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D J Ormrod

Publications and source records attributed to D J Ormrod.

18 recordsLinked to original sources
PubMed1992

A low molecular weight component derived from the milk of hyperimmunised cows suppresses inflammation by inhibiting neutrophil emigration.

An earlier study demonstrated that hyperimmunisation of dairy cows with a polyvalent bacterial vaccine stimulated the secretion of a small molecular weight anti-inflammatory moiety in the milk. This hyperimmune milk factor (HIMF) has been further investigated in the present experiments. HIMF was found to suppress the cellular phase of the response to carrageenin and also the neutrophil-dependent reverse passive Arthus reaction. These results, together with the observation that the administration of HIMF led to an increase in the number of circulating neutrophils, suggested that the agent might inhibit inflammation by interfering with the ability of neutrophils to emigrate from the vasculature. In vivo studies carried out to evaluate this possibility demonstrated that HIMF suppressed neutrophil emigration by up to 75%. In vitro experiments established that the ability of neutrophils to respond to chemotactic stimuli or adhere to endothelial cells was not affected by HIMF. It is possible, therefore, that the agent modulates inflammation by down-regulating the synthesis of inducible pro-inflammatory cytokines or adhesion molecules. Attempts are presently being made to isolate the active moiety to allow the activity of the agent at the molecular level to be studied in more detail.

Animals↗
PubMed1992

Suppression of inflammation by cyclosporin A is mediated via a T lymphocyte-independent process.

An athymic mutant rat strain was used to examine the hypothesis that modification of diseases with an inflammatory component by cyclosporin A (CsA) results from the suppression of nonspecific inflammatory mechanisms, rather than T-lymphocyte function, as is commonly inferred. Confirmation that the animal host was grossly depleted of T cells was obtained from anatomic and morphologic examination and functional tests of T-lymphocyte responsiveness. The experimental approach was to determine the effect of CsA on the course of experimentally induced infection with Escherichia coli, and extracellular pathogen. Host protection against this microorganism is dependent on an effective nonspecific inflammatory response. CsA administration prior to bacterial challenge resulted in a highly significant increase in bacterial numbers in the kidneys of both euthymic and athymic hosts. The data have provided a direct demonstration that modulation of the nonspecific inflammatory response by CsA can occur via a T lymphocyte-independent process.

Animals↗
PubMed1991

The anti-inflammatory activity of a low molecular weight component derived from the milk of hyperimmunized cows.

"Immune" milk has been utilized as a source of biologically active compounds for many years. In the present study, a low molecular weight fraction, isolated from the milk of dairy cows hyperimmunized with a multivalent bacterial vaccine (HIMF), has been evaluated for anti-inflammatory activity. Analysis was carried out using the rat hind-paw oedema assay. HIMF was shown to have a marked anti-inflammatory effect in this model and carrageenin-induced oedema was suppressed by up to 80% in individual experiments. The agent was active following oral, subcutaneous, intramuscular, intraperitoneal or intravenous administration. Intravenous injection was particularly effective and amounts as small as 1 mg significantly reduced the inflammatory response to carrageenin. The experiments have established that milk from hyperimmunized cows contains a highly active anti-inflammatory compound and form a basis for further studies, which will attempt to isolate and further characterize the active moiety.

Animals↗
PubMed1991

Assessment of antiinflammatory agents using 125I-labeled human serum albumin to quantify footpad edema volume in the rat.

Intravenously injected human serum albumin, labeled with radioactive iodine ([125I]HSA), accumulates at inflammatory foci in proportion to the volume of the exudate, making it possible to quantify the volume of edema. This paper describes the use of [125I]HSA to measure edema formation in the carrageenin rat-footpad model, both continuously and at a single time point. In assessing antiinflammatory agents, the method was shown to be more sensitive than the most commonly used technique of thickness measurement. Because anesthetics are known to suppress inflammation, the comparative effect of five anesthetic agents on the inflammatory response was determined. Ether was the only anesthetic tested that did not substantially inhibit the accumulation of edema. The technique overcomes many of the limitations of previously used procedures and has the potential to become the method of choice when assessing edema in the rat footpad.

Anesthetics↗
PubMed1990

Cyclosporin A modulation of the acute inflammatory response: an explanation for the effect of CsA on host defences in infection.

Previous studies have shown that the administration of cyclosporin A (CsA) to animals with experimentally induced pyelonephritis resulted in considerable exacerbation of infection. T-lymphocytes are not involved in the host response to pyelonephritis but neutrophils are known to be a key component in the pathogenesis of this infection, so the effect of CsA on this inflammatory component was investigated. CsA administration did not affect the metabolic activity of neutrophils in vitro nor their ability to phagocytose and kill microorganisms. However, the ability of neutrophils to mobilize to a sterile inflammatory focus in vivo was significantly impaired. Further experiments, using models of pyelonephritis and subcutaneous infection, demonstrated that the CsA-induced suppression of neutrophil mobilization was directly related to the observed increase in bacterial numbers and exacerbation of tissue damage. Additionally, the actual effect of CsA on host defences and the outcome of infection was found to be dependent on the level of the initial infectious challenge. The results of this study provide an explanation for the current pattern of infectious disease in patients treated with CsA, in whom infection with extracellular pathogens is still common. It is also clear that the effect of CsA on inflammatory mechanisms may explain the efficacy of the agent in inflammatory diseases such as rheumatoid arthritis. This suggests a wider therapeutic role for CsA than is currently recognized.

