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PubMed1998

[Molecular modeling of immunological proteins by bioinformatics].

The antibody combining site is composed of six complementarity determining regions (CDRs), whose typical structures have been classified as "canonical structures" except CDR-H3, depending upon the segment lengths and the positions of specific amino acid residues in the segments. Using the method of structural bioinformatics, we have proposed a novel classification of the CDR-H3 structures, and revealed several remarkable relationships between their sequences and the loop conformations. Based upon the canonical structures and our new rules, structural models of antibodies have been built in order to understand the molecular basis of antigen recognition. Another new computational method of almost exhaustive conformational search is introduced for future applications.

Amino Acid Sequence↗
PubMed1998

Peptide models of immunological recognition: paratope dissection by multiple peptide synthesis.

New approaches to obtain information about the residues of the antibody paratope involved in the interaction with antigen would be very useful to help perform rational mutagenesis of antibodies for improving sensitivity or selectivity in immunoassays. We have evaluated the possibility of dissecting the antibody paratope into large sets of short (12 residues) overlapping peptides to determine the contribution of each peptide to antigen binding. Our results show that the systematic analysis of the antigen-binding properties of heavy chain variable segment and light chain variable segment derived peptides of HyHEL-5, a model anti-lysozyme antibody, can be an experimental approach to the selection of paratope-derived peptides with antigen-binding activity. Detailed analysis of the contribution of each residue from each binding peptide permitted the identification of residues contributing to antigen binding. Of the 38 residues we identified, 22 corresponded to residues that had been shown by X-ray crystallography to be at the interface between HyHEL-5 and lysozyme. The peptide analysis we have developed is thus a way to map the subset of residues from the antibody paratope involved in antigen recognition. The same peptide approach was used to map the idiotope that an anti-idiotypic antibody recognized in the paratope of its cognate antibody.

Antibodies, Anti-Idiotypic↗
PubMed1977

The Dunning R3327 prostate adenocarcinoma in the Fischer-Copenhagen F1 rat: a useful model for immunological studies.

The Dunning R3327 tumor sublines in the Fischer-Copenhagen F1 rat provide a spectrum of transplantable prostate adenocarcinomas for the study of host-tumor interactions. The tumor can be transplanted with both fresh and cryopreserved cell suspensions. The F1 rat is an appropriate animal for immunological studies based on humoral and cellular immune responses. Preliminary evidence of the host-tumor relationship in the F1 rat indicates that purified membrane preparations induced a specific cytotoxic population of lymphocytes.

Adenocarcinoma↗
PubMed2006

Covalent modification of a melanoma-derived antigenic peptide with a natural quinone methide. Preliminary chemical, molecular modelling and immunological evaluation studies.

A LigandFit shape-directed docking methodology was used to identify the best position at which the melanoma-derived MHC class-I HLA-A2-binding antigenic peptide ELAGIGILTV could be modified by attaching a small molecule capable of fitting at the interface of complementary determining regional (CDR) loops of a T-cell receptor (TCR) while triggering T-cell responses. The small molecule selected here for determining the feasibility of this alternative track to chemical alteration of antigenic peptides was the electrophilic quinone methide (+)-puupehenone (), a natural product that belongs to a family of marine metabolites capable of expressing immunomodulatory activities. A preliminary chemical reactivity model study revealed the efficacy of the thiol group of a cysteine (C) side-chain in its nucleophilic addition reaction with in a regio- and diastereoselective manner. The best TCR/HLA-A2 ligand [i.e., ELAGCGILTV-S-puupehenol ()] then identified by the LigandFit docking procedure was synthesized and used to pulse HLA-A2(+) T2 cells for T-cell stimulation. Among the ELAGIGILTV-specific T-cell clones we tested, five of them recognized the conjugate in spite of its low binding affinity for the HLA-A2 molecules. The resulting T-cell stimulation was determined through the intracytoplasmic secretion of IFN-gamma and the percentage of T-cells thus activated. These highly encouraging results indicate that small non-peptidic natural product-derived molecules attached onto the central part of an antigenic peptide can fit at the TCR/HLA-A2 interface with induction of T-cell responses.

