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Biomedical subjects

J Westermann

Publications and source records attributed to J Westermann.

At least 37 records · Page 2Linked to original sources
PubMed2000

In vivo immunomodulation by peripheral adrenergic and cholinergic agonists/antagonists in rat and mouse models.

Our work is devoted to defining relationships between the immune system and the adrenergic and cholinergic systems in vivo. In the rat model, we have shown that the cells of different immune compartments express the genes of a defined set of adrenergic/cholinergic receptors, and it was shown that lymphocytes are a site of non-neuronal production of norepinephrine and acetylcholine. Furthermore, using implantable slow-release tablets containing adrenergic or cholinergic agonists/antagonists, distinct and partly opposite effects were observed on peripheral immune functions. Concerning sympathetic immunoregulation, our data--in contrast to those of other studies--suggest that an enhanced adrenergic tonus leads to immunosuppression primarily via alpha 2-receptor-mediated mechanisms. Beta-blockade strongly enhances this effect, most likely by inhibition of pineal melatonin synthesis. In recent experiments on the kinetics it was found that the continuous alpha-adrenergic treatment entails a strong suppression of cellular responsiveness during the first few hours, which is increasingly followed by a general loss of lymphocytes in blood and lymphoid organs most likely due to enhanced apoptosis. More recently, we have extended our studies to the mouse model. First data obtained with RNAse protection assays suggest a biphasic effect on the gene expression of several cytokines in spleen cells due to adrenergic in vivo treatment.

Animals↗
PubMed2000

Infection of human monocyte-derived macrophages with Chlamydia trachomatis induces apoptosis of T cells: a potential mechanism for persistent infection.

Viruses can escape T-cell surveillance by infecting macrophages and thereby induce apoptosis of noninfected T cells. This ability had not been demonstrated for bacteria. We investigated whether infection of macrophages with the important human pathogen Chlamydia trachomatis can induce T-cell apoptosis. Because Chlamydia-Mycoplasma coinfection is a frequent event, the ability of Mycoplasma fermentans-infected macrophages to induce T-cell apoptosis was also studied. Infected macrophages were cocultivated with autologous T cells in different activation states. Propidium iodide-based fluorescence-activated cell sorter analysis demonstrated that macrophages infected with viable chlamydiae induced T-cell death. Apoptosis was identified as the mode of death induction by using a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay. Induction of T-cell death was macrophage dependent. Incubation of T cells with infectious chlamydiae in the absence of macrophages did not lead to T-cell apoptosis. UV irradiation of chlamydiae diminished the ability to induce death. T-cell death was induced by a cell-free supernatant of infected macrophages. Not only phytohemagglutinin-preactivated T cells but also non-mitogen-preactivated T cells were susceptible to C. trachomatis-induced apoptosis. In contrast, M. fermentans infection of macrophages did not induce T-cell death. Coinfection had no additional effect. In summary, intracellular chlamydial infection of macrophages can induce T-cell apoptosis. Apoptosis induction by chlamydiae possibly explains how persistently infected macrophages escape T-cell surveillance and why the Chlamydia-specific T-cell response is diminished during persistent chlamydial infection.

Apoptosis↗
PubMed2000

Conditioned suppression of contact sensitivity is independent of sympathetic splenic innervation.

The present study investigated the role of sympathetic innervation of the spleen in conditioned suppression of a contact hypersensitivity (CHS) reaction. Behavioral conditioning was achieved by pairing saccharin drinking solution (conditioned stimulus, CS) with injection of cyclosporin A (CsA, 20 mg/kg; unconditioned stimulus, UCS). Four days after sensitization of the animals by application of a 5% 2,4-dinitrochlorobenzene (DNCB) to abdominal skin, the animals were challenged by applying a 1% DNCB solution to the ear. The CHS response was monitored by measuring the degree of ear swelling. Saccharin re-presentation reduced ear swelling to a magnitude that approached that achieved by CsA treatment. Histological examination demonstrated that the conditioned reduction of ear swelling was produced by a reduced leukocyte infiltration of the ear. Prior sympathetic denervation of the spleen did not alter the conditioned suppression of the CHS response. These data indicate that behavioral conditioning using CsA produces alterations of CHS that, unlike conditioned prolongation of heart allograft survival, are independent of sympathetically regulated conditioned alterations in the spleen.

Animals↗
PubMed2000

Conditioned alterations of specific blood leukocyte subsets are reconditionable.

