Topical levocabastine compared with orally administered terfenadine for the prophylaxis and treatment of seasonal rhinoconjunctivitis.

BACKGROUND: This study was designed to compare the efficacy and tolerability of a new topical (nasal spray and eye drops) H1-receptor antagonist, levocabastine, with that of orally administered terfenadine for the prophylaxis and treatment of seasonal allergic rhinoconjunctivitis. METHODS: A total of 115 patients with documented birch pollen allergy were enrolled in this randomized, double-blind, double-dummy, parallel-group trial. Treatment was initiated immediately before the birch pollen season started and continued for a total of 8 weeks. Xylometrazoline (Otrivin) nasal spray was permitted as rescue medication. RESULTS: The investigator's evaluation of symptoms showed similar effects for levocabastine and terfenadine. Both the patients' and the investigator's global evaluations of ocular and nasal symptoms disclosed a somewhat higher percentage of good or excellent results for levocabastine, but the differences were not statistically significant. Visual analog scale ratings from the patients' diaries showed better results for levocabastine. Levocabastine was significantly more effective than terfenadine in relieving sneezing, rhinorrhea, lacrimation, itch, and burning sensation (p < 0.05). For some symptoms, levocabastine was significantly more effective than terfenadine on days when the pollen count was high. There were no statistically significant differences in the use of rescue medication or in the incidence of adverse reactions reported in each treatment group. CONCLUSIONS: In the present study topical levocabastine was frequently more effective than orally administered terfenadine for the treatment of seasonal allergic rhinoconjunctivitis. Both drugs were well-tolerated.

Significance of different J chain profiles in human tissues: generation of IgA and IgM with binding site for secretory component is related to the J chain expressing capacity of the total local immunocyte population, including IgG and IgD producing cells, and depends on the clinical state of the tissue.

Most IgA producing cells in normal intestinal and nasal mucosa synthesize dimers or larger polymers as evidenced by 90% cytoplasmic affinity for secretory component (SC) in vitro and almost 100% J chain positivity. The comparable median figures for normal exocrine glands (salivary, lacrimal, lactating mammary) were 84% and 92%, respectively. Conversely, IgA immunocytes in the subepithelial areas of palatine tonsils and in other extraglandular tissues, such as inflamed gingiva and intestinal submucosa, showed only 16-28% SC binding capacity and 18-51% J chain positivity. Similarly decreasing J chain expression, from glandular to extraglandular sites, was revealed not only for IgM immunocytes but also for those producing IgD or IgG, particularly the latter. This observation indicated more extensive overall clonal maturation in tissues without glandular elements since J chain expression seems to be a feature of relatively early memory B cells. The results were supported by studies in patients with selective IgA deficiency. Inflammatory disease caused significantly reduced SC binding capacity of IgA cells, both in intestinal mucosa and tonsils; this change was paralleled by decreased J chain expression, not only for mucosal and tonsillar IgA cells but also for mucosal IgG cells, suggesting local appearance of more mature clones. The resulting change to production of monomeric IgA may adversely affect secretory immunity and thus contribute to perpetuation of chronic inflammatory disease.

Immunohistochemical characterization of cellular immunoglobulins and epithelial marker antigens in Warthin's tumor.

Lymphoid and epithelial cell marker studies based on paired immunofluorescence staining were performed on ethanol-fixed specimens from six Warthin's tumors of the parotid gland. A polyclonal pattern of isotype and light-chain expression was demonstrated for immunoglobulin-producing cells and afforded definitive evidence for the reactive nature of B-cell proliferation. The average percentages of IgG, IgA, IgM, IgD, and IgE immunocytes were 48.6, 38.5, 8.9, 3.3, and 0.7, respectively. The percentages of J-chain-positive cells within the first four isotypes were 11.3, 47.0, 67.2, and 64.4. Both features were more typical of immune responses in lymphoid tissues than in exocrine glands. In five of the six specimens, IgE was present in a prominent lacy pattern in some follicular centers, often extending to lymphocyte membranes of the mantle zone. Mast cells positive for IgE were seen in all cases. The two latter features indicate that type 1 hypersensitivity might contribute to the lesion. Parts of the tumor epithelium stained selectively for dimeric IgA and secretory component (SC), signifying secretory capacity. In addition, lactoferrin and carcinoembryonic antigen (CEA) occasionally were present in a narrow cytoplasmic luminal rim. Carcinoembryonic antigen was also seen in papillary epithelial projections. Lysozyme was found in isolated epithelial cells, whereas amylase was completely lacking. Except for the presence of CEA, this pattern of epithelial markers resembled that seen in striated ducts of normal salivary glands.

