Atrophy of the thymus and thymic lymphodepletion occurs after exposure to sublethal doses of TCDD. Previous studies using high doses of TCDD (150 micrograms/kg) have indicated a preferential lymphodepletion of the thymus cortex on day 4 after a single oral intubation. Here we describe the effects of a single oral intubation of lower dose levels of TCDD (1, 5, and 25 micrograms/kg) on thymic weights and thymocyte subpopulations in Wistar rats on day 4 after exposure. A single administration of 1 micrograms/kg TCDD induced a significant reduction in the number of immature CD4+CD8+ double-positive (DP) thymocytes. At this time point the numbers of mature CD3high medullary thymocytes were not affected at any dose level tested. We conclude that also lower dose levels of TCDD induce thymic atrophy via a preferential lymphodepletion of the thymus cortex.

Administration, Oral↗

PubMedDate not supplied

Covalent linkage of ruthenium polypyridyl compounds to poly(L-lysine), albumins, and immunoglobulin G.

A series of ruthenium polypyridyl complexes has been covalently bound to poly(L-lysine), bovine serum albumin, human serum albumin, ovalbumin, and immunoglobulin G using different binding methods. The conjugation ratios and the luminescence properties of the bioconjugates are reported. All conjugates show nonsingle-exponential decay curves. Quenching of the emission by oxygen has been studied.

Albumins↗

PubMedDate not supplied

Traffic-related air pollution affects peak expiratory flow, exhaled nitric oxide, and inflammatory nasal markers.

The authors used a longitudinal observational design, with repeated measures, to study the association between traffic-related air pollutants (i.e., nitric oxide, nitrogen dioxide, carbon monoxide, and Black Smoke) and respiratory symptoms. Subjects (N = 82) attended an elementary school in either Utrecht (i.e., urban children) or Bilthoven (i.e., suburban children). These two geographic areas differed with respect to levels of Black Smoke (means = 53 microg/m3 and 18 microg/m3, respectively). Levels of nitric oxide, nitrogen dioxide, carbon monoxide, and Black Smoke were consistently higher in Utrecht than in Bilthoven (mean daily ratios were 8, 1.5, 1.8, and 2.7, respectively). The authors compared mean levels of short-term effects of the aforementioned air pollutants on suburban and urban children. Urban children had higher mean levels (p = .05) of interleukin-8 (32%), urea (39%), uric acid (26%), albumin (15%), and nitric oxide metabolites (21%) in nasal lavage than did suburban children. Peak expiratory flow, exhaled nitric oxide levels, and nasal markers were associated with levels of particulate matter with diameters less than or equal to 10 microm, Black Smoke, nitrogen dioxide, and nitric oxide. With respect to per-unit increases in air pollution, urban children had more increased peak expiratory flow, higher levels of exhaled nitric oxide, and more increased release of uric acid, urea, and nitric oxide metabolites than suburban children. In summary, urban children had increased levels of inflammatory nasal markers, and their responses were more pronounced than were the suburban children's responses to the same increments of air pollution.

Adolescent↗

PubMedDate not supplied

Histopathologic approaches to detect changes indicative of immunotoxicity.

Toxicologic pathology is crucial in the identification and characterization of health effects following exposure to xenobiotics, mainly in toxicity experiments in rodents. Regarding regulatory toxicology, histopathology of lymphoid organs and tissues is a cornerstone in the identification of immunotoxic compounds. A 2-tier testing system is usually employed in which the first tier is a general screen for (immuno)toxicity and the second tier consists of specific immune function studies, including host resistance tests or mechanistic studies. The role attributed to histopathology of lymphoid organs in the updated Organisation for Economic Cooperation and Development and Food and Drug Administration guidelines requires improvement and standardization of the histopathology procedures. Optimalization and standardization was started in an international collaborative immunotoxicity study (ICICIS). However, several problems were left unaddressed, mostly because of the few compounds tested in this study. Based on the results of the ICICIS study and the morphologic changes induced by immunotoxic/immunomodulatory compounds observed in other investigations, suggestions are given to further improve the identification and (semi)quantification of histopathologic changes in lymphoid organs and tissues.

