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Biomedical subjects

A C Allison

Publications and source records attributed to A C Allison.

At least 109 records · Page 6Linked to original sources
PubMed1989

IL-6 is the principal factor produced by synovia of patients with rheumatoid arthritis that induces B-lymphocytes to secrete immunoglobulins.

First, IL-6 is produced by synovial tissue of patients with rheumatoid arthritis (RA) and is the principal mediator produced by that tissue inducing differentiation of B-lymphocytes into antibody-forming cells. The Leu-1+ subset of B-lymphocytes is induced by IL-6 to secrete rheumatoid factor (IgM with anti-Fc gamma specificity). Second, the main cell types producing IL-6 in cells dissociated from RA synovial tissue are mononuclear leukocytes. Connective tissue type cells (synoviocytes) cultured from RA synovial tissue produce IL-6 in response to IL-1 beta, and IL-6 formation is increased by TGF-beta. Glucocorticoids strongly inhibit and PGE2 slightly inhibits IL-1-induced IL-6 mRNA expression in synoviocytes. Production of IL-6 increases when undissociated RA synovial tissue is maintained in culture, thus suggesting release from inhibition by a factor or factors not yet identified. Third, the major known local effect of IL-6 in RA synovial tissue is the augmentation of antibody formation and the major known systemic effect is the induction of the synthesis by the liver of acute-phase proteins, especially C-reactive protein. Levels of circulating C-reactive protein are reported to decrease in RA patients receiving long-acting antirheumatic drugs, which would be consistent with the interpretation that immature monocyte-derived macrophages are major producers of IL-6 in these patients.

Antibody Formation↗
PubMed1989

Induction of articular cartilage degradation by recombinant interleukin 1 alpha and 1 beta.

The purpose of this study was to compare the effects of human recombinant interleukin 1, alpha and beta, on articular cartilage. The effects of rIL-1 alpha and rIL-1 beta on proteoglycan degradation and synthesis following treatment of bovine articular cartilage in serum-free organ culture were quantified. Purified human IL-1 and both rIL-1 alpha and rIL-1 beta induced a two-fold or greater increase in glycosaminoglycan (GAG) release from cultured articular cartilage. Levels or rIL-1 alpha as low as 15 pM induced increased proteoglycan degradation whereas identical levels of rIL-1 beta did not. Killing of the cartilage cells abolished induced GAG release by all forms of IL-1. Analysis of proteoglycan size following IL-1 treatment showed limited degradation of material released into the culture medium or remaining within cartilage. Both forms of recombinant IL-1 inhibited GAG synthesis when continually present in the culture medium. Actinomycin D and cycloheximide inhibited IL-1 dependent cartilage destruction whereas indomethacin did not.

Animals↗
PubMed1989

Interleukin 1 protects against the lethal effects of irradiation of mice but has no effect on tumors in the same animals.

Interleukin 1 (IL-1) is a radioprotector of bone marrow and is cytotoxic to some tumor cells. This investigation examines these two properties in the same host animals and gives evidence of radioprotection against localized x-irradiation of the head and neck region. By LD50 analyses, recombinant human IL-1 (100 ng/mouse, approximately 3 micrograms/kg) was found to be radioprotective against whole-body irradiation for both C3H/Km and C57BL/Ka mice. The combined potency ratio for the two strains was 1.07 (95% confidence limit: 1.02-1.12). It was also radioprotective against the injury leading to acute lethality resulting from localized head and neck irradiation of C3H/Km mice; 100 ng of IL-1/mouse produced a potency ratio of 1.05 (95 confidence limit: 1.03-1.07). However, two tumors that originated in C3H/Km mice, RIF-1 and SCCVII, showed neither in vitro nor in vivo response to IL-1. Also, there was no IL-1-induced reduction in in vivo growth of the RL 12NP lymphoma in C57BL/Ka mice.

Animals↗
PubMed1988

Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA.