Epitopes↗
PubMed1976

A virally induced osteosarcoma in rats. A model for immunological studies of human osteosarcoma.

Inoculation of Moloney sarcoma virus into the medullary canal of the tibia in newborn Wistar-Lewis rats resulted in an initially localized osteosarcoma which usually metastasized to the lung and resulted in the death of the animal within four to five weeks. Tumor cells were grown in tissue culture and used as target cells in the assay of lymphocyte-mediated cytotoxicity using a microcytotoxicity and a radioisotope labeling method. Lymphocyte-mediated cytotoxicity was demonstrated throughout the course of the clinical disease as well as in a small number of animals which showed spontaneous regression of their tumors. Serum factors which could "block" or augment the cellular response were also identified. This model resembles the spontaneous osteosarcoma of humans in many respects and may be useful for studies of the human disease.

Animals↗
PubMed1989

The release of interleukin-1-like activity by macrophages in two models of immunological inflammation in the rat.

Interleukin-1 (IL-1) is a putative mediator of inflammation released by activated macrophages in vitro. The IL-1 release by rat macrophages collected either from exudates in pertussis-induced air pouches or from the peritoneum during adjuvant arthritis has been investigated. In air pouch inflammation LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at day 6 after challenge. This enhanced IL-1 release parallels the extent of mononuclear cell migration in the inflammatory lesion. In adjuvant arthritis LPS-stimulated macrophages collected from sensitized animals release more IL-1 than cells from control rats at days 16 and 23 after adjuvant injection. The secondary inflammation in arthritic rats was statistically significant at days 16 to 28. These results indicate that during immunological inflammation macrophages either from the inflamed area or from a non-inflamed region release more IL-1 than control cells. This release parallels the extent of the inflammation and may be important in its pathogenesis.

Air↗
PubMed1996

The role of tumor necrosis factor-alpha in the pathogenesis of anorexia and bulimia nervosa, cancer cachexia and obesity.

In this paper a new immunological model of anorexia and bulimia nervosa will be presented in which the inflammatory cytokines are conceived as the fundamental regulators of body metabolism. This conception differs from the conventional view in which the inflammatory cytokines are perceived primarily as peptide molecules utilized by the immune system to control infection, inflammation and tissue or neuronal damage. Given that the inflammatory cytokines are also fundamental regulators of body metabolism, when they become dysregulated they create physiological chaos which results in the development of a number of autoimmune, metabolic and psychiatric disorders. In this proposed immunological model of anorexia and bulimia nervosa, elevated tumor necrosis factor-alpha features as the primary cause of these conditions. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia in terms of the causal role the cytokines, neuropeptides and neurotransmitters play in the manifestation of shared symptoms. These shared symptoms include elevated tumour necrosis factor-alpha, down-regulated interleukin-2 and interleukin-4 and depletion of lean body mass. Furthermore, the following neuropeptides are dysregulated in both anorexia nervosa and cancer cachexia: vasoactive intestinal peptide, cholecystokinin, corticotropin-releasing factor, neuropeptide Y, peptide YY and beta-endorphin. In addition, in anorexia and bulimia nervosa, secretion of the neurotransmitter serotonin is inhibited while norepinephrine is enhanced. It will be argued that the causal interplay between the cytokines, neuropeptides and neurotransmitters initiates a cascade of biochemical events which may result in either anorexia or bulimia nervosa, or cancer cachexia. The extent to which these inflammatory cytokines, neuropeptides and neurotransmitters are causally efficacious in the pathogenesis of other autoimmune disorders, such as diabetes mellitus and rheumatoid arthritis, will also be addressed.

Anorexia Nervosa↗
PubMedDate not supplied

[Model for immunologic testing of biomaterials].

