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Suid herpesvirus 1 (SHV-1) is the causative agent of Aujeszky's disease (AD, pseudorabies), known worldwide as a major economical threat to pig farming. Measures are taken in many countries to control or eradicate the disease and considerable effort therefore has been focused on the elucidation of the epizootiology of the infection. These studies were greatly facilitated by the possibilities, first reported in the early eighties, to identify SHV-1 strains by means of restriction fragment pattern (RFP) analysis. In the present thesis some molecular biological aspects of SHV-1 are reviewed. In addition, studies are reviewed focusing on three topics: (i) methodological aspects of molecular strain identification, (ii) various epizootiological features of the SHV-1 infection, and (iii) the population dynamics of coexisting virus particles comprising a field strain, tentatively defined as a transmissible entity. A systematization of the European isolates of SHV-1 was elaborated based on molecular characterization of various genome types and an evolutionary tree for some of the distinct types was suggested. For some of the types geographical niches could be identified indicating that the intertypic differences had been stable for decades. By the characterization of 5-10 isolates from each herd, in which a SHV-1 strain had been newly introduced, strain inherent non-intertypic genomic variations consistently could be demonstrated. Some strains appeared to consist of fairly homogeneous pools of genomic variants, while other strains appeared highly heterogeneous. Some exhibited hypervariable regions in the genome. The pool of genomic variants present in a strain was found to be a highly specific and most often a conservative characteristic of a strain. Yet, fluctuations in the proportions of subpopulations occasionally were seen. Thus, while one isolate from an outbreak might be a poor representative of the pool of variants comprising the causative strain, the analysis of 5-10 isolates from each outbreak might taken together provide the basis of an extremely fine resolving potential. Outbreaks of AD during the finishing stage of the Danish eradication campaign were subjected to intensive molecular epizootiological studies. The analysis of representative older isolates of SHV-1 revealed that only type III was present in Denmark prior to 1985. In 1985 type IIa isolates emerged in a border area, and since 1986 type IIp and IIa were the only types identified in Denmark. Severe epizootics have been recorded in border areas in Denmark since the winter of 1986/87.(ABSTRACT TRUNCATED AT 400 WORDS)

The aim of the present thesis was to summarize some important immunological mechanisms in the pathogenesis of chronic Pseudomonas aeruginosa lung infection in patients with cystic fibrosis (CF). The continuous presence of bacteria in the lungs induce a strong immunological response in the patients both locally in the lungs and systemically with high amounts of circulating specific anti-P. aeruginosa antibodies. Our work has been concentrating on anti-lipopolysaccharide (LPS) antibodies. We have shown an increasing antibody response in CF patients, to all three parts of the LPS molecule; lipid A, core, and O-sugars, during the course of chronic P. aeruginosa infection. The antibodies belonged to both IgA, IgM, and all four subclasses of IgG, and were detected in serum and sputum. We detected immune complexes (IC)s in sputum from chronically infected CF patients. The ICs were composed of P. aeruginosa LPS and immunoglobulins of both IgG1-4, IgA and IgM. The concentration of circulating ICs were significantly higher in chronically infected patients compared to non-infected CF patients. The presence of ICs containing LPS in sputum were positively correlated to the amount of tumor necrosis factor alpha (TNF alpha) in the same sputum sample. TNF alpha is a very potent inflammatory mediator, stimulating cells for release of several cytokines attracting polymorphonuclear neutrophil granulocytes (PMNs), which release proteolytic enzymes and toxic oxygen radicals. We detected high concentrations of both TNF alpha, interleukin (IL)-1 alpha, IL-1 beta, IL-6, and the IL-1 receptor antagonist (IRAP) in sputum from chronically infected CF patients. The corresponding concentrations of the cytokines in serum were low or undetectable. Relatively high concentrations of serum-IRAP before the diagnosis of chronic P. aeruginosa infection were correlated to development of poor pulmonary function. We made ICs in vitro of purified P. aeruginosa LPS and hyperimmune serum from chronically infected CF patients. The biological activity of these ICs was investigated in two different assays. LPS by itself induced TNF alpha liberation in vitro, but the ICs made in vitro were also able to stimulate TNF alpha release from mononuclear cells, and they were a more potent stimuli compared to the corresponding amount of LPS alone. The IC preparation did also induce an oxidative burst response in PMNs. We conclude P. aeruginosa LPS is biological active and formation of ICs involving P. aeruginosa LPS and anti-LPS antibodies takes place in the lungs of chronically infected CF patients.(ABSTRACT TRUNCATED AT 400 WORDS)