Transcription of the interleukin 1 beta (IL-1 beta) gene was studied by mRNA hybridization with a cDNA probe in the human promonocytic cell line U-937. Phorbol ester and lipopolysaccharide increased the steady-state level of IL-1 beta mRNA. Glucocorticoids markedly decreased IL-1 beta mRNA levels by two mechanisms. Transcription of the IL-1 gene was inhibited, as shown by in vitro transcription assays with nuclei isolated from glucocorticoid-treated cells. Moreover, kinetic analyses and pulse-labeling of mRNAs showed that glucocorticoids selectively decrease the stability of IL-1 beta mRNA, without affecting the stability of beta-actin and FOS mRNAs. Inhibition of the formation and effects IL-1 is a mechanism by which glucocorticoids can exert antiinflammatory and immunosuppressive effects.

Cycloheximide↗
PubMed1988

The disc angiogenesis system.

A new system for the study of angiogenesis in vivo has been devised. It consists of a small disc of polyvinyl alcohol foam, covered on both flat sides by Millipore filters, leaving only the edge as the area for cell penetration into the disc. Angiogenic agonists or antagonists, as well as other substances to be studied, are placed in the center of the disc. The slow release of these substances is maintained by a film of ethylene-vinyl acetate co-polymer, or by the use of agarose. The disc is implanted subcutaneously in the host animal through a distant skin incision. In mice, the optimal times for examination of the discs are 7 to 12 days after implantation for discs containing angiogenic stimulants and 12 to 20 days for those without stimulants. After a period of growth is completed, the disc is removed, fixed, and embedded in paraffin or methacrylate. Medial plane sections, stained by a variety of methods, are used to observe and measure the growth of vessels and stroma into the disc. Whether stimulated or not, this growth is centripetal and can be easily quantitated by simple morphometric technics. This system has already been used in mice, to study the proliferation of vessels and fibroblasts into discs devoid of, or containing angiogenic stimulants (epidermal growth factor, acidic fibroblastic growth factor). We have also utilized the discs to demonstrate the inhibition of vessel growth by hyperthermia. Examples of these applications are presented. The disc angiogenesis system is easy to prepare, inexpensive, and well tolerated, at least by mice. Its simplicity and reproducibility make it suitable for a wide range of applications beyond those described here.

Angiogenesis Inducing Agents↗
PubMed1987

Monoclonal antibodies to human recombinant interleukin 1 (IL 1)beta: quantitation of IL 1 beta and inhibition of biological activity.

Monoclonal antibodies (McAb) were developed to the Mr 17,500 form of human recombinant interleukin 1, IL 1 beta. Four McAb have been identified that inhibit the biological activity of IL 1 beta. McAb H34 and H67, at 1 microgram/ml (6 X 10(-9) M), completely inhibit the capacity of 1 ng/ml (6 X 10(-11) M) recombinant IL 1 beta to stimulate the proliferation of murine thymocytes or human fibroblasts in vitro. McAb H6 and H21 are approximately 10-fold less potent, and completely inhibit IL 1 beta activity at 10 micrograms/ml (6 X 10(-8) M) in both assays. The McAb do not have a significant effect on the biological activity of human recombinant IL 1 alpha in either assay. These McAb block the binding of recombinant [125I]IL 1 beta to IL 1 receptors on mouse 3T3 fibroblasts and have affinity constants for IL 1 beta in the range of 10(9) to 10(10) liters/mol. Competition studies suggest that two nonoverlapping epitopes on the IL 1 beta molecule are recognized by the McAb. H6 and H34 recognize one epitope, and H21 and H67 another. McAb H6 and H67 have been used together in a two-site ELISA to detect IL 1 beta. The sensitivity of the ELISA, which is 15 pg/ml (0.86 pM), approaches the limit of sensitivity of the thymocyte proliferation assay. The ELISA and thymocyte proliferation assay were used to quantitate IL 1 beta in E. coli LPS-stimulated human monocyte culture supernatants (HMCS). The level of IL 1 beta detected by ELISA in culture supernatants from eight donors ranged from 1.7 to 5.6 ng/ml, with a mean value of approximately 3 ng/ml. By comparison, the thymocyte proliferation assay gave levels of IL 1 in HMCS that were eight fold higher when quantitated by using recombinant IL 1 beta as a standard. This discrepancy with the bioassay used was reflected by the three fold higher maximum stimulation of thymocyte proliferation by HMCS as compared with recombinant IL 1 alpha or IL 1 beta, and only 45% inhibition of HMCS IL 1 activity by McAb. Thus, factors other than IL 1 beta account for the IL 1-like activity in monocyte culture supernatant as measured by the bioassay. The ILB1 McAb and ELISA allow for the first time-sensitive, accurate, and convenient quantitation of IL 1 beta levels in biological fluids or specimens.

