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Biomedical subjects

H B Richerson

Publications and source records attributed to H B Richerson.

At least 55 records · Page 3Linked to original sources
PubMed1985

Cyclosporine immunomodulation in a rabbit model of chronic hypersensitivity pneumonitis.

Rabbit models of chronic experimental hypersensitivity pneumonitis and desensitization were used to evaluate the effects of systemic cyclosporine. When administered 12 to 18 h before each inhalational challenge with aerosolized antigen and the adjuvant muramyl dipeptide, cyclosporine suppressed the development of disease as well as the anamnestic antibody response, particularly in bronchoalveolar lavage fluids. When administered at the time of sensitization only, cyclosporine suppressed the primary antibody response but not the anamnestic antibody response or the disease. Antigen- and mitogen-induced blastogenesis was inhibited by cyclosporine in vitro, but antigen-specific blastogenesis was not abrogated by cyclosporine previously administered in vivo. These results indicate that cyclosporine caused profound immunomodulation in this model, which can be at least partially explained by transient suppressive effects on T cells, particularly the helper/inducer and delayed hypersensitivity subset(s).

Alveolitis, Extrinsic Allergic↗
PubMed1985

Methods for bronchoalveolar lavage in asthmatic patients following bronchoprovocation and local antigen challenge.

We employed bronchoalveolar lavage (BAL) of subsegmental airways to study the local inflammatory effects of aeroallergen bronchoprovocation (BPC) and local instillation of allergen in allergic asthmatic patients, allergic rhinitis patients, and normal subjects. Two protocols were used: (1) BAL was performed in three subsegments following BPC or during spontaneous seasonal exposure, and (2) 5-ml aliquots of increasing doses of allergen were instilled into a single subsegment until there was at least 30 percent closure of the airway; the airway was then immediately lavaged. A subsegment in the opposite lung was lavaged as a control site. These same two segments were lavaged again two to 14 days later and the cells and fluid analyzed. Fifty-five lavages have been performed without complications. Pulmonary function tests (FEV1) were not significantly disturbed by either local challenge or lavage procedures. Cells were examined using light and electron microscopy and showed inflammatory cells in alveolar airways and dissolution of mast cell and eosinophil granules. Using selected criteria, we were able to use these methods in mildly, seasonally asthmatic patients to obtain safely cells and fluid for analysis. These techniques may permit studies which further our understanding of the mechanisms responsible for allergic asthma.

Adolescent↗
PubMed1985

Site of airflow obstruction during early and late phase asthmatic responses to allergen bronchoprovocation.

Chronic asthma and late asthmatic responses (LAR) are associated with local inflammation which might be expected to produce airflow obstruction in small airways and to increase nonspecific airway reactivity. In contrast, early asthmatic responses (EAR) are primarily bronchospastic and probably involve more central airways. We challenged 17 nonsmoking, mildly asthmatic atopic subjects with allergen bronchoprovocation and measured changes in spirometry (FEV1) over the next 24 hours. Each subject also performed a helium-oxygen (He-O2) flow-volume loop before challenge (baseline), during the EAR, and six hours and 24 hours after challenge to measure the effect of gas density on flow rates at midvital capacity. Twelve subjects had both an EAR and a LAR; five subjects had only a LAR. Of these 17 subjects, 15 were initially density dependent, while only two were density independent. During the EAR, 13 percent of the density dependent population had significant decreases in delta Vmax 50 percent; 47 percent had significant decreases during LAR. The He-O2 flow data analyzed at specified time points after challenge revealed significant decreases in the mean delta Vmax 50 percent at six hours in those who had only a LAR (p less than 0.01). In those who had a dual airway response, density dependence increased during the EAR, but decreased at six and significantly at 24 hours (p less than 0.05) postchallenge. There was a strong trend for the severity of the LAR (measured by changes in FEV1) to be directly related to the total decrease in delta Vmax 50 percent during the LAR. We conclude that late asthmatic responses occur frequently after a single antigenic bronchial challenge and can be associated with persistent symptoms. The LAR were often associated with a decrease in density dependence of maximal expiratory airflow, and therefore, may involve small airways.

Adult↗
PubMed1985

Protamine-induced fatal anaphylaxis. Prevalence of antiprotamine immunoglobulin E antibody.

