Zymosan-induced experimental hypersensitivity pneumonitis in rabbits.

An experimental model of hypersensitivity pneumonitis is presented. New Zealand white rabbits, previously immunized against yeast-derived zymosan, reacted to intratracheal challenge developing extensive pneumonitis. The lesions healed in a few weeks. Control animals challenged with inert particulate material (latex beads) or suspending fluid (PBS-Mg++) did not show pulmonary inflammation. Nonimmunized rabbits developed only transient pneumonitis after zymosan challenge. This reaction was clearly different from that seen in the group of immunized animals. The model reveals that biologically active substances such as zymosan, which is able to activate the alternate pathway of complement and mononuclear phagocytes, requires an active immune state in order to cause significant tissue damage. Isolated exposure to this kind of substance may not be sufficient to cause lung disease.     

Fatal hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an uncommon, non-IgE-mediated interstitial lung disease caused by the inhalation of a variety of organic dusts, most commonly from exposure at work or in the pursuit of hobbies. Typically, after the disease is recognized, the causative allergen or environment is identified and treatment initiated through avoidance measures and corticosteroids. Progression of the disease is then usually halted and even reversed. Fatal cases of HP are unusual. OBJECTIVE: To report a case of progressive and deadly HP in a 40-year-old printer who developed subacute bird fancier's disease with its clinical characteristics and positive precipitins to pigeon proteins. METHODS: Chest x-ray examinations and tests of lung function were performed in the patient. Two months after initial consultation, when the diagnosis was still elusive, an open lung biopsy was performed and the patient was treated with prednisone for 3 months. A subsequent chest x-ray examination was performed 4 months after the biopsy. RESULTS: With avoidance of birds and treatment with corticosteroids, the patient's symptoms resolved and lung function normalized. He was subsequently diagnosed as having asthma followed by bronchitis and 2 episodes of pneumonia. He did not fully recover from these but developed progressive dyspnea. After linking his symptoms to work by history, he underwent lung biopsy with findings consistent with chronic HP. Serum antibody titers were positive for Aspergillus but not pigeon proteins. Based on exposure to water-based coolants, he was suspected of having chronic occupational HP, although this could not be confirmed. Despite aggressive treatment, he developed a progressive course that was ultimately fatal. CONCLUSIONS: This report details the progressive disease course in an individual who presented initially with subacute HP. Unfortunately, even after appropriate diagnosis and management, the course of the disease can be fatal.     

Immunopatholgenesis of hypersensitivity pneumonitis.

This review describes antigenic and host factors of possible significance in the immunopathogenesis of hypersensitivity pneumonitis (HP). Although certain immunologic studies suggest immune complex mechanisms in HP, recent experimental and clinical data accumulated support a role for cell-mediated immunity. In addition, some data support roles for anaphylactic and cytotoxic antibody-mediated reactivity as well. One type of reactivity alone may not be sufficient for production of HP, and local pulmonary immune responses may be most relevant to the pathogensis. Whether immune damage will be produced in an exposed individual or not may depend on the characteristics of the antigenic exposure as well as inherited and acquired individual differences in immunologic reactivity and possibly target organ sensitivity.     

Mast cell hyperplasia: role of cytokines

Mast cell hyperplasia is found in different pathologies such as chronic inflammatory processes, fibrotic disorders, wound healing or neoplastic tissue transformation. The functional significance of the accumulation of mast cells in these processes is largely unknown. It is now established that bone marrow-derived mast cell progenitors circulate in peripheral blood and subsequently migrate into the tissue where they undergo final maturation under the influence of local microenvironmental factors. Cytokines are of particular importance for mast cell recruitment, development, and function. Stem cell factor (SCF) is a unique mast cell growth factor, since mast cells disappear completely in the absence of SCF. However, several other cytokines such as IL-3 and IL-4 have been shown to influence mast cell proliferation and function also. This review focuses on the role of cytokines in the regulation of mast cell hyperplasia.     

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.     

Down regulation in hypersensitivity pneumonitis

Levels of soluble interleukin-2 receptor (sol-IL-2R) in the bronchoalveolar lavage fluid (BALF) of pigeon breeders with hypersensitivity pneumonitis were compared with BALF levels in asymptomatic pigeon breeders who had been exposed to pigeon allergens for an equivalent length of time. No mean difference in sol-IL-2R levels was detected when these levels were expressed per milliliter BALF, epithelial lining fluid, or per T-lymphocyte. In sarcoidosis, the availability of sol-IL-2R per T cell was significantly higher for the group with inactive sarcoidosis compared with the group with active sarcoidosis. The results do not support the hypothesis that down regulation, in subjects exposed to allergens causing hypersensitivity pneumonitis, is a function of cell-free sol-IL-2R levels in BALF. In the dynamic situation, however, the hypothesis appears tenable.     