Acute-Phase Reaction↗
PubMed1987

Inhibition of neutrophil myeloperoxidase activity by selected tissues.

Myeloperoxidase, a polymorphonuclear leukocyte-specific enzyme, has been used previously to quantify the number of polymorphonuclear leukocytes in tissue. When this method was employed in an attempt to measure polymorphonuclear leukocyte numbers in infected kidneys, it was found that myeloperoxidase could not be demonstrated, although significant numbers of neutrophils were present in the pyelonephritic lesions. Further studies were carried out to determine the effect of other tissues on free and cell-bound exogenous myeloperoxidase. We have shown that while skin had little effect on enzyme levels, liver and spleen totally destroyed myeloperoxidase activity within 30 sec. Cardiac and striated muscle had an intermediate effect. When intact neutrophils were added to fresh cardiac tissue 72.5% myeloperoxidase activity was destroyed during the enzyme solubilization procedure. These findings indicate that the technique can only be used for the quantification of polymorphonuclear leukocytes in selected tissues and that appropriate controls are essential. Previous studies in which myeloperoxidase levels have been used to estimate polymorphonuclear leukocyte numbers in cardiac tissue will need reevaluation.

Animals↗
PubMed1987

An animal model for chronic infection of the unobstructed urinary tract.

Chronic cystitis due to Escherichia coli is frequently associated with anatomical or functional abnormalities of the lower urinary tract, but there is no satisfactory animal model available to help resolve biological and management problems. We have induced chronic infection of the unobstructed urinary tract in the rat by implanting a small polyurethane sponge into the dome of the bladder, 14 days before bacterial challenge. This manipulation provides a focus of infected urine and leads to the establishment of a chronic cystitis. Both the predisposing factor and the pathological details mimic important features of the disease in man.

Animals↗
PubMed1986

Sustained release of a corticosteroid using polymeric implants.

An effective sustained release method of drug administration, using methylprednisolone incorporated into acrylic bone cement, has been developed. The effect of this form of treatment on peripheral blood leukocytes, lymphoid tissue weight and the inflammatory response has been evaluated. This mode of methylprednisolone administration was compared with conventional systemic therapy and was found to produce rapid and prolonged pharmacological effects at very low plasma levels of drug. A dose response relationship was established and we determined that, for a given quantity of drug, the level and duration of suppression was greater using sustained release therapy. The inflammatory response was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of SIMPLEX P bone cement, suggest that further development may lead to useful clinical protocols.

Adrenal Cortex Hormones↗
PubMed1986

Mucosal mast cells as a component of the inflammatory response to lower-urinary tract infection.

Globule cells have been observed in mucosae for many years. Recently, a subpopulation of these globule cells in the intestinal mucosa of man and rodents have been identified as unique mast cells. In this communication, intraepithelial globule cells and some lamina-propria mast cells found in the normal rat urinary-bladder wall have been characterized as mucosal mast cells, similar to intestinal mast cells, and differentiated morphologically and histochemically from rat peritoneal mast cells. The number of mast cells in the bladder wall increased significantly during various bladder manipulations, including mechanical trauma, parasitic infestation and bacterial infection. The origin and function of the mucosal mast cells remains unknown.

Animals↗
PubMed1985

Extended immunosuppression with cyclophosphamide using controlled-release polymeric implants.

An effective method of prolonged immunosuppressive therapy using cyclophosphamide incorporated into acrylic bone cement has been developed. We have studied the effect of this form of administration of cyclophosphamide on circulating immune cells and the inflammatory response. When the slow release mode of cyclophosphamide administration was compared with conventional systemic therapy, it was found to produce a more rapid and prolonged immunosuppression. A dose-response relationship was established and the biological effects of varying the composition and surface area of the implant were determined. The inflammatory response, assessed by measuring the mobilisation of cells into subcutaneously implanted sponges, was also depressed using this mode of administration. These results, coupled with the commercial availability and existing clinical approval of Simplex P bone cement, suggest that the procedure could lead to useful clinical protocols.

Animals↗
PubMed1985

Host immune status in uraemia. VI. Leucocytic response to bacterial infection in chronic renal failure.