Corrosion products and electric fields are capable of changing proteins to antigens, thus permitting the immunological system to identify the biomaterial as foreign. The reaction between corrosion products and a macro-molecule also leads to an antigen (carrier antigen), such as conformational changes of a macro-molecule, e.g. a protein, caused by the electric field at the implant surface (modified macro-molecule antigen). While the sensitivity to corrosion and the effectiveness of galvanic elements is measurable by electrochemical methods, suitable methods of determining the field strength in the vicinity of biomaterial surfaces are still unavailable. The influence of the double layer of uncoated and coated titanium surfaces on the conformation of proteins and their conversion to antigens are investigated with polyclonal antibodies capable of identifying the unchanged protein despite adsorption to the surface. 14C-marked Bovine Serum Albumin serves as a model protein. Determination of the total number of protein molecules adsorbed is effected via the detection of the emitted electrons. The quotient of the concentration of natural proteins to the concentration of adsorbed molecules gives the biocompatibility index, which is independent of the surface area, and gives an indication of the expected biocompatibility of the material. The results of the biological tests of titanium and two coating materials on titanium were confirmed in an animal experiment. It is possible that in the future immunological tests may replace experiments in animals.

Animals↗
PubMed1990

The BALB/c mouse as a model for immunological studies of microfilariae-induced pulmonary eosinophilia.

Tropical pulmonary eosinophilia (TPE) is believed to result from extreme immediate hypersensitivity to microfilariae localized in the pulmonary vasculature of some persons with lymphatic filariasis. Female BALB/c mice repeatedly immunized by ip injection of Brugia malayi microfilariae become amicrofilaremic within 24 hr of iv parasite challenge, whereas non-sensitized control animals remain patent for greater than 72 hr. Immunized, but not control mice, develop peripheral blood and pulmonary eosinophilia (2,000 cells/mm3 and 65,000 cells/bronchoalveolar lavage, respectively). Serum and bronchoalveolar lavage filarial-specific IgG antibodies are greater in sensitized mice than in controls (ELISA absorbance values 20- and 10-fold higher, respectively). Serum IgE antibody levels are also greater (P less than 0.01) in immunized parasite-challenged mice than in controls (mean cpm 125I-labeled anti-mouse IgE bound to B. malayi antigen-coated Sepharose beads: 7,852 vs. 1,741, respectively). This model exhibits several of the major features of human TPE: amicrofilaremia, elevated levels of serum IgG and IgE antibodies to microfilariae, and blood and pulmonary eosinophilia. This model may be useful in the examination of the role of filarial antigen-specific lymphoid cells and antibodies in regulating the pathologic responses to microfilariae trapped in the lung.

Animals↗
PubMed1987

A model of immunologic lung injury induced by trimellitic anhydride inhalation: antibody response.

We studied lung injury induced in Sprague-Dawley rats by trimellitic anhydride (TMA) inhalation. Groups of 40 male and 20 female rats were exposed to TMA by inhalation at target concentrations of 0, 10, 30, 100, and 300 micrograms/m3, 6 hours per day, 5 days per week, for 2 weeks. Rats in each exposure group were sacrificed after 10 exposures or rested for 12 days and either sacrificed or received a 6-hour TMA challenge at their initial exposure levels and sacrificed at 24 hours. At each sacrifice, serum antibody to radiolabeled trimellityl rat serum albumin (RSA-TM) was measured by an ammonium sulfate technique, and lung pathology was determined. After 10 days of exposure, external hemorrhagic lung foci were directly related to the exposure concentration of TMA. Serum antibody binding of RSA-TM correlated with exposure concentration, hemorrhagic lung foci, and lung weight. There was healing of lung lesions 12 days after exposure with a return of lung lesions only 18 hours after the 6-hour inhalation challenge. A correlation between serum antibody to RSA-TM, hemorrhagic foci, and lung weight existed after challenge. This model clarifies two clinical entities observed in exposed workers, the late respiratory systemic and the pulmonary disease-anemia syndromes.

