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Biomedical subjects

A R Lloyd

Publications and source records attributed to A R Lloyd.

At least 55 records · Page 3Linked to original sources
PubMed1994

Serum amyloid A is a chemoattractant: induction of migration, adhesion, and tissue infiltration of monocytes and polymorphonuclear leukocytes.

Serum amyloid A (SAA) is an acute phase protein that in the blood is bound to high density lipoproteins; SAA is secreted mainly by hepatocytes, and its concentration increases in the blood up to 1000 times during an inflammatory response. At present, its biological function is unclear. Since some forms of secondary amyloidosis are caused by deposition in tissues of peptides derived from the SAA and leukocytes seem to be involved in this process, we investigated the effect of human SAA on human monocytes and polymorphonuclear cells (PMN). When recombinant human SAA (rSAA) was used at concentrations corresponding to those found during the acute phase (> 0.8 microM), it induced directional migration of monocytes and polymorphonuclear leukocytes. Preincubation of rSAA with high density lipoproteins blocked this chemoattractant activity for both monocytes and PMN. rSAA also regulated the expression of the adhesion proteins CD11b and leukocyte cell adhesion molecule 1 and induced the adhesion of PMN and monocytes to umbilical cord vein endothelial cell monolayers. When subcutaneously injected into mice, rSAA recruited PMN and monocytes at the injection site. On the basis of these data, we suggest that SAA may participate in enhancing the migration of monocytes and PMN to inflamed tissues during an acute phase response.

Animals↗
PubMed1994

Structure, genomic organization, and expression of the human interleukin-8 receptor B gene.

Two distinct receptors for the chemoattractant interleukin-8 (designated IL-8RA and -B) have been cloned recently. The receptors are expressed almost exclusively on neutrophils and myelomonocytic cell lines. In an attempt to understand the tissue-specific expression and to identify transcriptional regulatory elements we have cloned, sequenced, and characterized the human IL-8RB gene. The gene consists of 3 exons, interrupted by two introns of 3 and 5.4 kilobases (kb). A 1065-base pair open reading frame is encoded entirely in the third exon. A 1.4-kb 3'-untranslated region contains clustered AU-rich elements, similar to those described for genes regulated by altering mRNA stability. The start site of transcription was mapped by a modified rapid amplification of cDNA ends technique and revealed an unexpectedly long 5'-untranslated region of 423 base pairs. A TATA box equivalent was found in the 5'-flanking region 20 nucleotides upstream of the start of the first exon. The promoter was separated from the ATG-initiation codon by 8.75 kb. Comparison of the IL-8RB promoter with the promoter region of the receptor for another chemoattractant ligand, the bacterial peptide f-Met-Leu-Phe, revealed 3 novel but conserved motifs occupying similar positions. The immediate 5'-flanking region was GC-rich with 3 SP-1-like and 2 AP-2 sites identified in close proximity to the transcription start site. This essential promoter region was found to be responsible for constitutive expression, inducible by granulocyte colony-stimulating factor and controlled by silencer elements located further upstream between positions -779 and -118.

Amino Acid Sequence↗
PubMed1994

Purification and cloning of a novel serine protease, RNK-Tryp-2, from the granules of a rat NK cell leukemia.

We have biochemically purified a 27-kDa serine protease (designated RNK-Tryp-2) from the granules of the rat large granular lymphocyte leukemia cell line (RNK-16) which has tryptase activity. Utilizing molecular sieve chromatography and reverse-phase HPLC, we purified RNK-Tryp-2 to homogeneity and sequenced 33 NH2-terminal amino acids. Oligonucleotide primers were used in the PCR to generate a 528-bp cDNA clone encoding a novel serine protease from RNK-16 mRNA. This cDNA clone was used to isolate an 884-bp RNK-Tryp-2 cDNA from an RNK-16 lambda-gt11 library. The open reading frame predicts a mature protein of 233 amino acids which does not have potential sites for N-linked glycosylation. The cDNA encodes a leader peptide of at least 25 amino acids. The characteristic Ile-Ile-Gly-Gly amino acids of the N-terminus, and the His, Asp, and Ser amino acids that form the catalytic triad of serine proteases, are conserved. The amino acid sequence has less than 45% identity with any other member of the serine protease family, indicating that RNK-Tryp-2 is distinct protease. Southern blot analysis suggests the existence of one or more related genes. A single 1.3-kb mRNA transcript was detected by Northern blot analysis of total cellular RNA from the in vivo passaged RNK-16, rat splenocytes, lung and liver nonparenchymal cells, as well as in highly purified rat LGL and T cells. RNK-Tryp-2 is a novel serine protease that is expressed in the granules of large granular lymphocytes.

