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PubMedDate not supplied

[Mathematical modelling of perorally induced immunological tolerance].

A mathematical model of the mechanism of development of orally induced immunologic tolerance has been suggested. The model presents a system of differential non-linear equations, and it is realized as a program in FORTRAN. The model describes primary and secondary immune responses, reflects the main features of the immune system response to antigen intake with food. The immune system model response to varying doses and frequency of the antigen intake with food has been studied. It has been established that repeated administration of small doses of the food antigen leads to a deeper tolerance due to lower stimulation of the immune system. The existence of optimal tolerogenic doses of the food antigen has been proved. Qualitative changes in the immune system response to the food antigen have been recorded in case of increased permeability of the intestinal wall.

Administration, Oral↗

PubMed2002

Chlamydia pneumoniae and atherosclerosis -- what we know and what we don't.

The clinical manifestations of atherosclerosis include coronary artery disease (CAD), stroke, abdominal aortic aneurysm and peripheral vascular disease. World-wide, CAD and stroke are the leading causes of death and disability. The recognition of atherosclerosis as an inflammatory disease in its genesis, progression and ultimate clinical manifestations has created an interesting area of vascular research. Apart from those well-known traditional risk factors for atherosclerosis, novel and potentially treatable atherosclerotic risk factors such as homocysteine (an amino acid derived from the metabolism of dietary methionine that induces vascular endothelial dysfunction) and infections have emerged. In fact, the century-old 'infectious' hypothesis of atherosclerosis has implicated a number of micro-organisms that may act as contributing inflammatory stimuli. Although cytomegalovirus, Helicobacter pylori and Chlamydia pneumoniae are the three micro-organisms most extensively studied, this review will focus on C. pneumoniae. Collaborative efforts from many disciplines have resulted in the accumulation of evidence from seroepidemiological, pathological, animal model, immunological and antibiotic intervention studies, linking C. pneumoniae with atherosclerosis. Seroepidemiological observations provide circumstantial evidence, which is weak in most prospective studies. Pathological studies have demonstrated the preferential existence of C. pneumoniae in atherosclerotic plaque tissues, while animal model experiments have shown the induction of atherosclerosis by C. pneumoniae. Finally, immunological processes whereby C. pneumoniae could participate in key atherogenic and atherothrombotic events have also been identified. Although benefits of the secondary prevention of atherosclerosis have been demonstrated in some antibiotic intervention studies, a number of negative studies have also emerged. The results of the ongoing large prospective human antibiotic intervention trials may help to finally establish if there is a causal link between C. pneumoniae infection and atherosclerosis.

Animals↗

PubMed1990

Heart transplantation model as an immunological monitor.

Various techniques have been described for the heart model, from which we standardized two. These are simple to perform and offer the possibility of a precise determination of rejection times. This is an advantage compared to other models, such as the kidney model, which is still in use, a rejection reaction, the recipient stays alive, making the recipient available for further experiments. One disadvantage of the heart model is that histological examinations are impossible without disturbing the heart function. Thus far, responsible laboratory parameters for rejection reactions could not be differentiated for confirmation of subjective diagnoses. However, we consider this model to be useful in investigating immunological questions.

Animals↗

PubMed2005

Helicobacter pylori vaccine development: facing the challenge.

An effective vaccine would be a desirable way to control Helicobacter pylori-induced gastric disease. Initial studies in animal models demonstrated the feasibility of immunization and led to high hopes for a human vaccine. In the mouse model immunological approaches have to date not brought a satisfactory explanation for the mechanisms of protection against this largely luminal pathogen. Recently, transcriptome studies have identified new factors. It is now proposed that non-classical immune mediators may be the key to vaccine-induced protection. Human trials of H. pylori vaccines are going ahead but although at least some formulations are clearly immunogenic, their effectiveness remains untested. The recent development of a human challenge model has now opened up new prospects for testing candidate vaccines and this will undoubtedly have a great impact in the near future. Future priorities for H. pylori vaccine development must be a better understanding of the protective mechanisms and the identification of biomarkers which can be used as reliable predictors of efficacy in humans. Despite some important advances in recent years, important issues must be resolved before an H. pylori vaccine will become a reality.

Adjuvants, Immunologic↗

PubMed2004

National conference to assess antibody-mediated rejection in solid organ transplantation.

