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At least 163 records · Page 9Linked to original sources
PubMed1991

The immune-neuroendocrine homeostatic network and aging.

A unified model of immune and neuroendocrine aging is proposed. In doing so, the idea of an immune-neuroendocrine homeostatic network in higher animals is introduced. Next the concepts of homeorrhesis (moving homeostasis), developmental program and their relation to systemic aging are discussed. Finally, the experimental evidence supporting the view that immune and neuroendocrine aging are interdependent processes is briefly reviewed. This evidence makes it clear that organismal aging can no longer be described in terms of purely neuroendocrine or immunologic models. It is hoped that the idea of an immune-neuroendocrine homeostatic network will provide a conceptual frame of reference where the growing body of experimental data regarding immune-neuroendocrine interactions during aging can be naturally accommodated.

Aging↗
PubMed1993

Pharmacologic manipulation of a four day murine delayed type hypersensitivity model.

A murine delayed-type hypersensitivity (DTH) model was developed as a tool for drug discovery. Time course studies indicated that hind paw swelling was maximal at four days post-sensitization with picryl chloride. A pharmacological survey involving daily administration of drugs revealed that as a class, the glucocorticoids (e.g. dexamethasone and corticosterone) were the most potent inhibitors of the DTH response. The immunosuppressants, methotrexate, cyclosporine A, cyclophosphamide, and azathioprine, were all able to suppress the DTH response, with methotrexate being the most potent suppressor of paw swelling. Likewise, non-steroidal anti-inflammatory agents (e.g. indomethacin, piroxicam, diclofenac, and naproxen) all suppressed the DTH response, with indomethacin and piroxicam being the most potent suppressors. A series of central nervous system affecting drugs, including serotonin agonists [e.g. trifluromethylphenylpiperazine (tfMPP), 1-(3-chlorophenyl)piperazine (mCPP), quipazine, and 8-hydroxy-DPAT hydrobromide (8-OH DPAT)], and serotonin antagonists (e.g. cyproheptadiene, ketanserin, and mianserin) were examined in the 4 day DTH model. Except for 8-OH DPAT, all of the serotonin agonists were able to suppress the DTH response, with mCPP being the most potent suppressor. In contrast, none of the tested serotonin antagonists had any effect on the DTH response. The histamine antagonists (e.g. cimetidine and chlorphineramine) were largely ineffective in suppressing the DTH response. These data provide a pharmacological profile for a series of immunomodulator, non-steroidal anti-inflammatory, and central nervous system active compounds in a classic immunologic model.

Animals↗
PubMed1995

Acute on chronic bronchitis: A model of mucosal immunology.

Acute bronchitis has been studied as a model of disturbed mucosal immunoregulation. A new hypothesis relating to the pathogenesis of acute bronchitis has been developed, based on altered host response as the prime mover. Infection-prone subjects had low levels of lysozyme. Effective oral immunization, especially if early, reduced levels of bacterial colonization. Future attention focuses on intra bronchial inflammation and its link to the host-parasite relationship.

Acute Disease↗
PubMed1985

Nephroimmunopathology and pathophysiology.

Immunologic models of renal injury are useful in the study of pathophysiology. Some of these models have already been used in glomerular micropuncture studies and were shown to be approachable with the same techniques that were developed to study normal renal function. The typical decrease in the glomerular permeability coefficient found in such studies is countered by an increase in the hydrostatic pressure gradient, minimizing decreases in single nephron filtration rate. Antibody mechanisms involving either direct glomerular (and tubular) fixation of antibody or accumulation of immune complex materials provide an array of acute and chronic lesions for evaluation with relevance to the bulk of immune glomerular and tubular lesions in humans. The influences of varied and overlapping immune mediator systems are also useful areas for physiologic assessment. The tools of the renal immunopathologist may be useful to the physiologist in identifying and localizing the effects of transport systems central to renal function. The collaborative interaction of investigators skilled in immunology, pathology, and physiology is necessary to achieve optimum scientific value.

Animals↗
PubMed1999

Toward a canine model of atopic dermatitis: amplification of cytokine-gene transcripts in the skin of atopic dogs.