Immunofluorescence study of secretory epithelial markers in pleomorphic adenomas.

Amylase (Am), lactoferrin (Lf), lysozyme (Ly), secretory component (SC), epithelial IgA, and epithelial IgM were traced by paired immunofluorescence staining in ethanol-fixed specimens from 15 pleomorphic adenomas of the parotid gland. Epithelial elements positive for some of the markers were detected in a variable number of the specimens (Am, 0; Lf, 11, Ly, 2; CEA, 6; SC, 11; IgA, 9; and IgM, 6); their expression seemed to depend on a certain degree of glandular differentiation. Variable co-expression of secretory epithelial markers probably reflected different degrees of differentiation, indicating that clonal diversification may explain the histological complexity of pleomorphic adenomas. The most consistent expression (in almost 75% of the specimens) shown by Lf and SC might further reflect histogenetic relationship to intercalated ducts in which these antigens are normally found in largest amounts.

Characterization of epithelial elements in human major salivary glands by functional markers: localization of amylase, lactoferrin, lysozyme, secretory component, and secretory immunoglobulins by paired immunofluorescence staining.

Human parotid and submandibular glands were studied by paired immunofluorescence staining, including a variety of combinations of fluorochrome conjugates with contrasting colors. Lactoferrin (Lf), secretory component (SC), and particularly amylase were demonstrated in serous acinar cells of both glands. In addition, lysozyme (Ly) was present in some acini, although mainly located in intercalated ducts where Lf was also most commonly seen. SC was present in acini, intercalated ducts, and striated ducts but not in large collecting ducts. Staining for SC was generally faint but increased in intensity at the cell periphery and particularly at the luminal face of striated duct cells. Immunoglobulin (Ig) A--and IgM when detectable--showed an epithelial distribution similar to that of SC, in accordance with the known secretory properties of these two Ig classes. Conversely, IgG was not present in epithelial cells, despite its high extravascular concentrations. Mucous epithelial elements did not show unequivocal staining for any of the proteins studied. Formaldehyde fixation, combined with pronase treatment of tissue sections and prolonged exposure (20 hr) to antibody, enhanced markedly the staining intensity for lysozyme; ethanol fixation and 30-min incubation with conjugates generally afforded better localization of the other epithelial components.

Influence of tonsillar disease on the expression of J chain by immunoglobulin-producing cells in human palatine and nasopharyngeal tonsils.

A significant reduction of the percentage of J-chain-positive intra- and extra-follicular IgA immunocytes was found in inflamed palatine tonsils. There was a tendency to similar alterations in hypertrophied adenoids. Tonsillar disease apparently enhances local maturation of the B-cell system, perhaps on the basis of intensified proliferation of memory clones. Alternatively, there may be a disease-associated defect in the mechanism(s) that normally induced switchover to the IgA isotype early in clonal development. It is speculated that, by decreasing the J-chain expression during local B-cell differentiation, tonsillar disease may jeopardize the potential of the tonsils as a putative precursor source for the secretory immune system of the upper aero-digestive tract.

Immunohistochemical evaluation of J-chain expression by intra- and extra-follicular immunoglobulin-producing human tonsillar cells.

