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Biomedical subjects

G Wick

Publications and source records attributed to G Wick.

At least 55 records · Page 3Linked to original sources
PubMed1999

Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis.

BACKGROUND: Growing evidence suggests that an immunological reaction against heat shock proteins (HSPs) may be involved in atherogenesis. Because HSPs show a high degree of amino acid sequence homology between different species, from prokaryotes to humans, we investigated the possibility of "antigenic mimicry" caused by an immunological cross-reaction between microorganisms and autoantigens. METHODS AND RESULTS: Serum antibodies against the Escherichia coli HSP (GroEL) and the 60-kDa chlamydial HSP (cHSP60) from subjects with atherosclerosis were purified by use of affinity chromatography. Western blot analyses and competitive ELISAs confirmed the cross-reaction of the eluted antibodies with human HSP60 and the bacterial counterparts. The cytotoxicity of anti-GroEL and anti-cHSP60 antibodies was determined on human endothelial cells labeled with 51Cr. A significant difference (40% versus 8%) was observed in the specific 51Cr release of heat-treated (42 degrees C for 30 minutes) and untreated cells, respectively, in the presence of these anti-HSP antibodies and complement. This effect was blocked by addition of 100 microg/mL recombinant GroEL. In addition, seropositivity against specific non-HSP60 Chlamydia pneumoniae antigens is more prominent among high-anti-HSP titer sera than low-titer sera. CONCLUSIONS: Serum antibodies against HSP65/60 cross-react with human HSP60, cHSP60, and GroEL; correlate with the presence of antibodies to C pneumoniae and endotoxin; and mediate endothelial cytotoxicity. These findings suggest that humoral immune reactions to bacterial HSPs, such as cHSP60 and GroEL, may play an important role in the process of vascular endothelial injury, which is believed to be a key event in the pathogenesis of atherosclerosis.

Adult↗
PubMed1999

Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response.

OBJECTIVE: While atherosclerosis is associated with high titers of autoantibodies to bacterial hsp65 crossreacting with human hsp60 (anti-hsp60 autoantibodies), myocardial infarction entails decreased humoral immune response to hsp65. We previously hypothesized that myocardial ischemia and subsequent infarction not only induce myocardial hsp60 expression, but also trigger release of myocardial hsp60 into the circulation, influencing the systemic hsp immune response via immune complex formation. METHODS: In the present study, organ culture of rat hearts under circulatory arrest provided a model of myocardiocyte injury due to ischemia. RESULTS: Reperfusion of ischemic hearts confirmed the occurrence of myocardial injury by a rise of heart enzymes. Myocardial hsp60 expression was induced up to threefold in response to ischemia, and most of hsp60 expression was localized to the muscle fibers. Analysis of coronary eluate revealed release of hsp60 from myocardium. In addition, hsp60-containing, but not hsp60-free, coronary eluate was recognized by anti-hsp65 serum antibodies and induced proliferation of hsp65-specific T cells. When hsp60-containing coronary eluate was reinjected into an hsp65-primed rat, both humoral and cellular hsp65-immune responses were strongly downregulated. CONCLUSION: Our findings demonstrate the release of highly immunogenic and crossreactive hsp60 into the circulation in response to myocardial ischemia and myocardiocyte injury.

Animals↗
PubMed1999

Proceedings of a symposium on "Immunosenescence--A major cause of disease in the elderly: from molecules to patients": summary.

Age-dependent immunological alterations are responsible for a large number of diseases in the elderly. It was the aim of a Symposium held in Kühtai, Austria, from December 3-5, 1998, to bring together basic scientists, clinicians, and representatives of pharmaceutical companies to discuss immunosenescence and its consequences. Strategies were worked out for applying recent research results to the prevention and treatment of diseases in the aged and for organizing collaborations between teams throughout Europe within the 5th EU Framework Programme.

Aged↗
PubMed1999

The role of providers in implementation of the National Kidney Foundation-Dialysis Outcomes Quality Initiative: Fresenius Medical Care North America perspective.

This is a brief review of the history of utilization of quality indicators by a major dialysis provider and how those indicators have been modified in response to the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI). Fresenius Medical Care North America (FMCNA) has monitored adequacy of dialysis, anemia management, and nutrition therapy for a number of years, using a self-directed continuous quality improvement program. FMCNA supports the NKF-DOQI Guidelines and has used the DOQI as it continues to enhance its patient quality care program. Specific goals and action thresholds of that program are delineated.

Foundations↗
PubMed1999

The natural history of the obese strain of chickens--an animal model for spontaneous autoimmune thyroiditis.