Administration, Inhalation↗
PubMedDate not supplied

Cytokine and nitric oxide levels in a rat model of immunologic protection from adjuvant-induced arthritis.

In the present study we investigated the correlation between the progression of adjuvant arthritis induced by Mycobacterium butyricum and the production of nitric oxide and some pro- and anti-inflammatory cytokines in arthritic rats and in rats treated with low intra-peritoneal doses of Mycobacterium 3 and 10 days after arthritis induction. The intra-peritoneal administration of Mycobacterium antigen significantly inhibited disease development. Compared to healthy rats, a rise in serum and peritoneal pro-inflammatory cytokines was observed in all arthritic rats already from the 14 day. The treatment with intra-peritoneal Mycobacterium was associated with a significant reduction in IL-6 serum concentrations and a slight decrease of IFN-gamma production by peritoneal macrophages. Nitrite/nitrate plasma and peritoneal levels were significantly higher in all arthritic rats. Intra-peritoneal administration of Mycobacterium caused a further increase in nitrite/nitrate plasma concentrations, while no differences were evident in nitric oxide production by peritoneal macrophages. From our data it is evident that among the variables here investigated, IL-6 seems to be the more representative marker of the disease and of the treatment effect. A possible role of nitric oxide as a modulator rather than a direct mediator in this model of inflammation is discussed.

Journal Article↗
PubMed1981

The black mink (Mustela vison). A natural model of immunologic male infertility.

Breeding for fine black fur has generated a colony of mink wherein 20-30% of the males are infertile. Two clinical groups are distinguishable: one being infertile from the start (primary infertility), and the other infertile after one or more years of fertility (secondary fertility). Although the etiology of primary infertility is unknown, the available data indicate that secondary infertility is associated with an autoimmune disease of the testis. Thus, male mink with secondary infertility have (a) higher prevalence and levels of anti-sperm antibody when compared with animals with primary infertility, and the antibody prevalence varies with fur color; (b) severe monocytic orchitis (47%) and/or aspermatogenesis (75%) with negative cultures for bacterial, fungal, mumps, or Coxsackie B viral organisms; (c) massive and extensive granular deposits of mink IgG and/or C3 (71%), typical of immune complexes, along the basal lamina of seminiferous tubules; (d) testes that when eluted with buffer or low pH yielded IgG that was 10-fold enriched in anti-sperm antibody activity as compared with serum IgG; and (e) no immunopathologic evidence of Aleutian mink disease. Although the sperm antigen-antibody complexes in the testis may be important as a pathogenetic mechanism of the testicular disease, there is no correlation between fluorescent anti-sperm antibody detection in the serum and the infertile state. The infertile black mink is a new model of infertility associated with naturally occurring autoimmune disease of the testis.

Animals↗
PubMed1976

Nonmalignant monoclonal immunoglobulinemia, pernicious anemia and gastric carcinoma. A model of immunologic dysfunction. Report of two cases and review of the literature.

The association of an autoimmune disease with a monoclonal immunoglobulin is not exceptional and most probably results from a dysfunction of the immunologic apparatus. This study describes two patients with monoclonal immunoglobulin A (IgA) and M (IgM) gammopathy, respectively, in whom pernicious anemia and finally gastric carcinoma developed. One patient had autoantibodies to gastric parietal cell and to thyroid microsomal antigen which could not be identified with the M-component. This observation, together with the fact that pernicious anemia occurred in one case before and in the other case after the discovery of M-component, suggests that different clones of cells were responsible for both disorders. Sixteen cases in which the patients had the same association have been collected from the literature and the data are compared with ours.

Aged↗
PubMed2001

Activation of pro-astacin. Immunological and model peptide studies on the processing of immature astacin, a zinc-endopeptidase from the crayfish Astacus astacus.