Animals↗
PubMed1987

Recombinant human interleukin-1 inhibits the induction by dexamethasone of alkaline phosphatase activity in murine capillary endothelial cells.

A mutual antagonism exists between interleukin-1s (IL-1s) as pro-inflammatory and glucocorticoids as anti-inflammatory mediators. This report examines the effects of IL-1 on the induction by dexamethasone of alkaline phosphatase in LEII murine endothelial cells. Dexamethasone increases the specific activity of alkaline phosphatase in a time- and dose-dependent fashion (maximum 14-fold induction at 10(-6) M, IC50 = 10(-8) M), and this induction can be completely inhibited by simultaneous incubation with picomolar concentrations of recombinant human IL-1 alpha or IL-1 beta. This IL-1-mediated antagonism of dexamethasone activity is not due to a down-regulation of glucocorticoid receptors in the cell line used, because the number of receptors and their affinity for dexamethasone is unchanged in IL-1-treated cells. However, induction of alkaline phosphatase by dexamethasone in LEII cells is receptor-mediated, since it can also be inhibited by glucocorticoid-receptor antagonists.

Alkaline Phosphatase↗
PubMed1987

Adjuvant formulation for use in vaccines to elicit both cell-mediated and humoral immunity.

Adjuvant formulations which elicit both humoral and cell-mediated immunity will be required for vaccines based on peptides, viral and bacterial subunits and genetically engineered antigens. This report describes an adjuvant formulation which increases both cell-mediated and humoral immunity and is free of significant side effects encountered with other adjuvants or vehicles. The components include the threonyl analogue of muramyl dipeptide, Tween 80, Pluronic L121 and squalane. This formulation was found to be effective with several antigens, in several species, including rodents, cats and monkeys. These results suggest that the formulation will be useful for both human and veterinary vaccines.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Inhibition by interleukin-1 of the action of erythropoietin on erythroid precursors and its possible role in the pathogenesis of hypoplastic anaemias.

Highly purified and cloned preparations of interleukin-1 (IL-1) were found to antagonize the capacity of erythropoietin (Epo) to stimulate the proliferation of mouse spleen and bone marrow erythroid precursor cells (EPC) in culture. Cloned murine IL-1 and purified and cloned human IL-1 alpha and IL-1 beta were approximately equipotent in this assay. IL-1 inhibited the proliferation response of EPC even when added as long as 17 h after Epo, suggesting that IL-1 does not affect binding of Epo to receptors or biochemical events following shortly thereafter. Indomethacin did not influence the inhibitory effect of IL-1 on Epo-induced proliferation, and PGE2 had no demonstrable effect on the process. Tumor-necrosis factor-alpha and interferons beta 1, and gamma did not affect Epo-induced proliferation. It is suggested that IL-1 mediated antagonism of the effects of Epo on erythroid precursors is a factor in the pathogenesis of many types of hypoplastic anaemia, including those associated with infections, rheumatoid arthritis and systemic lupus erythematosus, giant-cell arteritis, graft-versus-host disease and disorders associated with lymphocyte-mediated suppression of erythropoiesis.

Anemia↗
PubMed1986

An adjuvant formulation that selectively elicits the formation of antibodies of protective isotypes and of cell-mediated immunity.