Chickens of the Obese strain (OS) are hereditarily affected with spontaneous autoimmune thyroiditis that resembles Hashimoto's thyroiditis of humans in clinical, histopathological, serological, and endocrinological aspects. In this review, the natural history of the OS, reflecting the development and maintenance of the stock and its improvement of productivity over many years at Cornell University, is summarized. To underline the value and usefulness of this animal model, the concept of the multifactorial pathogenesis of autoimmune diseases, which was mainly established at the University of Innsbruck, Austria, is briefly outlined. This detailed analysis on the natural history of the OS was only made feasible by the availability of four decades of records on this chicken line at Cornell University. The report starts with the initial occurrence of a few pullets within the Cornell C-strain (CS) flock that showed obesity, long and silky feathers, and small body size, which, therefore, caused these birds to look notably different than the other CS birds. Experimental findings indicated an autoimmune basis for these characteristics, and the objectives of matings were initially focused on increasing the number of obese individuals for studies on the etiopathology and the mode of inheritance. In subsequent years, matings were directed toward increasing the penetrance and severity of the obese trait in the population. In recent years, the reproductive capability of the obese stock was improved by mating only the best breeders of the population in terms of body weight, egg weight, egg production, fertility, hatchability, and the expression of the obese phenotype. Housing conditions for OS chickens at Cornell and the qualification standards and selection procedures for breeders are described in detail, and results of blood typings are shown. A specific recent finding in OS hens is the high incidence of residues of the right Mullerian duct with cyst formation.

Animal Husbandry↗
PubMed1999

Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock protein-65.

Recent data suggest that the immune system is involved in atherogenesis. Thus, interest has been raised as to the possible antigens that could serve as the initiators of the immune reaction. In the current work, we studied the effects of immunization with recombinant heat shock protein-65 (HSP-65) and HSP-65-rich Mycobacterium tuberculosis (MT) on early atherogenesis in C57BL/6J mice fed either a normal chow diet or a high-cholesterol diet (HCD). A rapid, cellular immune response to HSP-65 was evident in mice immunized with HSP-65 or with MT but not in the animals immunized with phosphate-buffered saline (PBS) alone. Early atherosclerosis was significantly enhanced in HCD-fed mice immunized with HSP-65 (n=10; mean aortic lesion size, 45 417+/-9258 microm2) or MT (n=15; 66 350+/-6850 microm2) compared with PBS-injected (n=10; 10 028+/-3599 microm2) or nonimmunized (n=10; 9500+/-2120 microm2) mice. No fatty streak lesions were observed in mice fed a chow diet regardless of the immunization protocol applied. Immunohistochemical analysis of atherosclerotic lesions from the HSP-65- and MT-immunized mice revealed infiltration of CD4 lymphocytes compared with the relatively lymphocyte-poor lesions in the PBS-treated or nonimmunized mice. Direct immunofluorescence analysis of lesions from HSP-65- and MT-immunized mice fed an HCD exhibited extensive deposits of immunoglobulins compared with the fatty streaks in the other study groups, consistent with the larger and more advanced lesions found in the former 2 groups. This model, which supports the involvement of HSP-65 in atherogenesis, furnishes a valuable tool to study the role of the immune system in atherogenesis.

Animals↗
PubMed1999

Inhibition of arteriosclerosis by T-cell depletion in normocholesterolemic rabbits immunized with heat shock protein 65.

Previous studies in our laboratory have shown that arteriosclerotic changes can be induced in normocholesterolemic rabbits by immunization with mycobacterial heat shock protein (hsp) 65. To further investigate the immunologic mechanisms underlying such vascular lesions, 39 male New Zealand White rabbits were treated by triple immunization with fortified Freund's complete adjuvant containing 5 mg/mL Mycobacterium tuberculosis as a source of hsp65 and simultaneous immunosuppressive therapy twice per week with either anti-CD3 monoclonal antibody (1 mg/kg) and prednisolone (1 mg/kg) or prednisolone (1 mg/kg) alone. Sixteen weeks after the first immunization the animals were killed, and as expected, severe arteriosclerotic lesions in the intima of the aortic arch were found in 9 of 10 immunized rabbits. However, only 1 of 10 rabbits immunized and immunosuppressed with the combined anti-CD3 monoclonal antibody and prednisolone treatment showed a single moderate lesion in the aorta, whereas 5 of 9 rabbits immunized and immunosuppressed by prednisolone treatment alone showed lesions, albeit mild. In conclusion, the early inflammatory stages of arteriosclerotic lesions induced by immunization with hsp65 can be inhibited by immunosuppressive therapy with anti-CD3 monoclonal antibody.

Animals↗
PubMed1999

Suppressive effects of anti-inflammatory agents on human endothelial cell activation and induction of heat shock proteins.