Amino Acid Sequence↗
PubMed1994

Growth hormone promotes human T cell adhesion and migration to both human and murine matrix proteins in vitro and directly promotes xenogeneic engraftment.

Recombinant human growth hormone (rhGH) promotes human T cell engraftment in mice with severe combined immunodeficiency, suggesting that rhGH may have effects on T cell adhesion and migration in vivo. The ability of rhGH to directly affect the adhesion capacity of human T cells to a variety of human or murine adhesion molecules and extracellular matrix proteins was examined. rhGH induced significant human T cell adherence to both human and murine substrates via either beta 1 or beta 2 integrin molecules. rhGH was capable of inducing significant migration of resting and activated human T cells and their subsets. Most of the migratory response to rhGH was chemokinetic rather than chemotactic. In vivo engraftment studies in severe combined immunodeficiency mice receiving human T cells revealed that treatment with rhGH resulted in improved thymic engraftment, whereas treatment with non-human-reactive ovine GH demonstrated no significant effects. These data demonstrate that rhGH directly augments human T cell trafficking to peripheral murine lymphoid tissues. rhGH appears to be capable of directly altering the adhesive and migratory capacity of human T cells to molecules of either murine or human origin. Therefore, GH may, under either isogeneic or xenogeneic conditions, play a role in normal lymphocyte recirculation.

Animals↗
PubMed1993

Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells.

The human cytokine interferon-inducible protein 10 (IP-10) is a small glycoprotein secreted by activated T cells, monocytes, endothelial cells, and keratinocytes, and is structurally related to a family of chemotactic cytokines called chemokines. Although this protein is present in sites of delayed-type hypersensitivity reactions and lepromatous leprosy lesions, the biological activity of IP-10 remains unknown. We report here that recombinant human IP-10 stimulated significant in vitro chemotaxis of human peripheral blood monocytes but not neutrophils. Recombinant human IP-10 also stimulated chemotaxis of stimulated, but not unstimulated, human peripheral blood T lymphocytes. Phenotypic analysis of the stimulated T cell population responsive to IP-10 demonstrated that stimulated CD4+ and CD29+ T cells migrated in response to IP-10. This resembles the biological activity of the previously described T cell chemoattractant RANTES. Using an endothelial cell adhesion assay, we demonstrated that stimulated T cells pretreated with optimal doses of IP-10 exhibited a greatly enhanced ability to bind to an interleukin 1-treated endothelial cell monolayer. These results demonstrate that the IP-10 gene encodes for an inflammatory mediator that specifically stimulates the directional migration of T cells and monocytes as well as potentiates T cell adhesion to endothelium.

Antigens, CD↗
PubMed1993

Preferential migration of activated CD4+ and CD8+ T cells in response to MIP-1 alpha and MIP-1 beta.

Recombinant human macrophage inflammatory protein-1 alpha (rhMIP-1 alpha) and rhMIP-1 beta were potent chemoattractants of human T lymphocytes. These rhMIP-1 cytokines attracted only T cells activated by monoclonal antibody to CD3 and did not attract unstimulated lymphocytes. Phenotypic analysis revealed that CD4+ T cells were capable of migrating in response to rhMIP-1 beta, whereas rhMIP-1 alpha induced chemotaxis of predominantly CD8+ T lymphocytes. Activated naïve and memory T cells also migrated in response to rhMIP-1 cytokines. Furthermore, these cytokines enhanced the ability of T cells to bind to an endothelial cell monolayer. These results suggest that rhMIP-1 cytokines preferentially recruit specific T cell subsets during the evolution of the immune response.

Adult↗
PubMed1993

Immunity and the pathophysiology of chronic fatigue syndrome.