Behavioral conditioning has the ability to produce changes in immune function. However, it is unknown whether conditioned changes of immune function can be recalled on multiple occasions. To address this issue we paired a novel saccharin drinking solution with intraperitoneal cyclosporin A (CsA) injection in rats. Saccharin re-presentation produced a reduction in splenocyte proliferation that mirrored the effect of CsA. Such functional changes were paralleled by a significant conditioned leukopenia in peripheral blood, which opposed the leukocytosis induced by CsA. Using the conditioned leukopenia in blood as a 'diagnostic window' of conditioned immunosuppression, the maintenance of CsA-induced changes was investigated by examining blood samples collected repeatedly. Experiments on the same group of animals over a period of 1 year showed that the conditioned leukopenia was reproducible on multiple occasions by reimplementing either the whole conditioning paradigm or reexposure to the saccharin solution only. These results demonstrate that behaviorally conditioned alterations of immune parameters are maintained in subsequent trials, indicating the potential clinical feasibility of behavioral conditioning procedures.

Animals↗
PubMed2000

A targeted DNA vaccine encoding fas ligand defines its dual role in the regulation of experimental autoimmune encephalomyelitis.

This study used naked DNA vaccination to induce breakdown of tolerance to self and thus elicit immunological memory to native, membrane-bound Fas ligand (FasL). Upon induction of experimental autoimmune encephalomyelitis (EAE), this memory was turned on to provide protective immunity. FasL-specific autoantibodies isolated from protected animals differentially downregulated the in vitro production of TNF-alpha, but not IFN-gamma, by cultured T cells. These autoantibodies were highly protective when they were administered to rats at the onset of EAE. In contrast, administration of these FasL-specific Ab's to EAE rats after the peak of the acute phase of disease prevented spontaneous recovery from disease. This extended illness is partially explained by inhibition of mononuclear cell apoptosis at the target organ, which resulted in increased accumulation of T cells and macrophages at the site of inflammation. Hence, FasL exerts two distinct, stage-specific regulatory functions in the control of this T-cell mediated autoimmune disease of the central nervous system.

Animals↗
PubMed2000

Health status and health professional visits in a rural area.

Visits to physicians (MDs), physician assistants (PAs) or nurse practitioners (NPs) by residents of a rural county in the upper-middle west of the United States were analysed in this study. A telephone survey yielded 250 responses. The dependent variable was the natural logarithm of the number of times the respondent had seen a health professional (MD, PA or NP) in the past two years. Predisposing, enabling and medical need variables were tested as potential predictors of visits. Self-rated health status, being unable to perform usual activities, and feeling upset or 'down in the dumps' proved to be important predictors, as was having a usual source of care. Health insurance coverage and family income was not, however. Unexpectedly, smokers also reported more visits. The implications for policy and future research are discussed.

Adult↗
PubMed2000

Evaluation of a new simple and rapid enzyme-linked immunosorbent assay kit for neopterin determination.

A new commercially available enzyme-linked immunosorbent assay (ELISA) kit has been evaluated for the measurement of neopterin concentrations in serum, plasma and urine. This competitive ELISA is technically simple, requires only small sample volume and is rapid to perform. The assay procedure consists of sequential 1.5 h and 10 min room temperature incubation steps. The ELISA is accurate, sensitive, specific, and precise. Linear regression analysis of neopterin concentrations measured with the new ELISA and with an established method yielded a highly significant correlation (r = 0.99). The new assay is applicable to ELISA workstations, thus enabling determination of neopterin in large series of samples. The neopterin ELISA kit has been used in routine laboratory testing of blood donations in a blood bank.

Antibody Specificity↗
PubMed1999

Naive and memory T lymphocytes migrate in comparable numbers through normal rat liver: activated T cells accumulate in the periportal field.

Although the liver is known to contain a significant number of lymphocytes, migration of these through the compartments of the liver, parenchyma and periportal field, has not been studied. The periportal field, in particular, is affected in several immunological disorders of the liver. Populations of labeled naive, activated, and memory T cells were injected into congenic rats. The recipient livers and draining lymph nodes were removed at various time points, and cryostat sections were analyzed for the presence of donor cells using quantitative immunohistology. Donor cell proliferation and apoptosis were examined in vivo by BrdU (5 microM 5-bromo-2-deoxyuridine) incorporation and the TUNEL technique, respectively. Early after injection (0.5-1 h), naive, activated, and memory T cells were localized to the parenchyma and periportal field in comparable numbers. With time, all T cell subsets left the parenchyma but remained or, in the case of activated T cells, significantly accumulated in the periportal field. Furthermore, 12% of activated donor T cells proliferated in vivo within the periportal field, and 0.5% showed evidence of apoptosis. Taken together, not only activated and memory, but also naive T cells continuously migrate through the liver, showing a preference for the periportal field, and activated T cells mainly proliferate there. This may explain why many immunological liver diseases predominantly affect the periportal field.