Animals↗

PubMedDate not supplied

Intestinal T lymphocytes of different rat strains in immunotoxicity.

In order to study the intestinal mucosal immune cells, with emphasis on single T lymphocytes, an inventory was made of single and organized lymphocytes in the epithelium and lamina propria of the small intestines of untreated Wistar, Fischer 344, and Lewis rats. The single and organized lymphocytes were examined microscopically. In addition, the single lymphocytes in the epithelium (IEL) and lamina propria (LPL) were analyzed by flow cytometry. Next, the use of flow cytometry analysis was explored to detect changes in the IEL T-lymphocyte population in subacute oral studies with the immunomodulating agents azathioprine and hexachlorobenzene. Untreated random-bred Wistar rats exhibited a large interindividual variability in IEL composition, while the variability was small in inbred Fischer 344 and Lewis rats. The explorative study with the 2 model immunomodulating compounds demonstrated that hexachlorobenzene increased the number of intraepithelial T lymphocytes with CD8+ phenotype at the cost of T cells with CD4+ phenotype in Lewis rats. Azathioprine did not induce distinct effects on the percentages of IEL. The data indicate that the intraepithelial lymphocytes in the intestines are a potential target for orally administered immunomodulating compounds and should therefore receive more attention in toxicologic pathology studies.

Animals↗

PubMedDate not supplied

Cyclosporin and the rat thymus. An immunohistochemical study.

We studied the effect of Cyclosporin A on the thymus in rats. A daily subcutaneous injection of Cyclosporin A at a dose of 45 mg/kg body weight in young adult rats resulted in a 100% mortality within two weeks. Daily administration of 15 mg/kg for two weeks was well tolerated. Rats treated at this dose showed whole blood Cyclosporin concentrations around 6 mg/l. The thymus immediately after treatment showed the almost complete disappearance of the medulla, including the microenvironment made by medulla-type epithelium, interdigitating dendritic cells defined by their expression of MHC class II antigen, and lymphocytes with a mature T-cell phenotype. After discontinuation of Cyclosporin treatment, a rapid recovery occurred, with the reappearance of medulla areas after 2 weeks. These areas differed from the normal medulla by the absence of medulla-type epithelium. This cell population recovered in its normal location in about 4 weeks. The reappearance of medullary interdigitating cells was associated with reappearance of lymphocytes with a mature T-cell phenotype. In the regenerating thymus "holes" in the microenvironment were observed that lacked epithelium and interdigitating cells, and that were filled by lymphocytes with an immature cortex phenotype. Peripheral lymphoid organs, of which the spleen was studied in more detail, did not manifest changes in lymphoid and stromal components. Target organs for syngeneic graft-versus-host disease, as described under special conditions after Cyclosporin treatment, did not show any histologic abnormality. The changes in thymus (immuno)histology may be associated with changes in shaping the T-cell repertoire: but, clinical manifestations of such changes require special experimental conditions.

Animals↗

PubMedDate not supplied

Immunotoxic effects of TCDD and toxic equivalency factors.

This paper first summarizes the studies indicating that the immunotoxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), notably atrophy of the thymus and suppression of the thymus-dependent immunity, are mediated by binding to a soluble cytosolic protein, the aryl hydrocarbon (Ah) or TCDD receptor, present in the thymus in the epithelial cells. On the basis of a common receptor-mediated mechanism of toxic action, the relative (immuno)toxicity of individual PCDDs and PCDFs can be expressed relative to TCDD (i.e., toxic equivalents). Next, studies on TCDD-induced immunosuppression and impaired host resistance, and lowest observed effects levels of TCDD resulting in immune alterations, are summarized. Immune investigations performed in man are discussed and it is concluded that, for risk assessment purposes, further studies are necessary to determine the sensitivity of the human immune system to TCDD. For this purpose, a recent study is summarized in which the sensitivity of the human thymus to TCDD is investigated in so-called severe combined immunodeficient (SCID) mice in which human thymus grafts were transplanted. This study indicates that the human thymus and the Wistar rat thymus display a similar sensitivity to TCDD.

Animals↗