Protamine is used widely to reverse the anticoagulant effects of heparin and to delay the absorption of insulin. Although adverse reactions to protamine are reported infrequently and are usually mild, we recently observed the first fatal case of type I anaphylaxis resulting from protamine. This patient had previously been sensitized to protamine during cardiac catheterization and had high levels of protamine-specific immunoglobulin E in the serum. In a prospective study, we found that 10 of 19 diabetic patients (53%) who had received insulin containing insulin also had high levels of antiprotamine immunoglobulin E. In contrast, none of 27 nondiabetic healthy normal controls or 10 diabetics who had never received protamine or protamine-containing insulin had levels of antiprotamine immunoglobulin E over background. This study underscores the risks of routinely administering protamine to susceptible individuals and the need for alternative therapies.

Adolescent↗
PubMed1985

Enhancement of human neutrophil complement receptors: a comparison of the rosette technique with the uptake of radio-labelled anti-CR1 monoclonal antibody.

We have compared the rosette technique (using C3b-coated red cells) with the uptake of a 125I F(ab')2 anti-complement receptor type 1 (CR1) monoclonal antibody (E11) for studying the phenomenon of chemotactic factor (fMLP)-induced complement receptor enhancement (CRE) on human neutrophils. With both methods the dose responses of fMLP were similar with maximal CRE being observed at 10(-7) moles 1(-1). Conversely, the time course of CRE and the effects of disodium cromoglycate (DSCG) on inhibition of enhancement were discrepant. Maximal CRE with the rosette method was observed at 30 min, whereas increased uptake of anti-CR1 had still not reached a plateau after 1 h. DSCG inhibited fMLP-induced CRE, as assessed by the rosette technique, whereas this agent had no effect on increased binding of radio-labelled anti-CR1 antibody. These results suggest that in CRE the increased adherence of C3b-coated red cells to fMLP-stimulated neutrophils, as measured by the rosette technique, is not dependent exclusively on the increased numbers of CR1.

Antibodies, Monoclonal↗
PubMed1983

Synthesis of a biologically active fluorescent muramyl dipeptide congener.

A fluorescent-labeled muramyl dipeptide (MDP) has been prepared to probe immunoadjuvant cellular interactions. N-Acetylmuramyl-L-alanyl-D-isoglutamine (1) was synthesized in improved yield and reacted with 2-(fluoresceinylamino)-4,6-dichloro-s-triazine (DTAF, 2) to give the fluorescent adduct DTAF-MDP (3), attached through the 6-position of the sugar moiety. Adjuvant activity was assessed by using two different in vitro assays, macrophage spreading, and inhibition of macrophage migration. Both assays indicated that the apparent adjuvant activity of 3 is comparable to that of 1.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Carrier requirement for development of acute experimental hypersensitivity pneumonitis in the rabbit.

Fluorescein isothiocyanate (FITC) conjugated to protein carriers was used to explore carrier dependence in an established rabbit model of acute hypersensitivity pneumonitis (HSP). Rabbits were immunized via toepads with either FITC-ovalbumin (OA) or FITC-human gamma-globulin (HGG) in complete Freund's adjuvant, and were aerosol challenged with homologous or heterologous conjugates 30 days later. Only those rabbits challenged with the homologous carrier developed acute HSP, despite the presence of comparable levels of anti-FITC antibodies in the sera of all groups. These findings indicate a strict carrier dependence in the pathogenesis of HSP in this model and provide further evidence that the mechanism of inflammation depends upon a cellular immune response.

Acute Disease↗
PubMed1983

Hypersensitivity pneumonitis--pathology and pathogenesis.

Early reports of hypersensitivity pneumonitis postulated that the disease was infectious or resulted from the toxic properties of the inhaled organic dusts. The finding of precipitating antibodies to moldy hay in farmers afflicted with farmer's lung suggested a role for antibody in pathogenesis, and a type III (antigen-antibody complex-mediated or Arthus) hypersensitivity reaction based on the classification of allergic reactions by Gell and Coombs was postulated. Subsequent studies have indicated the importance of cell-mediated (delayed) hypersensitivity (type IV). It must be recognized that hypersensitivity mechanisms are quite complicated and that the classification of Gell and Coombs is an oversimplification; interreacting humoral and cellular responses are typical of most hypersensitivity reactions of whatever classic type as originally defined. The prime importance of T-cell- and macrophage-mediated inflammation in HP, however, is indicated by histopathology, animal models, and in vitro correlates in humans. Major difficulties in defining completely the exact effector mechanisms involved in the pathogenesis of HP include the absence of a reliable in vitro correlate of antigen-specific effector T cells (the so called TDH cell) and the overwhelming versatility of the macrophage. There is no direct evidence to support contributions by precipitins, complement, or genetic host factors in the pathogenesis of hypersensitivity pneumonitis, nor are there studies as yet of cellular cytotoxicity contributions. Cellular and antibody interactions may lead to immunosuppressive processes modulating inflammatory responses and preventing disease despite immunogenesis. Animal models are helpful in dissecting mechanisms and defining effector functions. The eventual goal in studies of pathogenesis is to provide better tools for definitive diagnosis and methods of disease prevention, modulation, and cure.