Adjuvants are required to elicit protective immune responses with bacterial toxoids, inactivated viruses and subunit antigens produced by recombinant DNA technology. Some adjuvants, such as muramyl dipeptide (MDP) analog formulations, preferentially induce the formation of antibodies of isotypes that interact with complement and antibody-dependent effector cells, and do not elicit reaginic antibodies. Aluminum salts and mineral oil emulsions increase antibody formation but not cell-mediated immunity (CMI), whereas MDP formulations also elicit CMI. Adjuvants such as MDP and lipopolysaccharide (LPS) stimulate the production by accessory cells of IL-1 that increases the circulation of lymphocytes through draining lymph nodes and act as a growth factor for lymphocytes. Vehicles such as mineral oil emulsions, liposomes and Pluronic polymer formulations provide large surface areas on which antigens can be retained in a two-dimensional matrix, from which they can readily be transferred to antigen-presenting cells. The development of an adjuvant formulation able to elicit the formation of protective antibodies and CMI without unacceptable side effects is described.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Effects of enprostil on platelets, endothelial cells, and other cell types, and second messenger systems by which these effects are mediated.

In human blood platelets, thromboxane A2, prostaglandin E2, and its analogue enprostil activate protein kinase C and promote the second phase of aggregation, whereas prostacyclin and prostaglandin E1 activate adenylate cyclase and inhibit aggregation. In each case, a characteristic group of proteins is phosphorylated following agonist binding. These observations may be related to the inhibitory effect of enprostil on the activation of adenylate cyclase in gastric parietal cells, which follows binding of histamine to H2 receptors. Another system in which enprostil opposes the effect of histamine is the microvasculature. Histamine binds to H1 sites on endothelial cells and induces changes in their shape that allow macromolecules to pass between them into the extravascular compartment. This effect may be mediated by activation of protein kinase C. Pretreatment with enprostil antagonizes the increase in vascular permeability induced by histamine and presumably other inflammatory mediators. Preservation of the integrity of the microvasculature of the gastric mucosa against the effects of cyclo-oxygenase inhibitors, ethanol, and other damaging agents may contribute to the mucosal protective effects of enprostil and some other prostaglandins.

Adenylyl Cyclases↗
PubMed1986

Inhibition of the respiratory burst of human neutrophils by the polyamine oxidase-polyamine system.

The addition of the polyamines, spermine and spermidine, to human neutrophils caused a depression of the hexose-monophosphate (HMP) shunt activity of neutrophils stimulated with latex particles but not of unstimulated cells. The effect was dependent on the presence of bovine serum and was not observed when normal human serum was substituted for bovine serum. The polyamine oxidase (PAO) in bovine serum was probably responsible for generating the activity since normal human serum lacks PAO. A role for PAO was further supported by the finding that partially purified bovine PAO in the presence of polyamines similarly mediated inhibition of HMP shunt activity in stimulated neutrophils. Catalase failed to prevent the inhibitory effects of the PAO-polyamine system suggesting that H2O2 is not the responsible product. In addition, our results show that human pregnancy serum known to contain PAO activity in the presence of polyamines mediated a similar inhibition of the respiratory burst.

Animals↗
PubMed1986

Increased myelopoiesis during Leishmania major infection in mice: generation of 'safe targets', a possible way to evade the effector immune mechanism.

BALB/c mice are highly susceptible to Leishmania major infection and develop a disseminated lethal disease. Previous experiments indicate that during infection the spleen is heavily populated with large mononuclear cells containing amastigotes. Morphologically these cells resemble undifferentiated monocytes and granulocytes. In this study we examined myelopoiesis in BALB/c and C57BL/6 (resistant) mice during infection with L. major. The number of macrophage-granulocyte precursors in the spleen of infected BALB/c mice, determined by colony forming units in soft-agar cultures (cfu-c), increased steadily to a level of about 60 times that of normal sex- and age-matched controls. In C57BL/6 mice, spleen cfu-c peaked at about 1 month post-infection (four times that of normal controls) and declined thereafter to about two times normal levels. The number of cfu-c in the bone marrow did not change significantly in either strain during the infection. Colony stimulating activity (CSA) was found in supernates of cultures of adherent cells from the spleen of infected BALB/c mice. Under the same conditions, CSA was non-detectable in supernates of nonadherent spleen cells of infected mice, and those of adherent or nonadherent spleen cells of control animals. A possible role of undifferentiated macrophage-granulocytes in the exquisite susceptibility of BALB/c mice to L. major infection is discussed.

Animals↗