The pathophysiology of chronic fatigue syndrome (CFS) remains unknown. The syndrome often follows a recognized or presumed infection and the disorder may therefore result from a disordered immune response to a precipitating infection or antigenic challenge. Abnormalities of both humoral and cellular immunity have been demonstrated in a substantial proportion of patients with CFS. The most consistent findings are of impaired lymphocyte responses to mitogen and reduced natural killer cell cytotoxicity. Cutaneous anergy and immunoglobulin G subclass deficiencies have also been found. Further studies are needed examining cytokine levels in serum and cerebrospinal fluid, and cytokine production in vitro in patients with CFS. Interpretation of the findings of published studies of immunity is limited by probable heterogeneity in the patient groups studied, and by the lack of standardization and reproducibility in the assays used. The pattern of abnormalities reported in immunological testing in patients with CFS is consistent with the changes seen during the resolving phases of acute viral infection. These data provide circumstantial support for the hypothesis that CFS results from a disordered immune response to an infection. Longitudinal studies of immunity in patients developing CFS after defined infectious illnesses will provide the best means of further examining this hypothesis.

Antibody Formation↗
PubMed1993

Chemokines and serpentines: the molecular biology of chemokine receptors.

Chemokines are pro-inflammatory molecules with a diverse array of biological and biochemical functions. These molecules induce the migration of a number of leukocyte subsets including monocytes, neutrophils, and T-cells. The recent cloning of the IL-8, GRO, and MIP-1 alpha chemokine receptors revealed that these glycoproteins belong to the serpentine family of seven transmembrane G-protein-coupled receptors. Other members of this family include the chemotactic receptors for fMLP and C5a, indicating that a common pathway for eliciting the directional migration of leukocytes is probably transduced via G proteins. Ligand binding to chemokine receptors is complex, featured by multiple chemokines binding to a single receptor and multiple receptors binding a specific ligand. Future directions in this field appear to be focused on the cloning of novel receptors and the identification of ligands for orphaned receptors.

Amino Acid Sequence↗
PubMed1993

Immunologic and psychologic therapy for patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial.

PURPOSE: To evaluate the potential benefit of immunologic therapy with dialyzable leukocyte extract and psychologic treatment in the form of cognitive-behavioral therapy (CBT) in patients with chronic fatigue syndrome (CFS). PATIENTS AND METHODS: Immunologic and psychologic treatments were administered to 90 adult patients who fulfilled diagnostic criteria for CFS in a double-blind, randomized, and placebo-controlled study. A four-cell trial design allowed the assessment of benefit from immunologic and psychologic treatment individually or in combination. Outcome was evaluated by measurement of global well-being (visual analogue scales), physical capacity (standardized diaries of daily activities), functional status (Karnofsky performance scale), and psychologic morbidity (Profile of Mood States questionnaire), and cell-mediated immunity was evaluated by peripheral blood T-cell subset analysis and delayed-type hypersensitivity skin testing. RESULTS: Neither dialyzable leukocyte extract nor CBT (alone or in combination) provided greater benefit than the nonspecific treatment regimens. CONCLUSIONS: In this study, patients with CFS did not demonstrate a specific response to immunologic and/or psychologic therapy. The improvement recorded in the group as a whole may reflect both nonspecific treatment effects and a propensity to remission in the natural history of this disorder.

Adolescent↗
PubMed1992

The economic impact of chronic fatigue syndrome.

OBJECTIVE: To estimate the economic impact of chronic fatigue syndrome (CFS) on the individual, the government, and the community. DESIGN: The financial burden produced by CFS was studied by calculating the direct and indirect costs arising from the disorder. Data regarding use of health resources, income and employment were obtained by questionnaire from patients with CFS. In addition, aggregate Medicare data on the incidence and fees charged for each Schedule item for these patients was obtained. SETTING: The Richmond Valley, New South Wales. PARTICIPANTS: Forty-two patients with CFS identified in our population-based prevalence study. RESULTS: The conservative estimate of the per annum costs of CFS in the Richmond Valley, with a prevalence of 37.1 cases per 100,000, was $396,000. If extrapolated to the Australian population, we estimate CFS would generate an annual cost of at least $59 million. CONCLUSION: This disorder constitutes a large but neglected area of health resource utilisation and economic burden.