Animals↗
PubMed1999

Lymphocyte migration in lymphocyte function-associated antigen (LFA)-1-deficient mice.

Using lymphocyte function-associated antigen (LFA)-1(-/-) mice, we have examined the role of LFA-1 and other integrins in the recirculation of lymphocytes. LFA-1 has a key role in migration to peripheral lymph nodes (pLNs), and influences migration into other LNs. Second, the alpha4 integrins, alpha4beta7 and alpha4beta1, have a hitherto unrecognized ability to compensate for the lack of LFA-1 in migration to pLNs. These findings are confirmed using normal mice and blocking LFA-1 and alpha4 monoclonal antibodies. Unexpectedly, vascular cell adhesion molecule (VCAM)-1, which is essential in inflammatory responses, serves as the ligand for the alpha4 integrins on pLN high endothelial venules. VCAM-1 also participates in trafficking into mesenteric LNs and Peyer's patch nodes where mucosal addressin cell adhesion molecule 1 (MAdCAM-1), the alpha4beta7-specific ligand, dominates. Both alpha4beta1, interacting with ligand VCAM-1, and also LFA-1 participate in substantial lymphocyte recirculation through bone marrow. These observations suggest that organ-specific adhesion receptor usage in mature lymphocyte recirculation is not as rigidly adhered to as previously considered, and that the same basic sets of adhesion receptors are used in both lymphocyte homing and inflammatory responses.

Animals↗
PubMed1999

Activated T cells enter rat lymph nodes and Peyer's patches via high endothelial venules: survival by tissue-specific proliferation and preferential exit of CD8+ T cell progeny.

Activated T cells reach the lymph nodes via afferent lymphatics but it is unknown to what extent they also enter them directly via high endothelial venules (HEV). Little is known about the mechanism mediating the proliferation of activated T cells within lymphoid tissues in vivo or the subsequent fate of the progeny. Therefore, we stimulated rat T cells via TCR and CD28 in vitro and after injection identified them in the blood and the HEV of lymphoid organs at several time points. In addition, the proliferation of these cells was studied after entering different lymphoid organs. Our results show that, firstly, activated T cells continuously enter lymph nodes and Peyer's patches directly via HEV. Second, they proliferate within lymphoid organs, the rate significantly depending on the microenvironment. Third, mainly CD8+ progeny are able to leave the tissues and re-enter the blood. Thus, the distribution of activated T cells circulating through the body can be regulated during entry, but also within the tissue by influencing their proliferation and subsequent release.

Animals↗
PubMed1999

Distribution of activated T cells migrating through the body: a matter of life and death.

The preferential distribution of lymphocyte subsets in tissues is attributed to a selective lymphocyte-endothelium interaction during entry. However, proliferation and death within the tissue, and exit from the tissue, might also play a role. Here, Jürgen Westermann and Ulrike Bode provide evidence that preferential survival in the tissue of initial stimulation is the major factor in the preferential distribution of activated T cells.

Animals↗
PubMed1999

CD95/Fas-triggered apoptosis of activated T lymphocytes is prevented by dendritic cells through a CD58-dependent mechanism.

T-cell apoptosis is a mechanism regulating T-cell homeostasis. Activation renders T cells susceptible to activation-induced cell death, a process mediated through CD95 ligand/CD95 (Apo-1/Fas) ligation. The aim of this study was to test whether antigen-presenting cells can inhibit CD95/Fas-triggered activation-induced cell death. Dendritic cells (DC), which are highly effective antigen-presenting cells, were generated in vitro from human peripheral blood monocytes by culture in granulocyte-macrophage colony-stimulating factor and interleukin 4. Subsequently, DC were cocultured with activated T cells and the effect of DC on CD95/Fas-mediated apoptosis was determined. Coculture with increasing amounts of DC prevented CD95/Fas-triggered apoptosis in a dose-dependent fashion by inhibiting activation of caspase 8 and caspase 3. This protective effect of the DC on T-cell death could be blocked by 50% by adding an anti-CD58 antibody, whereas further addition of anti-CD80 (B7.1) and anti-CD86 (B7.2) led to an even more pronounced effect. Our findings suggest that DC can protect T cells from activation-induced cell death, with CD58 ligation playing a key role.