The objectives of the present study were to characterize and compare the repertoire of cytokine-genes transcribed in skin homogenates obtained from normal dogs and dogs with atopic dermatitis (AD) using a reverse-transcriptase polymerase chain reaction and canine-specific cytokine-gene primers. Whereas IL-4 and IL-5 cytokine-gene transcripts were detected more commonly in atopic skin biopsy homogenates, IL-2 mRNA was amplified more often from normal control specimens. IFN-gamma mRNA was detected in 5/29 atopic specimens, 4 of them obtained from the only dog with chronic skin lesions. One-fourth of atopic samples exhibited clear type-2 cytokine profiles; the remainder did not demonstrate polarized repertoires. Conversely, type-1 cytokine profiles were characterized in one-fourth of normal control specimens. The present study establishes, for the first time, the transcription of type-2 cytokine-genes in the skin of dogs with AD. Future experiments investigating the cellular origin and dynamics of allergic cytokine-gene transcription are needed to confirm whether or not canine AD could be considered an immunological model for a human disease.

Animals↗
PubMed1992

Pharmacologic manipulation of graft versus host induced splenomegaly.

A murine graft versus host (GVH) model was developed as a tool for drug discovery. A pharmacological survey revealed that as a class the anti-rheumatics (e.g., auranofin, azathioprine, and methotrexate) were the most potent inhibitors of GVH induced splenomegaly. The immunosuppressants, cyclophosphamide and cyclosporine A, and the glucocorticoids (e.g., dexamethasone, hydrocortisone, and corticosterone) were all able to suppress the GVH response. Anti-inflammatory agents (e.g., indomethacin and piroxicam), and a series of central nervous system affecting drugs, including serotonin agonists (e.g., trifluromethylphenylpiperazine (tfMPP), 1-(3-chlorophenyl)piperazine (mCPP), and quipazine), and tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, and nortriptyline) typically were ineffective at doses up to 10 mg/kg. However, at high dose levels (30 mg/kg) piroxicam enhanced while amitriptyline and cyproheptadine (a mixed serotonin and histamine antagonist) suppressed GVH induced splenomegaly. These data provide a pharmacological profile for a series of immunomodulator, anti-inflammatory, and central nervous system active compounds in a classic immunologic model.

Animals↗
PubMed2006

Beneficial effect of tachykinin NK1 receptor antagonism in the development of hapten-induced colitis in mice.

The gastro-intestinal tract is highly innervated by both intrinsic and extrinsic sensory nerves and this neuronal component is thought to play a role in local inflammatory responses. This in vivo study was designed to determine the function of substance P and the tachykinin NK1 receptor in the pathogenesis of inflammatory bowel disease by the use of the specific antagonist RP 67580. The dinitrofluorobenzene (DNFB)-induced colonic hypersensitivity model is associated with increased levels of substance P in the colon. The tachykinin NK1 receptor antagonist RP 67580 was used to investigate the role of substance P on the development of diarrhea, mast cell infiltration and activation, colonic tissue damage, hypertrophy of colonic lymphoid structures and leukocyte infiltration. The formation of watery diarrhea could completely be abrogated by treatment with RP 67580 in DNFB-sensitized animals 72 h after challenge. Antagonizing the tachykinin NK1 receptor in these animals also resulted in significantly reduced colonic patch hypertrophy, leukocyte recruitment and tissue damage. Total levels of substance P in the colon of DNFB-sensitized mice treated with the inactive enantiomer of the tachykinin NK1 receptor antagonist were significantly higher compared to DNFB-sensitized mice treated with RP 67580 72 h after challenge. Although RP 67580 was capable of reducing the total number of mast cells present in the colon, mast cell activation was not affected by this treatment. In conclusion, in this chemically-induced immunological model for inflammatory bowel disease we demonstrated an important role for tachykinin NK1 receptors, and its ligand substance P, in the development of colitis downstream from mast cell activation.

Animals↗
PubMed1980

Preservation of renal function in experimental glomerulonephritis.