Alveolitis, Extrinsic Allergic↗
PubMed1982

The local and systemic IgA and IgG antibody responses of rabbits to a soluble inhaled antigen: measurement of responses in a model of acute hypersensitivity pneumonitis.

We evaluated local and systemic humoral responses to inhalational challenges with ovalbumin (OA) by measuring IgA and IgG isotypic antibodies to OA in serum and bronchoalveolar wash fluids (BAW), and by quantitating cells containing IgA, IgG, and anti-OA in lung, lymph nodes, spleen, and gut. Rabbit models of acute hypersensitivity pneumonitis and chronically-challenged "desensitized" animals were studied along with appropriate control animals. Systemic (via a toe pad) immunization or acute aerosol challenge with OA resulted in only trace amounts of IgG anti-OA antibodies in BAW and no apparent anti-OA-containing cells in the lung itself. Acute aerosol challenge of systemically immunized rabbits caused alveolitis, increased IgG anti-OA-containing cells in mediastinal and popliteal lymph nodes, and increased IgG anti-OA in BAW attributable to transudation from serum. Thrice-weekly inhalational challenge with aerosolized OA resulted in waning alveolitis, elevated concentrations of IgA and IgG anti-OA in BAW and serum, and increased concentrations of IgG and IgA anti-OA cells in the lung, but not in other tissues, including the gut. We conclude that these experiments have implicated IgG as well as IgA antibodies in local humoral responses to inhaled antigen, have not substantiated the notion of a common mucosal immune system involving lung and gut, have failed to demonstrate humoral tolerogenesis after inhalation of antigen, and have shown an effect of systemic priming on subsequent pulmonary immune responses in the models examined.

Alveolitis, Extrinsic Allergic↗
PubMed1982

Chronic hypersensitivity pneumonitis produced in the rabbit by the adjuvant effect of inhaled muramyl dipeptide (MDP).

An established rabbit model of acute hypersensitivity pneumonitis was used to evaluate adjuvant properties of synthetic muramyl dipeptide (MDP), the minimal adjuvant-active structure of mycobacteria. The authors studied MDP as a substitute for mycobacteria in immunization and as adjuvant during repeated inhalation of antigen (ovalbumin). They found that MDP could substitute successfully for mycobacteria in sensitizing animals for acute alveolitis following subsequent inhalation of a combination of ovalbumin and MDP aerosol for 4 to 14 weeks resulted in the development of chronic granulomatous pneumonitis, characterized by alveolar wall thickening, granulomas, and infiltrations with lymphocytes and macrophages. In addition, MDP boosted systemic and local IgG and IgA antigen-specific antibodies. Inhaled MDP, itself neither antigenic nor mitogenic, acted therefore as adjuvant for continued immunologic inflammatory effector mechanisms in the rabbit lung, which are ordinarily suppressed when antigen alone is inhaled. Possible mechanisms include stimulation of effector T cells and macrophages or the failure of suppressive mechanisms, with or without participation of immune complexes. This is the first successful model of chronic granulomatous alveolitis produced by inhalation of soluble materials. Further exploration of adjuvant mechanisms in this system should help clarify the pathogenesis of immunologic lung diseases in man.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1981

Antigen-specific densensitization in a rabbit model of acute hypersensitivity pneumonitis.

Rabbits that had been prepared to develop acute alveolitis after aerosol challenge with simple protein antigens did not develop chronic alveolitis but rather gradually recovered despite continued challenge. Immunologic accompaniments of waning disease were compared in this model to those associated with intravenous injections of antigen causing "desensitization." We also studied the effects of aerosol challenge prior to systemic immunization, antigen specificity, and the duration of desensitization by aerosolized and intravenous antigen. We found that repeated aerosol or intravenous challenges produced antigen-specific desensitization in this model, and the effect lasted several weeks. Prior exposure to aerosolized antigen was not protective. Neither aerosol nor intravenous desensitization maneuvers abrogated antigen-specific lymphocyte blastogenesis, although an early transient fall did occur. Humoral responses were boosted. These findings suggest that chronic alveolitis is prevented in this model by specific desensitization, without the induction of true tolerance or of nonspecific anergy. Such immunoregulation may result from development of antigen-specific blockade or blocking factors (e.g., lymphokines), antigen-antibody complexes, or suppressor cells affecting specific effector cells. Evaluation of these mechanisms may have implications for diagnosis and prognosis in human hypersensitivity pneumonitis.