The process of humoral rejection is multifaceted and has different manifestations in the various types of organ transplants. Because this process is emerging as a leading cause of graft loss, a conference was held in April 2003 to comprehensively address issues regarding humoral rejection. Though humoral rejection may result from different factors, discussion focused on a paradigm caused by antibodies, typically against donor HLA antigens, leading to the term 'antibody-mediated rejection' (AMR). Conference deliberations were separated into four workgroups: The Profiling Workgroup evaluated strengths and limitations of different methods for detecting HLA reactive antibody, and created risk assessment guidelines for AMR; The Diagnosis Workgroup reviewed clinical, pathologic, and serologic criteria for assessing AMR in renal, heart and lung transplant recipients; The Treatment Workgroup discussed advantages, limitations and possible mechanisms of action for desensitization protocols that may reverse AMR; and The Basic Science Workgroup presented animal and human immunologic models for humoral rejection and proposed potential targets for future intervention. This work represents a comprehensive review with contributions from experts in the fields of Transplantation Surgery, Medicine, Pathology, Histocompatibility, Immunology, and clinical trial design. Immunologic barriers once considered insurmountable are now consistently overcome to enable more patients to undergo organ transplantation.

Antibodies↗

PubMed1997

Bispecific monoclonal antibody complexes bound to primate erythrocyte complement receptor 1 facilitate virus clearance in a monkey model.

We investigated the feasibility of using bispecific mAb complexes to redirect and improve the efficiency of the primate E complement receptor 1-based clearance reaction to remove a virus from the circulation. As an initial approach, we used bacteriophage phiX174 as an immunologic model for mammalian viruses. Bispecific complexes were prepared by chemically cross-linking a mAb specific for complement receptor 1 with a mAb specific for the bacteriophage phiX174. In a monkey model these complexes facilitate rapid and quantitative binding of the target bacteriophage to E in vitro and in vivo. Moreover, after in vivo binding to E, the complexes containing mAb and prototype virus are rapidly cleared from the circulation of rhesus and cynomolgus monkeys without loss of E. Our findings suggest that bispecific mAb complexes, in concert with primate E complement receptor 1, may have therapeutic utility in the treatment of diseases associated with blood-borne pathogens.

Animals↗

PubMed2004

T cell uptake for the use of boron neutron capture as an immunologic research tool.

An immunologic tool based on manipulation of the boron neutron capture reaction was previously proposed in the context of heart transplantation research to examine the temporal relationship between parenchymal rejection (representing immune cell infiltration) and transplantation-associated arteriosclerosis (characterized by progressive vascular occlusion). Critical to the development of this method is the uptake of boron by specific cells of the immune system, namely T cells, without adverse effects on cell function, which may be assessed by the ability of boron-loaded cells to produce IFNgamma, a protein with substantial impact on rejection. This work presents the evaluation of two carboranyl thymidine analogs. Advantages of this type of boron compound are reduced risk of leakage and effective dose delivery based on their incorporation into cellular nuclear material. Results indicate that uptake of these boronated nucleosides is high with no adverse effects on cell function, thereby warranting the continued development of this technique that has potentially wide applicability in immunological models.

Animals↗

PubMed1979

[Significance of the complement system in acute pancreatitis in rats].

The influence of complement system in acute pancreatitis in the rat was examined. Two different experimental procedures were used to induce pancreatitis: distal choledochal ligature and the Pfeffer model as modified by NEVALAINEN. In both procedures an acute pancreatitis developed and complement depression was noted. These results showed that consumption of complement will occur even in pancreatitis induced by other than immunologic models. In a second series the same experimental procedures were used in rats that had been decomplemented by application of cobra venom factor. It was possible to produce an acute pancreatitis of moderate severity.

Acute Disease↗

PubMedDate not supplied

Oxisuran metabolism in the monkey.

Oxisuran metabolism was studied in the Rhesus monkey in order to assess the suitability of this species as an immunological model for man. The biotransformation pathways observed in the monkey are the same as those seen in rats and dogs. These pathways include the oxidation of oxisuran to a sulfone not found in human plasma or urine. Nevertheless, the monkey may merit immunological evaluation because the half-lives of biotransformation and elimination, although shorter than those exhibited by man, are greater than those in dogs and rats.

Animals↗

PubMed1999

Angiotensin-converting enzyme inhibition prevents loss of glomerular hydraulic permeability in passive heymann nephritis.