Antibodies, Monoclonal↗
PubMed1999

Conditioned immunosuppression makes subtherapeutic cyclosporin effective via splenic innervation.

The present study investigated the mechanisms by which conditioned immunosuppression enhances the effectiveness of cyclosporin A (CsA) treatment in prolonging heart allograft survival. Dark Agouti rats that were administered subtherapeutic CsA (7 x 2 mg/kg on alternate days) rejected heart allografts at the same time as non-CsA-treated rats. The addition of a behavioral conditioning regimen (conditioned stimulus, saccharin; unconditioned stimulus, 20 mg/kg CsA) to the subtherapeutic CsA protocol produced a significant prolongation of graft survival, including long-term survival (>100 days) in 20% of the animals. Prior sympathetic denervation of the spleen completely blocked this effect. In nontransplanted rats both conditioning and CsA treatment reduce interleukin-2 and interferon (IFN)-gamma in the supernatant of proliferating splenocytes. Additionally, therapeutic CsA treatment decreased the number of IFN-gamma-producing CD4(+) naive and memory T cells in the spleen. In contrast, behavioral conditioning increased that number. These data indicate that behavioral conditioning prolongs heart allograft survival by inhibiting the release of these cytokines in the spleen via sympathetic innervation, supplementing the inhibited cytokine production induced by CsA treatment.

Animals↗
PubMed1999

Increased expression of activation markers and adhesion molecules on lung T-cells compared with blood in the normal rat.

Lymphocytes play an important role in many lung diseases and are routinely accessible by bronchoalveolar lavage (BAL). Lymphocytes from the BAL (BAL pool) have a different subset composition to those from peripheral blood, consisting mainly of activated T-cells. The aim of this study was to examine whether preferential migration of activated T-cells to the bronchoalveolar space or factors of the specific microenvironment mediate this phenomenon. The expression of adhesion molecules and cellular activation markers (intercellular adhesion molecule-1, leukocyte function-associated antigen-1, CD2, CD44, interleukin-2 receptor and L-selectin) was studied on T- and B-cells not only in the BAL and peripheral blood (blood pool), but also in the compartments in between, such as the lung vascular perfusate (marginal pool) and the lung interstitium (interstitial pool), with the experiments being performed simultaneously in the same animals. Low levels of adhesion molecule expression were observed on T-cells in the blood and marginal pool, medium levels in the lung interstitium and the highest levels in the BAL. "Memory" (CD45R(low)) and "naive" (CD45R(high)) T-cells in the lung compartments showed a higher expression of adhesion molecules compared with blood. However, the predominating CD45R(low) T-cells showed a significantly higher expression than the CD45R(high) cells, indicating that CD4+ CD45R(high) T-cells had changed their phenotype to CD45R(low). In conclusion, a high level of expression of leukocyte function associated antigen-1 and intracellular adhesion molecule-1 on the bronchoalveolar lavage and interstitial T-cells is more likely to be the result of local, lung-specific induction than a prerequisite for migration into the bronchoalveolar space.

Animals↗
PubMed1999

Acute laryngitis in the rat induced by Moraxella catarrhalis and Bordetella pertussis: number of neutrophils, dendritic cells, and T and B lymphocytes accumulating during infection in the laryngeal mucosa strongly differs in adjacent locations.