Passive transfer of experimental hypersensitivity pneumonitis with lymphoid cells in the rabbit

Although precipitating antibody is associated with human hypersensitivity pneumonitis, there is evidence that cell-mediated hypersensitivity may be involved in disease pathogenesis. In this study, alveolar, interstitial, and peribronchial lesions were produced by respiratory challenge of rabbits passively sensitized with ovalbumin-sensitive lymph node cells. Ovalbumin sensitivity of donor rabbits and lymph node cells was demonstrated by skin testing, migration inhibition factor (MIF) production using alveolar wash cells as migrating cells, and lymphocyte stimulation. Passive cell transfer was accomplished by intraperitoneal injection with all lymph node cells obtained from one donor transferred to one recipient. Recipients were challenged by aerosol or intratracheal injection of antigen immediately or 24 hr after passive sensitization and were killed 48 hr after challenge. Lesions in rabbits passively sensitized by lymph node cells and challenged with antigen by intratracheal inoculation consisted of focal pneumonitis with intra-alveolar edema and infiltrates of mononuclear cells in alveoli and alveoli septa. Aerosol challenge of passively sensitised animals produced similar changes, but peribronchial lymphoid tissue containing macrophages and germinal centers was prominent in this group. Antiovalbumin serum recipients challenged by intratracheal injection demonstrated only mild peribronchial mononuclear cell infiltrates, without pneumonitis. Control animals receiving lymph node cells only or challenge only demonstrated no changes in lung histology.     

Pigeon-serum-induced hypersensitivity pneumonitis in the dog

Pigeon serum (PS) is one of the most common causes of hypersensitivity pneumonitis (HP). PS-induced HP was examined in a dog model. The dogs ( n =6) were immunized by i. m. injections of PS, followed by insufflation with aerosolized PS, while all control dogs ( n =3) received saline only. All animals insufflated with PS developed tachypnea 2–4 h after PS inhalation. After PS insufflation, a significant decrease in arterial oxygen tension (PaO₂) was detected in sensitized dogs. No change in PaO² was detected in sensitized dogs after saline or in the controls after PS insufflation. In intradermal skin tests with PS antigen, a positive skin reaction was found in 3/6 dogs in 30 min, and in 5/6 dogs in 6 and 48 h after the PS injections. Sensitized dogs showed a significant increase in PS-specific IgG in serum and lavage fluid (LF). In LF of sensitized dogs, an increase in the percentage of lymphocytes, eosinophils, and neutrophils was detected. Sensitized dogs developed chronic interstitial inflammation with lymphocytes, macrophages, plasma cells, and eosinophils in lungs. Granulomas with lymphocytes, histiocytes, and giant cells were detected in both the interstitium and the bronchiolar wall in the lungs of sensitized dogs. PaO² was lowest in dogs showing the most severe interstitial inflammation in the lungs. The results indicate that dogs can be successfully used in immunologic and physiologic studies of PS-induced HP.     

Activated lung lymphocytes in hypersensitivity pneumonitis

T-lymphocyte activation was investigated in peripheral blood and bronchoalveolar lavage (BAL) of four patients with hypersensitivity pneumonitis. The study was performed by flow cytometry with the use of immunofluorescence labeling with monoclonal antibodies to lymphocyte differentiation or activation antigens. Simultaneous measurement of DNA and RNA content by acridine orange staining was used for cell-cycle analysis. The various cell types were identified by their light-scattering properties. T cell activation was demonstrated in the BAL of all patients by the presence of T cells (OKT3 positive) bearing class II histocompatibility antigen (HLA-DR) and activated T cell markers (MLR 1-3). Lymphocyte proliferation was evidenced in BAL but not in blood of patients by an increased percentage of cells in S + (G2 + M) phases. In addition, T-lymphocyte subsets analysis revealed no abnormalities in the blood and no major imbalance in the BAL despite a slightly increased OKT4/OKT8 ratio. The finding of T cell activation and lymphocyte proliferation in hypersensitivity pneumonitis alveolitis is consistent with the contribution of a local type IV immune reaction to the pathogenesis of this disease.