To evaluate the protective effect of dietary phosphorus restriction in an immunologic model of experimental renal disease, we randomized 24 Sprague-Dawley rats with established nephrotoxic serum nephritis into two groups. Group A animals (N = 13) were fed a diet with a normal phosphorus content (0.5% phosphorus), and group B animals (N = 11) received an identical diet low in phosphorus (0.04% phosphorus). Over the ensuing 133 days, group A rats developed progressive renal failure and had a mean serum creatinine concentration of 3.0 +/- 0.5 mg/dl at the time of death or completion of the study. In contrast, group B animals maintained near normal renal function and had a final mean serum creatinine concentration of 0.93 + 0.2 mg/dl (P < 0.001). Survival was markedly improved in group B animals (P < 0.001). Histologic damage was diminished greatly in group B animals by both light and electron microscopy; immunofluorescence was positive in all animals. Group A animals had increased kidney calcium concentration (30 +/- 6 mmoles/kg) when compared to group B animals (18 +/- 1 mmoles/kg) and animals with normal kidneys (13 +/- 1 nmoles/kg, P< 0.001). Conclusion. Dietary restriction of phosphorus retards functional deterioration and reduces histologic damage in experimental immunologic renal disease. The mechanism for this protective effect has not been elucidated.

Animals↗
PubMed2005

Host immune responses in ex vivo approaches to cutaneous gene therapy targeted to keratinocytes.

Epidermal gene therapy may benefit a variety of inherited skin disorders and certain systemic diseases. Both in vivo and ex vivo approaches of gene transfer have been used to target human epidermal stem cells and achieve long-term transgene expression in immunodeficient mouse/human chimera models. Immunological responses however, especially in situations where a neoantigen is expressed, are likely to curtail expression and thereby limit the therapy. In vivo gene transfer to skin has been shown to induce transgene-specific immune responses. Ex vivo gene transfer approaches, where keratinocytes are transduced in culture and transplanted back to patient, however, may avoid signals provided to the immune system by in vivo administration of vectors. In the current study, we have developed a stable epidermal graft platform in immunocompetent mice to analyze host responses in ex vivo epidermal gene therapy. Using green fluorescent protein (GFP) as a neoantigen and an ex vivo retrovirus-mediated gene transfer to mouse primary epidermal cultures depleted of antigen-presenting cells (APCs), we show induction of GFP-specific immune responses leading to the clearance of transduced cells. Similar approach in immunocompetent mice tolerant to GFP resulted in permanent engraftment of transduced cells and continued GFP expression. Activation of transgene-specific immune responses in ex vivo gene transfer targeted to keratinocytes require cross-presentation of transgene product to APCs, a process that is most amenable to immune modulation. This model may be used to explore strategies to divert transgene-specific immune responses to less destructive or tolerogenic ones.

Animals↗
PubMed2001

Extraordinary variation in a diversified family of immune-type receptor genes.

Immune inhibitory receptor genes that encode a variable (V) region, a unique V-like C2 (V/C2) domain, a transmembrane region, and a cytoplasmic tail containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) have been described previously in two lineages of bony fish. In the present study, eleven related genes encoding distinct structural forms have been identified in Ictalurus punctatus (channel catfish), a well characterized immunological model system that represents a third independent bony fish lineage. Each of the different genes encodes an N-terminal V region but differs in the number of extracellular Ig domains, number and location of joining (J) region-like motifs, presence of transmembrane regions, presence of charged residues in transmembrane regions, presence of cytoplasmic tails, and/or distribution of ITIM(s) within the cytoplasmic tails. Variation in the numbers of genomic copies of the different gene types, their patterns of expression, and relative levels of expression in mixed leukocyte cultures (MLC) is reported. V region-containing immune-type genes constitute a far more complex family than recognized originally and include individual members that might function in inhibitory or, potentially activatory manners.

Amino Acid Sequence↗
PubMed1997

Mapping of the cellular immune responses to woodchuck hepatitis core antigen epitopes in chronically infected woodchucks.