Cytoplasmic J-chain expression by Ig-producing cells was characterized immunohistochemically in normal specimens of palatine and nasopharyngeal tonsils (adenoids). Altogether follicular immunocytes, which were mainly of ther IgG and IgM isotypes, showed a much higher percentage of J-chain positivity than the extrafollicular ones, in agreement with the idea that this polypeptide is principally a marker of differentiating or newly differentiated Ig-producing cells. Thus, in concurrence with the predominating IgG isotype, J-chain expression was almost 50% in the germinal centres of lymphoid follicles but only about 2% in the extrafollicular compartment. By contrast, a substantial number of J-chain-positive IgA immunocytes were found in the latter compartment. Since it is believed that extrafollicular Ig-producing cells are mainly derived from follicular centre cells, this result indicated that significant isotype switching is involved in tonsillar B-cell differentiation. Most tonsillar IgD immunocytes were J-chain-positive, in accordance with the notion that IgD expression is a feature of relatively early clonal development. It is postulated that J-chain-positive B-cell blasts may leave the tonsils and, through isotype switching, contribute to the dimer-producing IgA-cell populations normally found in the exocrine glands of the upper aero-digestive tract.

Quantitative immunohistochemistry of immunoglobulin- and J-chain-producing cells in human parotid and submandibular salivary glands.

Ig-producing cells were quantified by paired immunohistochemical staining in saline-extracted and paraffin-embedded normal tissue specimens from human parotid (ten) and submandibular (seven) salivary glands. The density of such cells (number/mm2 of 6 micron thick tissue section) was significantly higher in the submandibular than in the parotid gland (P less than 0.005), but the Ig-class distribution was fairly similar. The mean percentage class ratios for IgG, IgA, IgM and IgD cells in the parotid were 4.5:86.5:5.9:3.1, and in the submandibular gland 3.7:86.9:7.9:1.6. In the parotid gland of a patient with selective IgA deficiency the same class ratios were 27:0:20:53. Thus, the IgA cells were especially replaced by IgD cells. In normal glands most of the IgA (80-93%), IgM (99-100%) and IgD cells (81-95%) were J-chain-positive; this was likewise true for a substantial proportion of the IgG cells (32-46%). Of additional interest was the finding that in the IgA-deficient parotid gland, 99% of the numerous IgD cells and 86% of the increased number of IgG cells contained cytoplasmic J chain. IgE-producing cells were virtually absent from the IgA-deficient as well as from the normal salivary glands.

Immunohistochemical studies on the epithelial and lymphoid components of Warthin's tumour.

The lymphoid and epithelial elements of three Warthin's tumours (adenolymphomas) were studied by immunohistochemical technique. All classes of immunoglobulin (Ig)-producing cells were found, except IgE immunocytes. The numbers of cells/mm2 section area (median and range) were: 20.4 (15.2--27.2), 4.8 (2.8--12.4). 4.8 (0.4--9.6) and O (0--1.2) for IgG-, IgA-, IgM- and IgD-producing cells respectively. This gives percentage class ratios (68:16:16:0) which are quite different from those found in normal parotid tissue (3.6:91:3.1:2.6). Thus, the immunocytes found in Warthin's tumour are clearly polyclonal and show a class distribution comparable to that of lymphoid organs such as the tonsils. Also as in such organs, there were lymphoid follicles with mantle zone of B lymphocytes bearing membrane-bound IgM and IgD, and germinal centres showing reticular IgM staining. Apical staining for IgA and secretory component (SC) was shown in the luminal cells of the tumour epithelium, giving a fluorescence pattern similar to that of normal striated ducts. Selective transport of IgA apparently taken place into the cystic spaces of the tumour. Carcino-embryonic antigen (CEA), normally absent from striated ducts, was not generally present in the tumour epithelium, but was found in small groups of cells, especially in papilliferous parts of the epithelium. Warthin's tumour therefore seems to be composed of a fairly inactive normal lymphoreticular tissue and a neoplastic duct epithelium, most of which is highly differentiated with retention of immunoglobulin transport.