Acute Disease↗
PubMed1981

Clinical and immunologic evaluation of glutaraldehyde-modified tyrosine-adsorbed short ragweed extract: a double-blind, placebo-controlled trial.

Glutaraldehyde-modified, tyrosine-adsorbed ragweed extract (GTR) is a modification of allergen extract to reduce allergenicity but retain immunogenicity. We evaluated the clinical efficacy and immunologic changes associated with the administration of GTR (16,350 protein nitrogen units) or placebo to a group of 100 atopic subjects with ragweed hay fever. The study was carried out in a double-blind, placebo-controlled fashion. Clinical response was measured by daily symptom diaries. physician evaluations, and patient responses. Changes in ragweed-specific IgE and IgG antibody were evaluated with an amplified enzyme-linked immunosorbent assay (alpha-ELISA) and were compared with measurements by RAST and a protein A-binding assay for IgG antibody. Treatment with GTR resulted in a sixfold increase in blocking IgG antibody and a small increase in IgE-specific antibody. No changes occurred in the placebo treated group. Mild immediate local reactions occurred after 74% of injections, and late-onset local reactions occurred after 62% of injections in the treated group. The placebo-treated group experienced immediate or late local reaction after only 12% of injections. There were two mild late-onset urticarial reactions of a generalized nature in the treatment group. The treatment group experienced significantly fewer symptoms than the placebo group throughout the season (p less than 0.02), although the difference was not dramatic. The results showed that GTR could be safely given in five preseasonal injections, with retained immunogenicity but less potential for generalized reactions. GTR is an improved method of allergy immunotherapy with the potential for clinical benefit when used in a brief preseasonal treatment regimen.

Aldehydes↗
PubMed1981

Amplification of the enzyme-linked immunosorbent assay for measuring allergen-specific IgE and IgG antibody.

The amplified enzyme-linked immunosorbent assay (a-ELISA) has been successfully applied to the measurement of allergen-specific IgE and IgG antibodies. Data presented indicate a high positive correlation among measurements of IgE-specific antibodies to ragweed antigen E using the a-ELISA, RAST and radiometric assay of Zeiss. Similarly, a high correlation between allergen-specific IgG antibodies measured by the a-ELISA and Farr assay was also observed. Data presented indicate that the measurement of serum IgE antibodies in the linear region of the ELISA titration plot is unaffected by competition with IgG antibodies. The assay is sensitive, reliable, and without risk to laboratory personnel. It is capable of measuring both IgE and IgG antibodies in patients using the same assay system.

Allergens↗
PubMed1980

Systemic and local lymphocyte responses in experimental hypersensitivity pneumonitis.

The pathogenesis of hypersensitivity pneumonitis is incompletely understood; cell-mediated hypersensitivity mechanisms may be involved, but in vitro correlates have been studied in humans with inconclusive results. We used a rabbit model of hypersensitivity pneumonitis to study systemic and local antigen-specific lymphocyte responses as measured by in vitro incorporation of 3H-thymidine. Groups of animals were systemically immunized with ovalbumin and acutely or repeatedly challenged with aerosolized ovalbumin. Lymphocyte responses were measured in peripheral blood, mediastinal and popliteal lymph nodes, bronchus-associated lymphoid tissue, and bronchoalveolar wash fluids in these groups and in appropriate control animals. Lymphocyte proliferative responses to specific antigen, shown previously to be a T-cell response in this system, occurred after systemic or inhalation exposure to antigen. Acute alveolitis was associated with a decrease in peripheral blood lymphocyte responses and the presence of responsive lymphocytes in bronchoalveolar was fluids. Repeated inhalation challenge thrice weekly for 1 month, with waning of alveolitis, was not associated with significant changes in lymphocyte responsiveness. Antigen-specific lymphocyte blastogenesis did not define animals capable of developing alveolitis after aerosol challenge and did not appear, therefore, to distinguish effector cell activity in this model.

Alveolitis, Extrinsic Allergic↗