We used morphometric techniques and theoretical analysis to investigate structural and functional changes of the glomerular membrane that develop in passive Heymann nephritis (PHN), an experimental model of human membranous glomerulopathy The effect of angiotensin-converting enzyme (ACE) inhibition on the above parameters was also investigated to explore the mechanisms by which this treatment exerts functional and structural protection at the renal tissue level. Morphometric analysis of glomerular capillary by light and electron microscopy was performed in normal control rats and in rats injected with rabbit anti-Fx 1A antibody, 12 months after induction of PHN. A group of PHN rats treated with lisinopril during the observation period was also investigated. Glomerular capillary architecture was not significantly altered in PHN rats, thus glomerular volume and capillary lumen volume were comparable with normal controls; only mesangial volume was significantly elevated in PHN rats. Glomerular membrane structure was significantly affected by PHN: the thickness of the glomerular basement membrane (GBM) increased, and the frequency of epithelial filtration slits decreased. Electron-dense deposits in the subepithelial space of the GBM were estimated to occupy more than 20% of the GBM area. Theoretical analysis of glomerular hydraulic permeability allowed us to predict that, after these structural changes, the permeability of the GBM and the epithelial layer significantly decreased, with an average reduction in the ultrafiltration coefficient (Kf) of approximately 43%. ACE inhibition limited mesangial expansion and prevented changes of glomerular epithelial cells (filtration slit frequency) but not GBM thickening. Immune deposits within the GBM were only partially prevented by lisinopril. A selective effect on epithelial permeability was calculated in lisinopril-treated rats, and a partial preservation of Kf reduction was observed. These results suggest that structural changes of the GBM and epithelial cells that develop in PHN are responsible for the reduced filtration capacity observed in this model. ACE inhibition only partially prevented immune-deposits in the GBM and favorably affected epithelial cell structure. These selective effects on glomerular podocytes may contribute to preserve water and macromolecule permeability of the glomerular capillary wall in this immunologic model of kidney disease.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2004

Gene expression arrays reveal a rapid return to normal homeostasis in immunologically-challenged trophoblast-like JAR cells.

The immunologic adaptations of pregnancy have come under increasing scrutiny in the past 15 years. Existing experimental evidence clearly demonstrates that placental trophoblasts play an important role in regulating immunologic/inflammatory responses at the maternal-fetal interface. We used a well-developed gene expression array to examine in greater detail the physiologic response of trophoblast-like choriocarcinoma cells to a model immunologic 'challenge.' We co-cultured PHA-activated or resting peripheral blood mononuclear cells (PBMC) with the human choriocarcinoma cell line JAR for time periods ranging from 2 to 18 h. Messenger RNA expression in the JAR cells was then assessed using a 21,329-gene microarray and novel biostatistical analyses that we have previously published. Patterns of differential gene expression were assessed using a commercial pathway analysis software program. Differences in gene expression between JAR cells cultured with activated PBMC (experimental samples) and JAR cells cultured with resting PBMC (control samples) were seen only at the 2h time point. That is, multiple genes were transcribed in JAR cells in response to activated PBMC, but expression levels of the genes had all returned to baseline by 6h. Molecular modeling demonstrated that the differentially expressed genes were largely associated with cell growth and differentiation. This model was confirmed by noting a two-fold increase in CD10/neutral endopeptidase expression (a marker for cell differentiation) in JAR cells incubated with media from activated PBMC compared with JAR cells incubated with resting PBMC. These findings support the hypothesis that there is a delicate immunologic milieu at the maternal-fetal interface that must be maintained. Immunologic/inflammatory challenge at the maternal-fetal interface is compensated by cellular mechanisms that work to reduce inflammation and rapidly restore immunologic balance.

Biomarkers↗

PubMed2005

Pulmonary infection with Cryptococcus neoformans in the face of underlying sarcoidosis.

We present a case of limited pulmonary cryptococcal infection following exposure to pigeon excreta in a patient with sarcoidosis. The pathogenicity of Cryptococcus neoformans depends on the interplay between the immune status of the host and the virulence of the infecting strain. It can range from asymptomatic lung colonization in the immunocompetent host to rapidly progressive meningitis in immunocompromised patients. Immunological models of respiratory disease emphasize a distinction between infections associated with immune suppression on the one hand and diseases such as sarcoidosis believed to involve an excessive Th1-mediated immune response on the other. This case exemplifies the complex nature of immunological responses in the lung and highlights the importance of considering the possibility of co-existent fungal infection in individuals with sarcoidosis. Novel immunotherapeutic options for cryptococcal infection are discussed.