Infection often complicates renal failure and frequently causes death, but the association between renal failure, impaired immunity and infection has not been proved. A recent study showed that patients on dialysis did not show an expected leucocytic response to infection, suggesting that the blunted response was evidence of the immunocompromised state of the uraemic patient. In this study, the relationship between leucocytic responses and infectious challenge was investigated in an animal model of chronic renal failure. Bacteraemia, peritonitis and a chronic lung infection were induced in normal and uraemic rats; the leucocytic response was then monitored. In all three infections, the total white blood cell response was significantly less in the uraemic animals. Neutrophil numbers actually increased, but this response was disguised by a pronounced depression in lymphocyte numbers. Our conclusion is that, although the leucocytic response of the uraemic host to infection may be depressed, the changes to individual leucocyte components in the peripheral blood are sufficiently characteristic to provide useful evidence of infection.

Animals↗
PubMed1985

Immunopotentiation in infectious disease, I. Effect of bestatin on the immune response.

Few immunomodulators are available for the control of infectious disease. One reason has been the lack of a suitable protocol for evaluating such agents. We have presented a series of assays of immune function that will allow a standardized approach to this problem. The value of this protocol has been established using long-term low dose, and short-term high dose, administration of bestatin, a small molecular weight microbial product. The experiments were done using both normal and immunocompromised animals. Bestatin had no effect on circulating leukocytes or the reticuloendothelial system. Leukocyte mobilization and T cell responsiveness in immunocompromised animals were enhanced following bestatin treatment. The antibody response to SRBC doubled in normal animals while the same treatment schedule resulted in a marked reduction in the response to Escherichia coli lipopolysaccharide. These results have established the value of the protocol and identified some new immunomodulating properties of bestatin which may be useful in the control of infectious disease.

Adjuvants, Immunologic↗
PubMed1985

Immunopotentiation in infectious disease, II. Effect of bestatin on experimental infection.

A two-stage protocol designed to evaluate putative immunomodulators for use in infectious disease has been proposed. In this report the effect of bestatin on a series of clinically relevant, and sub-lethal infections is described. Pyelonephritis, peritonitis and bacteremia were induced with Escherichia coli, while Klebsiella pneumoniae was used to produce a lung infection. Bestatin had no effect on the course of these infections. In a further experiment we assessed the effect of combined bestatin/antibiotic therapy on the course of renal infection. Again no effect was observed. These findings are consistent with the known immunomodulatory properties of bestatin. This methodology will be used to evaluate selected agents for their potential in infectious disease and should lead to useful clinical protocols.

Adjuvants, Immunologic↗
PubMed1978

Complement-mediated immune mechanisms in renal infection.

The belief that the inactivation of complement by renal ammonia enhances the susceptibility of renal tissue to infection has been held for some years. This thesis has been investigated in the present experiments using cultures of renal tissue maintained in vitro under physiological conditions. The experiments have confirmed that exposure of normal serum to renal issue in culture does result in the rapid loss of complement activity, but that the inactivation was not due to renal ammonia. Furthermore, in quantitative experiments, the liver was found to have even greater anti-complementary activity than renal tissue. In experiments where the biological significance of this phenomenon was examined, it was shown that the bactericidal capacity of serum was maintained even after exposure to renal tissue. The results of these investigations suggest that the biological significance of the inactivation of complement by renal tissue in vitro has been over-emphasized and requires further studies in vivo.

Ammonia↗
PubMed1976

Depression of the T-lymphocyte response to phytohaemagglutinin by renal cells.

The lymphocytic infiltrate in the renal parenchyma is a consistent histological feature of pyelonephritis, but the role of the lymphocytes in the immunobiology of pyelonephritis is not known. In this investigation the influence of the local environment on the potential function of T lymphocytes in the kidney was investigated. The experiments have demonstrated that the response of rat lymphocytes to stimulation in vitro with phytohaemagglutinin (PHA) can be entirely ablated by normal kidney cells. Even when the number of kidney cells added to cultures of lymphocytes was less than 2% of the cells present some ablation of T-lymphocyte function could be detected. The biological characteristics of the factor causing ablation of the PHA responsiveness of T lymphocytes were partially characterized and the factor appears to have unique features that differentiate it from lymphocyte chalones and other tissue factors influencing lymphocyte function. The results may explain recent findings where T lymphocytes were found to be the predominant lymphocyte in the inflammatory infiltrate but were not responsive to PHA in vitro.

Animals↗
PubMed1975

Quantitation of immunoglobulin-bearing lymphocytes and the lymphocyte response to PHA in experimental pyelonephritis.

In these experiments the effect of experimental pyelonephritis on the distri-ution of B lymphocytes in the peripheral blood and lymphoid sites in the rat has been determined and the functional capacity of T cells during the course of infection has been investigated. The studies have shown that renal infection affects the distribution of lymphocytes and has a marked effect on the functional capacity of splenic T lymphocytes early in infection. Most of the lymphocytes forming the round cell infiltrate in the kidney have been identified as thymus-derived lymphocytes on their surface labelling characteristics. Evidence is presented to demonstrate the inability of T lymphocytes to function normally in the environment of the kdiney. It is suggested that ablation of cell-mediated immunity may be a factor contributing to the persistence of renal infection.

Animals↗