BACKGROUND: Studies from our laboratory have shown that the earliest stages of atherosclerosis may be mediated by an autoimmune reaction against heat shock protein 60 (Hsp60). The interactions of Hsp60-specific T cells with arterial endothelial cells (EC) require expression of both Hsp60 and certain adhesion molecules shown to be induced simultaneously in EC by mechanical and other types of stress. Recently, it was shown that suppression of T cell-mediated immune responses by cyclosporin A (CyA) enhanced atherosclerotic lesion formation in mice. In contrast, aspirin was found to lower the risk of myocardial infarction in men. These conflicting observations may be due to different effects of anti-inflammatory agents on adhesion molecule and Hsp expression in EC, respectively. MATERIAL AND METHODS: In the present study, we analyzed the effects of CyA, aspirin, and indomethacin on T cell proliferation using a proliferation assay. To explore the expression of adhesion molecules, monocyte chemoattractant protein-1 (MCP-1), and Hsp60 in human umbilical vein endothelial cells (HUVECs), Northern blot analyses were used. To examine the activation status of the transcription factors nuclear factor kappaB (NF-kappaB) and heat shock factor-1 (HSF-1), electrophoretic mobility shift assays were performed. RESULTS: With the exception of indomethacin, the used immunosuppressive and anti-inflammatory agents significantly inhibited T cell proliferation in response to influenza virus antigen in a dose-dependent manner. Interestingly, CyA and indomethacin did not suppress tumor necrosis factor-alpha (TNF-alpha)-induced adhesion molecule expression on HUVECs, whereas aspirin had an inhibitory effect. These observations correlated with the modulation of NF-kappaB activity in EC. All agents tested induced expression of Hsp60 6 hr after application. In addition, aspirin and indomethacin, but not CyA, induced Hsp70 expression in HUVECs that correlated with induction of HSF-1 activity. CONCLUSION: Our results show that the tested agents (except indomethacin) are inhibitors of the T cell-mediated immune response, as expected, that aspirin is an effective suppressor of adhesion molecule expression, and that all three agents can induce Hsp60 in HUVECs. These data provide the molecular basis for the notion that (1) part of the anti-atherogenic effect of aspirin may be due to the prevention of the adhesion of sensitized T cells to stressed EC; (2) that part of the atherosclerosis-promoting effect of CyA may be due to its potential as an inducer of Hsp60 expression and its inability to down-regulate adhesion molecule expression on EC; and (3) that down-regulation of MCP-1 expression by aspirin may result in decreased recruitment of monocytes into the arterial intima beneath stressed EC.

Adult↗
PubMed1999

Atherosclerosis--an autoimmune disease.

Immune-inflammatory processes are increasingly discussed as possible pathogenetic factors involved in the development of atherosclerosis. Here, we summarize data on which we have built our "immunological" hypothesis of atherogenesis. This concept is based on the observation that nearly everybody shows protective cellular and humoral immune reactions against microbial heat shock protein 60 (HSP 60). Because a high degree of antigenic homology exists between microbial (viral, bacterial, parasitic) and human HSP 60, this protective immunity may have to be "paid for" by the danger of cross-reactivity with human HSP 60 that is expressed by endothelial cells of stressed arteries. Arterial endothelial cells are more prone to produce HSP 60 and various adhesion molecules upon exposure to stress factors, including classical risk factors for atherosclerosis, due to their life-long exposure to the high arterial as compared to venous blood pressure. Also, endothelial cells are the first potential targets encountered by circulating HSP 60-specific T cells or antibodies. This concept not only opens new avenues for diagnostic approaches, but also may form the basis for new ways of therapeutic intervention.

Animals↗
PubMed1998

Induction of mitogen-activated protein kinase phosphatase-1 by arachidonic acid in vascular smooth muscle cells.

Arachidonic acid (AA) and its metabolites play important roles in a variety of biological processes, such as signal transduction, contraction, chemotaxis, and cell proliferation and differentiation. It was demonstrated recently that AA can activate mitogen-activated protein kinases (MAPKs), which are crucial for transducing signals initiating cell growth and apoptosis. Here we studied the effect of AA on the induction of MAPK phosphatase-1 (MKP-1) in vascular smooth muscle cells (VSMCs) and found that AA stimulated induction of MKP-1 mRNA and proteins in VSMCs in a time- and dose-dependent manner. Specific inhibitors of cyclooxygenase-, lipoxygenase-, and cytochrome P450-dependent metabolism did not affect AA-induced MKP-1 expression, indicating that eicosanoid biosynthesis was not involved in this process. The glutathione precursor N-acetylcysteine, an antioxidant, abolished AA-stimulated MKP-1 gene expression, whereas inhibition of protein kinase C by calphostin C had no influence on MKP-1 induction. VSMC pretreatment with genistein, a tyrosine kinase inhibitor, completely blocked AA-stimulated MKP-1 induction. MAPK kinase inhibitor PD 98059 did abolish AA-stimulated activation of extracellular signal-regulated kinases but not MKP-1 induction. Furthermore, agonists that increase AA release stimulated MKP-1 induction and activation of MAPKs, including extracellular signal-regulated kinases and c-Jun NH2-terminal protein kinases or stress-activated protein kinases. Taken together, our findings demonstrate that AA induced MKP-1 expression in VSMCs via activation of tyrosine kinases involving AA-induced free radical generation, suggesting an important role for MKP-1 in the regulation of AA-initiated signal transduction in VSMCs.

