulfate↗
PubMed1983

Airway response to leukotriene D4 in rhesus monkeys.

We studied the effect of leukotriene D4(LTD4) given by aerosol challenge on asthmatic and normal monkeys. The response to LTD4 occurred within 2 min., was prolonged at higher concentrations, was reversed by epinephrine, and more closely resembled an antigen response than a histamine response. Since LTD4 concentrations of 30-100 micrograms/ml produced a response similar to 2-20 mg/ml of histamine, the LTD4 was 300-900 times as potent as histamine on a molar basis. Thus, LTD4, which appears to reproduce an antigen-induced response in rhesus monkeys, may be a mediator of allergic asthma in these animals.

Airway Obstruction↗
PubMed1983

Induction of IgE-mediated cutaneous, cellular, and airway reactivity in rhesus monkeys by Ascaris suum infection.

In order to maintain a colony of rhesus monkeys with IgE-mediated Ascaris asthma, we evaluated the response of four animals to infection with Ascaris suum ova. All four animals developed immediate-type cutaneous reactivity and airway responses. Serum IgE and IgG antibody responses against Ascaris antigen, as quantitated by the ELISA, were seen in all animals. Peripheral blood histamine release after stimulation with Ascaris antigen was positive in all animals. Airway reactivity to aerosol challenge with Ascaris antigen became positive in all animals and has remained positive for 6 months in three of four animals. Both standard and threshold dose airway types of responses were present. Except for transient eosinophilia, the animals remained in good health. The studies demonstrate that infection with A. suum results in rhesus monkeys with IgE-mediated immediate-type reactivity that simulates the naturally occurring model of asthma.

Animals↗
PubMed1983

The activity of aerosolized and intracutaneous synthetic platelet activating factor (AGEPC) in rhesus monkeys with IgE-mediated airway responses and normal monkeys.

AGEPC, a synthetic platelet activating factor was studied by aerosol or cutaneous challenge in rhesus monkeys with or without IgE-mediated airway responses. The AGEPC qualitatively reproduced an antigen type of airway response. The monkeys with airway reactivity to antigen were reactive to lower concentrations of AGEPC than normal monkeys. Although very low concentrations of AGEPC produced cutaneous reactions, no cutaneous hyperreactivity was present in antigen-reactive animals. The threshold concentrations of AGEPC producing an airway reaction were 1/600 and 1/20,000 those of leukotriene D4 and histamine, respectively. These results could be consistent with AGEPC as a highly active mediator of airway responses in antigen-reactive airways of primates.

Aerosols↗
PubMed1982

Immune response of dogs and rabbits to intrabronchial trimellitic anhydride.

8 dogs and 7 rabbits were immunized intrabronchially with trimellitic anhydride (TMA) using three different immunizing doses. An immune response occurred in both animal species. Predominantly IgG with lower levels of IgM and IgA antibodies against trimellityl-erythrocytes (TM-E) were detected on both dogs and rabbits. Antibody binding of TM125I dog serum albumin (TM125I-DSA) occurred in most dogs and of TM125I rabbit serum albumin (TM125I-RSA) in 1 out of 7 rabbits. Lymphocyte reactivity was present in all 8 dogs. Death occurred in the 2 dogs immunized with the low dose (0.1 mg/kg) of TMA, in 2 of the 4 dogs immunized with the moderate dose (1.0 mg/kg), and in neither of the 2 dogs immunized repeatedly with the high dose (10.0 mg/kg). No correlation of deaths could be made with serum levels of anti-TM-E antibody or anti-TM125I-DSA antibody binding, or lymphocyte reactivity. The deaths occurred early in the TMA immunizations. All antibody levels in the diseased animals were less than those seen in human workers with TMA-related respiratory disease. Autopsy findings in the 4 dogs showed hemorrhagic pneumonitis possibly analogous to the pulmonary lesions seen in the hemorrhagic pneumonitis of some workers exposed to TMA fumes. TMA as used in these experiments was not toxic to dogs as the high doses of TMA (10.0 mg/kg) did not lead to death which did occur at the lower doses. No deaths occurred in the 7 rabbits immunized with 1.0 mg TMA/kg. The immune responses and pathological findings in dogs encourage further work in the development of animal models of TMA immunologic lung disease.

Animals↗