Infectious laryngotracheitis results in fulminant respiratory distress. During the disease, the subglottic mucosa is selectively infected and swollen, the reason for this preference being unknown. Therefore, in the present study the immunoreaction of the laryngeal mucosa was studied in the rat after inhalation of either heat-killed Moraxella catarrhalis (PVG rats) or application of viable Bordetella pertussis (BN rats). The number of neutrophils, macrophages, dendritic cells, and T and B lymphocytes was determined in the mucosa of the supraglottic, glottic, and subglottic area of the larynx as well as in the trachea. After application of the pathogens, the mucosa of the subglottic area was significantly more affected than the glottic mucosa. Already 1 h after application of M. catarrhalis, not only neutrophils but also dendritic cells and T and B lymphocytes were found both subepithelially and within the epithelium. They showed a similar kinetic progression, although at a different level. Two hours after application of M. catarrhalis, at the peak of inflammation, dendritic cells (173 +/- 10 cells/0.1 mm2) outnumbered neutrophils (54 +/- 9 cells/0.1 mm2), T lymphocytes (25 +/- 2 cells/0.1 mm2), and B lymphocytes (4.3 cells/0.1 mm2). The subglottic area (and the trachea) contained about three to five times more cells than the glottic area. In contrast, the number of local macrophages was lower in the subglottic area (24 +/- 5 cells/0.1 mm2) compared with that of the glottic area (38 +/- 6 cells/0.1 mm2), and did not change after application of both M. catarrhalis and B. pertussis. Thus, infectious laryngotracheitis in the rat closely resembles the clinical picture in children. In addition, the present results show a major difference in cellular influx in the mucosa of the glottic and subglottic area. This demonstrates that even in two closely adjacent locations, inflammatory responses of different magnitudes can occur, and it underlines the importance of regulatory mechanisms specific for the respective microenvironment.

Animals↗
PubMed1999

Lymphocyte subset analyses in blood, spleen and lymph nodes of female Sprague-Dawley rats after short or prolonged exposure to a 50 Hz 100-microT magnetic field.

Based primarily on the results of in vitro studies, it has been suggested that power-line (50 or 60 Hz) magnetic fields (MFs) may reduce immune function, which could lower resistance to infection or cancer. This study was conducted to evaluate the influence of acute and chronic in vivo exposure to a linearly polarized 50 Hz MF on immune function in female Sprague-Dawley rats. Groups of rats were exposed continuously to the MF at a flux density of 100 microT for periods of 3 days, 14 days or 13 weeks. For each exposure period, one control group of rats was sham-exposed together with each MF-exposed group. Experimental end points included analyses of T-lymphocyte subsets as well as other immune cells involved in cell-mediated immune responses, i.e. natural killer (NK) cells, B lymphocytes, macrophages, and granulocytes in blood, spleen and mesenteric lymph nodes. In addition, immunohistochemical methods were used to detect proliferating and apoptotic cells in the various compartments of spleen tissue. The results obtained failed to demonstrate a significant effect of short or prolonged MF exposure on different types of leukocytes, including lymphocyte subsets. Furthermore, the experiments on the in vivo proliferation activity of lymphocytes and the extent of apoptosis in spleen samples did not indicate a difference between the MF-exposed and sham-exposed groups, indicating that MF exposure does not affect the mechanisms involved in the control of lymphocyte homeostasis. The lack of MF effects in the immune tests used in the present in vivo study makes it highly unlikely that MF exposure induces immunotoxicity, at least under the experimental conditions used. However, the data do not exclude the possibility that functional alterations in T-cell responses to mitogens and in NK cell activity as recently described for MF-exposed rodents may be one mechanism involved in the carcinogenic effects of MF exposure observed in some models of co-carcinogenesis.

Animals↗
PubMed1998

FcgammaRIII (CD16)-deficient mice show IgG isotype-dependent protection to experimental autoimmune hemolytic anemia.

In autoimmune hemolytic anemia (AIHA), there is accumulating evidence for an involvement of FcgammaR expressed by phagocytic effector cells, but demonstration of a causal relationship between individual FcgammaRs and IgG isotypes for disease development is lacking. Although the relevance of IgG isotypes to human AIHA is limited, we could show a clear IgG isotype dependency in murine AIHA using pathogenic IgG1 (105-2H) and IgG2a (34-3C) autoreactive anti-red blood cell antibodies in mice defective for FcgammaRIII, and comparing the clinical outcome to those in wild-type mice. FcgammaRIII-deficient mice were completely resistent to the pathogenic effects of 105-2H monoclonal antibody, as shown by a lack of IgG1-mediated erythrophagocytosis in vitro and in vivo. In addition, the IgG2a response by 34-3C induced a less severe but persistent AIHA in FcgammaRIII knock-out mice, as documented by a decrease in hematocrit. Blocking studies indicated that the residual anemic phenotype induced by 34-3C in the absence of FcgammaRIII reflects an activation of FcgammaRI that is normally coexpressed with FcgammaRIII on macrophages. Together these results show that the pathogenesis of AIHA through IgG1-dependent erythrophagocytosis is exclusively mediated by FcgammaRIII and further suggest that FcgammaRI, in addition to FcgammaRIII, contributes to this autoimmune disease when other IgG isotypes such as IgG2a are involved.

Anemia, Hemolytic, Autoimmune↗