T-cell responses to hepatitis B virus nucleocapsid antigens (HBcAg and HBeAg) play an important role in disease outcome in those infected with hepatitis B virus (HBV). The woodchuck is naturally infected in the wild with woodchuck hepatitis virus (WHV), which shows a high degree of genetic homology to HBV and produces a similar pattern of infection in its natural host. Twenty-three overlapping peptides were constructed to cover the entire WHV core region and used to identify immunodominant cellular epitopes in the nucleocapsid antigen using peripheral blood lymphocytes from 12 chronic WHV carrier and 4 uninfected control animals. A peripheral blood lymphocyte response was seen in all of the chronic WHV carrier animals to at least one peptide, and in 8 of the 12 chronic carrier animals a response was observed to 5 common peptides: peptide analogues of amino acids 16-30, 38-52, 50-69, 76-90 and 91-105. Peptide 91-105 produced maximal proliferation in 5 out of 12 infected animals. In addition, a difference in response was observed between wild and laboratory infected animals; the latter appeared to have a lower response to peptides than animals infected in the wild. This study provides evidence that the woodchuck has a population of peripheral blood cells which are sensitised to epitopes within the nucleocapsid protein and provides a basis on which to develop the use of the woodchuck as an immunological model of HBV infection for testing therapeutic means of enhancing this response.

Animals↗
PubMedDate not supplied

Prediction of IgE(Lb4)-ligand complex structures by automated docking.

A mouse monoclonal anti-2,4,6-trinitrophenyl IgE (clone Lb4) was screened with a random set of over 2000 compounds, and several ligands were found to bind with affinities comparable to that of the immunizing hapten (KD in the microM range). An automated docking algorithm was used for the prediction of complex structures formed by 2,4-dinitrophenyl (DNP) and non-DNP ligands in the fragment variable region of IgE(Lb4). All ligands were found to dock in an L-shaped cavity of 15 x 16 x 10 A, surrounded by complementary-determining regions L1, L3, H2 and H3. The ligands were found to occupy the same binding site in different orientations. For rigid ligands the most stable orientation could be predicted with high probability, based on the calculated energy of binding and the occurrence frequencies of identical complexes obtained by repeated simulations. The localization of a flexible ligand (cycrimine-R) was more ambiguous, but it still docked in the same site. The results support a model for heteroligating antibody (Ab) binding sites, where different ligands utilize the total set of available contacts in different combinations. It is suggested that although pseudoenergies calculated by the docking algorithm do not correlate with experimentally measured binding energies, the screening-and-docking procedure can be useful for the mapping of Ab and other receptor binding sites ligating small molecules.

2,4-Dinitrophenol↗
PubMedDate not supplied

Fine mapping of the antigen-antibody interaction of scFv215, a recombinant antibody inhibiting RNA polymerase II from Drosophila melanogaster.

A bacterially expressed single chain antibody (scFv215) directed against the largest subunit of drosophila RNA polymerase II was analysed. Structure and function of the antigen binding site in scFv215 were probed by chain shuffling and by site-specific mutagenesis. The entire variable region of either the heavy or light chain was replaced by an unrelated heavy or light chain. Both replacements resulted in a total loss of binding activity suggesting that the antigen binding site is contributed by both chains. The functional contributions of each complementarity determining region (CDR) were investigated by site specific mutagenesis of each CDR separately. Mutations in two of the CDRs, CDR1 of light chain and CDR2 of heavy chain, reduced the binding activity significantly. Each of the amino acids in these two CDRs was replaced individually by alanine (alanine walking). Seven amino acid substitutions in the two CDRs were found to reduce the binding activity by more than 50%. The data support a computer model of scFv215 which fits an epitope model based on a mutational analysis of the epitope suggesting an alpha-helical structure for the main contact area.

Alanine↗
PubMedDate not supplied

A model for a glutamate receptor agonist antibody-binding site.

A combination of mutagenesis, computer modeling and immunoreactivity has been used to develop a structural model of a segment of the glutamate receptor (GluR), termed GluR3B, which is bound by receptor-activating autoantibodies. In this model, the GluR3B epitope is located in a reverse hairpin loop that places key residues important for antibody recognition and receptor activation in a linear arrangement on the solvent-exposed surface. The conformation of the loop is stabilized by a hydrophobic core which is critical for functional integrity of the epitope. The proximity of the amino- and carboxy-terminal residues suggested that the GluR3B peptide could be cyclized without diminishing immunoreactivity through replacement of these residues with cysteines and formation of a disulfide bond. This prediction was confirmed experimentally since the cyclized peptide retained full immunoreactivity. The model provides insight into GluR subunit-specific functional diversity and the role of autoantibodies to this region in neurological disease.