Adult↗

PubMed1989

Peptide mapping of conformational epitopes in a human malarial parasite heat shock protein.

A protein of 75 kDa is found in large quantities throughout the blood stages of the human malarial parasite, Plasmodium falciparum. Based on a partial amino acid sequence for p75, previously deduced from a cDNA clone encoding approximately 40% of the molecule, secondary structural predictions were made. The potential role of long range effects on the tertiary structure of the protein stabilized by disulfide bridges was determined by reduction and alkylation of the fusion protein. Five regions were then chosen for peptide modeling. Peptides of 16, 28, 49, 64, and 76 residues were synthesized and used to immunize rabbits. All but the 16-residue peptides were capable of stimulating boostable IgG antibody responses in rabbits, but the antibody produced against the 49 mer did not react with the native parasite protein. Thus, the 28, 64, and 76 residue peptides represent good immunologic models for portions of the P. falciparum 75-kDa protein capable of stimulating both T and B cells in rabbits. The peptides were also used to probe whether any of the selected regions contain epitopes which react with antibodies from owl monkeys immune to P. falciparum. Of these peptides, two were found to be consistently recognized in ELISA by four owl monkey antisera raised in response to malarial infection. Because these two peptides model a cysteine-containing region of the protein, owl monkey sera were also used as probes of the importance of disulfide bonding in maintaining the native structure. The results obtained were consistent with a folding pattern for p75 that incorporates a disulfide bond between cysteines 161 and 194. These results also suggest that most of the epitopes recognized in this part of p75 by the immune system of the monkey are created by folding of the molecule.

Amino Acid Sequence↗

PubMed2004

A single major chromosomal region controls natural killer cell-like activity in rainbow trout.

We report the identification of a single major chromosomal region controlling natural killer (NK) cell-like activity in rainbow trout (Oncorhynchus mykiss). A genetic map based on 484 AFLP and 39 microsatellite genotypes from 106 doubled haploid fish was constructed. These fish were produced by androgenesis from a hybrid of two clonal lines divergent in NK-like activity. NK-like activities for 75 of the doubled haploids were quantified by an in vitro chromium release assay utilizing (51)Cr-labeled YAC-1 target cells. Composite interval mapping revealed a single major quantitative trait locus (QTL) associated with NK-like activity in this rainbow trout model. Genetic mapping revealed this QTL to also be unlinked to: fragmented MHC class I and MHC class II regions, the leukocyte receptor cluster, the natural killer cell enhancement factor ( NKEF) gene, the RAG-1 gene, and two QTL associated with resistance to infectious pancreatic necrosis virus in rainbow trout. Collectively, these results extend the utility of rainbow trout as an immunological model and are consistent with the idea that a single chromosomal region homologous to the natural killer cell complex (NKC) located on syntenic portions of mouse chromosome (Chr) 6, human Chr 12, and rat Chr 4 may exist in a lower vertebrate model.

Animals↗

PubMed2002

Toward a topological model of the NCX1 exchanger.

The Na(+)/Ca(2+) exchanger (NCX1) catalyzes the counter-transport of sodium and calcium ions. Understanding how this is accomplished requires knowledge of the structure of NCX1 and identifying amino acid residues involved in binding and transport of ions. The amino acid sequence of NCX1 has been known for more than a decade. Based on hydropathy analysis, NCX1 was modeled to contain 12 transmembrane segments. In this model, the alpha-repeat regions, which are the result of a gene duplication event (see below), are oriented on the extracellular face of NCX1. In the years since NCX1 was sequenced, a considerable amount of effort has gone into testing the initial 12-transmembrane-segment model. Immunologic and protein-processing studies as well as functional analyses of mutants have determined the location of the amino and carboxy termini and several intracellular regions. However, disulfide bond analysis and cysteine mutagenesis coupled with accessibility studies indicate that the structure of NCX1 diverges from a simple membrane protein consisting only of transmembrane alpha-helical segments. These recent data support a model containing 9 transmembrane alpha-helices with the alpha-repeat regions forming nonhelical re-entrant loops. A bacterial protein containing a pair of alpha-repeat regions but of unknown function has also been shown to have oppositely oriented alpha-repeats.

Animals↗

PubMed1994

The human pre-B cell receptor: structural constraints for a tentative model of the pseudo-light (psi L) chain.