To contribute knowledge of the processing and activation of invertebrate proteolytic enzymes, we studied the metalloprotease astacin, a digestive enzyme from the freshwater crayfish Astacus astacus (decapod crustacean). It is the prototype of the protein family of astacins, members of which occur in organisms from bacteria to man and are involved in a variety of physiological reactions. According to its genomic structure, astacin is produced as a zymogen [Geier, G., Jacob, E., Stöcker, W. & Zwilling, R. (1997) Arch. Biochem. Biophys. 337, 300-307]. To localize and follow the processing of pro-astacin in different parts of the digestive tract, we synthesized two peptides covering the pro part of pro-astacin and raised antibodies against them. In addition, antiserum against the whole active astacin was produced. Using immunohistochemical investigation, we detected pro-astacin in the F cells of the hepatopancreas and all the way into the tubular lumen and the collecting ducts of this gland. Immunoblot assays revealed only active astacin, and never pro-astacin, present in the cardiac stomach. We conclude from these studies that astacin is secreted into the lumen of the hepatopancreatic tubules in its pro form and is activated on its way to the stomach. To investigate which of the two endopeptidases found in the digestive tract of crayfish, astacin or trypsin, is responsible for cleaving the propeptide from pro-astacin, we synthesized different peptides that mimick the activation site. MS analysis of the cleavage products of astacin and trypsin showed that astacin is capable of catalyzing its own activation. Any contribution of trypsin would require the successive action of an aminopeptidase. Substituting glycine for arginine at position -1 of the activation site does not prevent astacin activity. As most members of the astacin protein family have basic amino-acid residues in this position, in these cases also astacin-specific cleavage would be possible.

Amino Acid Sequence↗
PubMed1970

Hapten-carrier relationships of isoantigens. A model for immunological maturation based on the conversion of haptens of carriers by antibody.

In chickens, erythrocyte isoantigens have hapten-carrier relationships. Specific anticarrier antibody depresses the immune response to the carrier and enhances the immune response to the hapten. Antigenic determinants of "haptenic" isoantigens behave as carriers if they are coated with specific antibody. It is postulated that every humoral antibody response involves the cooperation of a carrier with a hapten and the progressive conversion by antibody of haptens to carriers. Thus a carrier is viewed as an antigenic determinant which is coated with antibody. The antibody-forming cell only synthesizes antibody to the uncoated haptenic determinants. The consequences of this interpretation for the development of immunological maturity and the secondary immune response are discussed.

Animals↗
PubMed2000

Fundoplication: a model for immunologic aspects of laparoscopic and conventional surgery.

BACKGROUND AND PURPOSE: Immunologic investigations of laparoscopic and conventional procedures have recently been performed during cholecystectomy or colon resection, but the results might have been influenced by the amount of dissection or the presence of malignant tumor. Because fundoplication is characterized by moderate dissection and no resection, we supposed it to be an appropriate procedure for comparing immunologic changes during laparoscopic and conventional surgery. PATIENTS AND METHODS: Immunologic analysis (interleukin [IL]-6, IL-10, leukocytes, HLA-DR monocytes) was carried out on the peripheral blood of 34 patients who underwent elective Nissen fundoplication by the laparoscopic (LAP; N = 26) or conventional (OPEN; N = 8) technique for gastroesophageal reflux disease. Blood samples were obtained before and 1 and 4 hours after the beginning of the operation and on days 1, 2, 4, 7 after the procedure. RESULTS: A very fast and significant (P < 0.01) increase of the proinflammatory cytokines (IL-6, IL-10) and leukocytes and a decrease of cell-mediated functions (HLR-DR monocytes) were detected. Most of the analyzed measures had returned to preoperative values by 2 days after the procedure. All of the changes were similar in the two groups with the exception of IL-6. Throughout the post-operative study period, IL-6 concentrations were higher in the OPEN group, being significant 4 hours, 1 day, 2 days, and 4 days after the operation. CONCLUSION: The investigation measures do not give evidence that laparoscopic fundoplication is superior to conventional fundoplication in its immunologic effects.

Adult↗