Amino Acid Sequence↗
PubMedDate not supplied

Unraveling the effect of changes in conformation and compactness at the antibody V(L)-V(H) interface upon antigen binding.

We have analyzed conformational changes that occur at the interface between the light (V(L)) and heavy (V(H)) chains in antibody variable fragments upon binding to antigens. We wrote and applied the Tiny Probe program that computes the buried atomic contact surface area of three-dimensional structures to evaluate changes in compactness of the V(L)-V(H) interface between bound and unbound antibodies. We found three categories of these changes, which correlated with the size of the antigen. Upon binding, medium-sized nonprotein antigens cause an opening of the V(L)-V(H) interface (less compact), small antigens or haptens cause a closure of the interface (more compact), whereas large protein antigens have little effect on the compactness of the V(L)-V(H) interface. The largest changes in the atomic buried contact surface area at the V(L)-V(H) interface occur in residue pairs providing two 'shock absorbers' between the edge beta-strands of the V(L) and V(H) beta-sheets forming the antibody binding site. Importantly, the correlation between the size of antigens and conformational changes indicates that the V(L)-V(H) interface in antibodies plays a significant role in the antigen binding process. Furthermore, as the energy involved in such a motion is significant (up to 3 kcal/mol), these results provide a general mechanism for how residues distant from the combining site can significantly alter the affinity of an antibody for its antigen. Thus, mutations introduced at the V(L)-V(H) interface can be used to change antibody binding affinity with antigens. Due to the tightly packed V(L)-V(H) interface, the introduction of random mutations is not advisable. Rather our analysis suggests that concerted mutations of residues preceding CDRL2 and following CDRH3 or residues preceding CDRH2 and at the end of CDRL3 are most likely to alter or improve antigen binding affinity.

Antigen-Antibody Reactions↗
PubMed2000

A mathematical analysis of TCR serial triggering and down-regulation.

Despite the increasing knowledge on the pathways involved in TCR signal transduction and T cell activation, the molecular mechanism of TCR triggering by ligand, MHC-peptide complexes, is still elusive and controversial. The present paper addresses the controversy on the early events of TCR engagement and triggering. Mathematical modelling techniques are applied to experimental data to infer plausible molecular mechanisms of TCR triggering and down-regulation. A similar approach has been followed by Bachmann et al. (Eur. J. Immunol. 1998, 28: 2571 - 2579), who concluded that the TCR triggering requires the formation of MHC-TCR dimers or trimers. We report here the failure to generalize this conclusion to the data reported by Valitutti et al. (Nature 1995, 375: 148 - 151). We show that there are several kinetic features in these experimental curves of TCR down-regulation that cannot be explained by the simple model proposed by Bachmann et al. unless some phenomenological extensions are considered. These extensions are: (1) a ligand independent turnover of the TCR; (2) a transient accumulation of triggered TCR; (3) a high order of TCR triggering kinetics; and (4) two pools of membrane TCR in dynamic equilibrium.

Animals↗
PubMed2002

Hydrodynamic properties of rigid macromolecules composed of ellipsoidal and cylindrical subunits.

A procedure is devised for the calculation of hydrodynamic properties of rigid macromolecules composed subunits that are modeled as ellipsoids of revolution and cylinders. Owing to the axial symmetry of these shapes, smooth shell models can be constructured for the subunit structure. The bead shell model so constructed is employed for the calculation of the properties. A computer program, HYDROSUB, has been written implementing both the model building and the hydrodynamic calculation. A detailed example of the use of this methodology is presented for the case of the solution properties of the human antibody molecule immunoglobulin G3 (IgG3). Finally, hints are given on other uses and applications of the procedure.

Biophysical Phenomena↗