Adolescent↗
PubMed1991

Muscle performance, voluntary activation, twitch properties and perceived effort in normal subjects and patients with the chronic fatigue syndrome.

The decrease in maximal force-generating capacity, the degree of central activation of the muscle, and the subjective perception of effort were measured during prolonged submaximal isometric exercise in 12 male patients suffering from the 'chronic fatigue syndrome' and 13 naive, healthy male subjects. Maximal voluntary isometric torque generated by the elbow flexors was measured before, and at 5 min intervals during an endurance sequence of 45 min of repetitive isometric contractions (6 s duration, 4 s rest interval) producing 30% of the initial maximal voluntary torque. Electrical stimuli were also delivered to the elbow flexors to measure the contractile force in the intervals between voluntary contractions. The degree of central motor activation during maximal voluntary contractions was assessed using a sensitive method of twitch interpolation. In addition, the perceived effort required to achieve the target submaximal contractions was recorded using a standardized self-report scale. A high degree of central activation was achieved in maximal contractions during the endurance sequence both in the patients (mean of maximal force 93.6%; SD 7.8%), and in the control subjects (mean 90.9%; SD 9.5%). The relative torque produced by either voluntary or electrically stimulated contractions was not significantly different between patients and control subjects throughout the test. There was no significant difference in the perceived exertion between the patients and control subjects. These findings support the concept that neither poor motivation, nor muscle contractile failure is important in the pathogenesis of 'fatigue' in patients with the chronic fatigue syndrome.

Elbow Joint↗
PubMed1990

Prevalence of chronic fatigue syndrome in an Australian population.

An epidemiological study was undertaken to provide the first reported estimate of the point prevalence of chronic fatigue syndrome in an Australian community. After a pilot study in a separate location, the population of the Richmond Valley, New South Wales, was sampled using a structured case-finding technique, which included notification from local medical practitioners, the use of a screening questionnaire and standardised interviews conducted by a physician and psychiatrist. In addition, investigations were performed to exclude alternative diagnoses and to assess cell-mediated immunity. Forty-two patients with chronic fatigue syndrome, with a female:male ratio of 1.3:1.0, were detected in a population of 114,000. The mean age at onset of symptoms was 28.6 years (SD, 12.3 years), and the median duration of symptoms from onset to sampling date was 30 months. The social status of the patients was distributed in accordance with that of the remainder of the population sampled, with no bias towards the middle or upper social classes. The disorder was causing considerable incapacity, with 43% of patients unable to attend school or work. The conservative estimate from this study suggests a prevalence on June 30 1988 of 37.1 cases per 100,000 (95% confidence interval [CI], 26.8-50.2). Chronic fatigue syndrome is an important disorder in this Australian community that affects young individuals from all social classes and causes considerable ill health and disability.

Activities of Daily Living↗
PubMed1989

Immunological abnormalities in the chronic fatigue syndrome.

The chronic fatigue syndrome is a disorder of unknown aetiology which is characterized by debilitating fatigue. Recent evidence has suggested that viruses may persist in the tissues of patients with chronic fatigue syndrome. A concurrent immunological disturbance is likely to be associated with the persistence of viral antigens. Therefore, the humoral and cellular immunity of 100 patients who were suffering from chronic fatigue syndrome and that of 100 healthy, age- and sex-matched control subjects were compared. This study documents the frequent occurrence of abnormalities within the cellular and humoral immune systems of patients with well-defined chronic fatigue syndrome. Disordered immunity may be central to the pathogenesis of chronic fatigue syndrome. In patients with chronic fatigue syndrome, a significant (P less than 0.01) reduction was found in the absolute number of peripheral blood lymphocytes in the total T-cell (CD2), the helper/inducer T-cell (CD4) and the suppressor/cytotoxic T-cell (CD8) subsets. A significant (P less than 0.001) reduction also was found in T-cell function, which was measured: in vivo by delayed-type hypersensitivity skin-testing (reduced responses were recorded in 50 [88%] of 57 patients); and in vitro by phytohaemagglutinin stimulation. Reduced immunoglobulin (Ig) levels were common (56% of patients), with the levels of serum IgG3- and IgG1-subclasses particularly (P less than 0.05) affected.

Adolescent↗