Animals↗
PubMed1998

The role of (auto-) immunity in atherogenesis.

Recent data from different laboratories have provided evidence that the first stages of atherosclerosis are inflammatory in nature. Research in the last decades on this multifactorial disease has primarily focussed on the role of lipids, with only a few anecdotal findings suggesting the involvement of the immune system in atherogenesis. Within the group of antigens that may be responsible for this immunoactivation during atherogenesis, heat shock protein (hsp) 65/60 became a serious candidate based on the fact that immunization] of normocholesterolemic rabbits with hsp65 leads to the development of arteriosclerotic lesions in the aortic intima and these primary inflammatory lesions are aggravated by a cholesterol-rich diet, thus completely resembling human fatty streaks and atherosclerotic plaques. Furthermore, T cells in atherosclerotic lesions of rabbits have been shown to react specially with mycobacterial hsp65, suggesting that cell-mediated immune responses to hsp60 are also involved in the pathogenesis of this disease In a large epidemiological study we demonstrated that serum antibodies to mycobacterial hsp65 were significantly increased in clinically healthy subjects with sonographically demonstrable carotid atherosclerosis. These antibodies crossreact with human hsp60. Thus further elucidation of the role of the role of the immune system in atherogenesis could enhance our understanding of the mechanism of this vascular disorder, and may lead to new therapeutic strategies for atherosclerosis.

Animals↗
PubMed1998

Neuroendocrine-immune disturbances in animal models with spontaneous autoimmune diseases.

According to our concept, the development of autoimmune disease depends on the presence of two sets of essential genes, one coding for an abnormal autoreactivity of the immune system, the other for a primary susceptibility of the target organ/structure for the immune attack. The final outcome of the disease in a given individual is then fine tuned by modulatory factors, such as diet or hormones. With regard to the latter, the immuno-endocrine interaction via the hypothalamo-pituitary-adrenal (HPA) axis has proven to be of special importance. Investigating the so-called Obese strain (OS) of chickens, an animal model with a spontaneously occurring Hashimoto-like autoimmune thyroiditis, we have first shown an impaired surge of glucocorticoid hormones after stimulation of the HPA axis by antigens or certain cytokines (glucocorticoid-increasing factors--GIFs). More recently, we have found a similar behavior in models with systemic autoimmune diseases, that is, murine lupus erythematosus and avian scleroderma. More detailed studies have, however, proven that the mechanisms underlying this altered immuno-endocrine communication via the HPA axis differs in different models. Finally, recent data point to the possibility that the classical pathways of glucocorticoid-T-cell interactions also take place in the thymus itself, which has been shown to be a site of steroid hormone production.

Animals↗
PubMed1998

Interleukin-1 receptor defect in autoimmune NZB mouse brain.

Interleukin-1 receptors (IL-1R type I and II) have been characterized in murine nervous structures (hippocampus and frontal cortex), in vascular structures (vessels, choroid plexus), and in the anterior pituitary. Because interleukin-1 (IL-1), injected or induced in the brain, is a powerful regulator of the stress axis and immune functions, it was of interest to investigate IL-1Rs and IL-1 in autoimmune mice. In control mice, bacterial lipopolysaccharide (LPS), administered i.p. or i.c.v., induces a sharp decrease in available brain IL-1 receptors, in spite of a moderate increase in mRNAs for both receptor types. This is concomitant with an increase in IL-1 alpha, beta, and ra mRNA. Ligand production clearly overcomes receptor turnover. In autoimmune mice (NZB and NZB/NZW F1), a strong defect in IL-1R (type I) is demonstrated in the dentate gyrus. This tissue-specific defect cannot be explained by increased occupancy by endogeneous ligands as for LPS-treated mice. The transmission of the defect is Mendelian and suggests the involvement of a single gene. However patterns of IL-1R mRNAs (evaluated by RT-PCR) are similar in NZB and in controls, suggesting a translational or post-translational abnormality. The contribution of this genetic disorder in the development of autoimmunity remains to be clarified. Because the brain IL-1 system sends inhibitory signals towards immune functions, this lack of functional IL-1 binding sites might participate in the disregulations observed in NZB autoimmune mice.

Animals↗