In human pre-B cells, the mu chain is associated with a surrogate light chain composed of the lambda-like and Vpre-B gene products. This pre-B cell receptor presumably triggers early steps of B cell differentiation, We have determined the NH2-terminal amino acid sequence of the lambda-like chain, showing that the mature chain results from the cleavage of a leader segment of 44 residues, leaving a polypeptide of 169 amino acids having partial features of the Ig light chain domains, with the exception of the first 50 amino acid NH2-terminal region. We have completed the nucleotide sequence of the Vpre-B gene, which appears to contain 126 residues in its mature form of which the 24 COOH-terminal portion was not Ig-related. Analysis of transfectants has provided direct evidence that lambda-like and Vpre-B chains assemble together even in the absence of heavy chain, prompting the search for a structural basis of this interaction. Comparison with the domain organization of the regular Ig lambda chain suggests that most of the psi L chain can be accommodated within a CL-VL-like structure, with an extra "subdomain" contributed by the non-Ig-like portions of both the lambda-like and Vpre-B polypeptides.

Amino Acid Sequence↗

PubMed1994

Extrathymic expression of the intracellular hepatitis B core antigen results in T cell tolerance in transgenic mice.

We previously developed a transgenic (Tg) murine lineage (B10.S-Tg31e), which secretes the hepatitis B e Ag (HBeAg) into the serum at a concentration of 10 ng/ml. This serum concentration was sufficient to render B10.S-Tg31e mice functionally tolerant at the T cell but not B cell level. To determine the tolerogenic potential of an intracellular form of this Ag, namely the hepatitis B core Ag (HBcAg), expressed outside the thymus, the B10.S-Tg10c lineage was developed. In B10.S-Tg10c mice the HBcAg is expressed as an intracellular "self"-Ag predominantly in the liver, and cannot be detected in the serum, the thymus or in nonthymic lymphoid tissue. Despite the liver-specific and intracellular location of this transgenic self-protein, B10-STg10c mice demonstrate a significant degree of HBcAg-specific T cell tolerance at the level of T cell proliferation. Similarly, in vivo anti-HBc antibody production after HBcAg immunization is significantly reduced as compared with non-Tg littermate controls. No spontaneous anti-HBc antibody is produced in B10.S-Tg10c mice, however, adoptive transfer of HBcAg-specific T cells from non-Tg B10.S mice elicits anti-HBc specific "autoantibody" production. Interestingly, antibodies with specificity for the HBeAg as well as the HBcAg are produced. Antibody production in B10.S-Tg10c mice adoptively transferred with T cells indicates that sufficient native HBcAg can gain access to the extracellular compartment to engage HBcAg-specific B cells that are clearly not tolerant in this model. No liver injury was observed as a consequence of HBcAg expression, even in B10.S-Tg10c mice adoptively transferred with HBcAg-specific T cells. Unless HBcAg is unique in this regard, these results suggest that organ-specific, intracellular self-Ag may be released during normal cell turnover in sufficient concentrations to elicit systemic T cell tolerance. B10.S-Tg10c mice also serve as an immunologic model system for chronic infection with the HBeAg-negative mutant of the hepatitis B virus.

Animals↗

PubMed2000

Plasma exudation, hyperaemia, and epithelial permeability in rats with oxazolone-induced colitis: modulatory effects of budesonide.

BACKGROUND: Oxazolone-induced colitis in the rat is an immune-driven model of human colitis. The aim of the present study was to measure the changes in the absorptive and exudative permeabilites, oedema formation, and local blood flow in this model during the development of inflammation. We also assessed the effects of acute (<1 h), topical glucocorticosteroid (GCS) treatment on these factors. METHODS: Colitis was induced by local instillation of oxazolone in previously sensitized animals. Calculating the 40-min plasma-equivalent extravascular volume quantitated the plasma exudation rate. This was determined by using labelled albumin as marker for total tissue content of plasma and Evans blue content as marker for the intravascular volume. Absorptive permeability was simultaneously measured as uptake of rectally administered (51Cr)-labelled ethylenediaminetetraacetic acid (EDTA). In separate experiments regional blood flows were measured by means of the labelled microsphere method. RESULTS: At both 3 and 24 h after challenge marked enhancements of both exudative and absorptive permeabilities were found. At 24 h there was also an increase in local blood flow. GCS treatment abolished all of the hyperaemia and the main part of the exudative response but had no significant effect on the absorptive permeability. CONCLUSIONS: In this model immunologic mechanisms induce permeability and blood flow changes similar to those in the human disease. It seems suitable for the study of GCS and other anti-inflammatory or immune-modulating drugs.

Administration, Topical↗