In normal individuals, peak bone mass is reached at 25-35 years of age and thereafter a decrease with age occurs in both sexes. An acceleration in the bone loss is observed in normal women at menopause. Because of either a low peak bone mass or a more pronounced bone loss with age or during menopause, some individuals reach the fracture threshold for bone mass and suffer spontaneous fractures. To understand the mechanism behind age related bone loss, one must recognize that bone in adults is continually renewed through internal reorganization by which bone is turned over by localized osteoclastic resorption followed by osteoblastic formation (remodelling). A total reconstruction of the resorptive and formative phase can be performed by histomorphometric methods applied on iliac crest bone biopsies and thereby give a detailed description of resorptive and formative events. By the remodelling process bone may be gained or lost by 3 mechanisms: 1. Reversible bone loss depending on the magnitude of the remodelling space, which is the amount of bone resorbed and not yet reformed during the remodelling sequence. 2. Irreversible thinning of the trabeculae due to a negative balance at the remodelling site. 3. Irreversible loss of whole trabecular elements caused by deep resorption lacunae perforating the trabecular plates. Although the bone mass is significantly reduced by 20-30% in postmenopausal osteoporotic patients with vertebral fractures compared with normal controls a substantial overlap exists. Our study and several other studies have shown that beside the slight reduction in trabecular bone volume significant differences in microstructure exist between osteoporotic patients and normal controls. These changes in structure are probably a consequence of trabecular plate perforations. Although osteoporotic patients in term of remodelling (bone turnover) are a very heterogeneous group, with patients having a low, normal and even increased bone turnover, no signs in the ongoing remodelling process was found in our study that could explain why these patients had developed osteopenia and changes in the trabecular structure. The bone balance was in the patients slightly negative but no different from the balance found in normal controls. The cause of osteoporosis may therefore be factors occurring earlier in life, maybe long before the manifestation of the disease. Bone mass at any age is the result of two variables--the amount of bone achieved during growth and the subsequent rate of bone loss. Peak bone mass at maturity may be of great importance in determining the risk of developing symptomatic osteoporosis.(ABSTRACT TRUNCATED AT 400 WORDS)

In adoptive immunotherapy (AIT) of cancer, lymphocytes are isolated from the patient's blood and activated in vitro by the cytokine interleukin-2 (IL-2). In response to the IL-2 the lymphocytes proliferate vigorously and their cytotoxic potential increases several fold. After 5-10 days in culture, the cells-now called lymphokine-activated killer (LAK) cells-are injected back into the patient together with IL-2. The many positive results from preclinical animal models justified the rapid transit of AIT into the clinic, but the clinical results have far from fulfilled expectations. Many cancer centers have concluded that AIT in its present configuration is not cost-effective given that the average response rate is as low as 20-30%. Since a significant group of patients has shown complete responses after AIT, the challenge is to elucidate the conditions leading to optimal efficacy of AIT. It is generally accepted that the antineoplastic effect of LAK cells requires a close contact between the LAK cells and tumor cells. A central question in analyses of the mechanisms behind AIT is the ability of the LAK cells to localize to the malignant tissues. The earliest studies of the tissue distribution of 51Cr- and 111In-labeled LAK cells indicated that LAK cells, upon intravenous (i.v.) injection, are initially retained in the lungs, but redistribute to liver and spleen during the following 16-24 hours. However, our studies of the traffic and fate of i.v. injected tumor cells have shown that the use of 51Cr and 111In as cell labels often results in an over-estimation of the traffic of cells to liver and spleen and leads to falsely high predictions as to the survival of the injected cells, due to non-specific accumulation of 51Cr and 111In in liver and spleen after their release from dead cells. Use of 125IUdR, which does not accumulate in liver and spleen following release from dead cells, shows that the traffic of LAK cells into these organs was much lower than previously thought. These experiments have now been repeated using other cell labels (such as fluorescence dyes and immunohistochemistry) and they confirm that only few LAK cells redistribute from the lungs to the liver and spleen and that most die within the first 24 hours following injection. Thus, the circulatory potential of LAK cells is very low and chances that i.v. injected LAK cells will be able to localize into tumors and metastases located in other organs than the lungs, seems small. Indeed, while fluorescence-labeled LAK cells selectively localize into pulmonary metastases following intravenous injection, no infiltration of extrapulmonary metastases is seen. Furthermore, quantitative analyses have shown that even though the localization of LAK cells into pulmonary metastases is highly specific (5-10 fold higher numbers of LAK cells are often found in the metastases compared to the surrounding normal lung tissue), only 5% of the injected cells reach the malignant tissues. It is there