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Biomedical subjects

D A Rowley

Publications and source records attributed to D A Rowley.

At least 55 records · Page 3Linked to original sources
PubMed1983

Formation of hydroxyl radicals from hydrogen peroxide and iron salts by superoxide- and ascorbate-dependent mechanisms: relevance to the pathology of rheumatoid disease.

1. Superoxide and hydrogen peroxide are formed by activated phagocytes and react together in the presence of iron salts to form the hydroxyl radical, which attacks hyaluronic acid. Ascorbic acid also interacts with hydrogen peroxide and iron salts to form hydroxyl radical in a reaction independent of superoxide. Since iron salts, ascorbate and activated phagocytes are present in the rheumatoid joint, experiments were designed to see whether ascorbate-dependent or superoxide-dependent formation of hydroxyl radicals would be more important in vivo. 2. In the present study, addition of ascorbate to a superoxide-generating system at concentrations of 100 mumol/l provoked a superoxide-independent formation of hydroxyl radicals for a short period. Lower concentrations of ascorbate did not do this. It is therefore suggested that the superoxide-dependent reaction is probably more important. 3. It is further suggested that destruction of ascorbate by oxygen radicals formed by activated phagocytes accounts for the previously reported low concentrations of this compound in the serum and synovial fluid of rheumatoid patients.

Arthritis, Rheumatoid↗
PubMed1982

Superoxide-dependent formation of hydroxyl radicals and lipid peroxidation in the presence of iron salts. Detection of 'catalytic' iron and anti-oxidant activity in extracellular fluids.

Synovial fluid from rheumatoid patients and normal cerebrospinal fluid contains micromolar concentrations of non-protein-bound iron salts that can promote lipid peroxidation and also the superoxide-dependent formation of hydroxyl radicals from hydrogen peroxide. These iron catalysts of oxygen radical reactions cannot be detected by conventional assays unless interfering high-molecular-weight substances, probably proteins, are removed by ultrafiltration or inactivated by exposure to low pH values. The bleomycin assay for ;catalytic' iron [Gutteridge, Rowley & Halliwell (1981) Biochem. J.199, 263-265] does not suffer from these artifacts.

Animals↗
PubMed1981

Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. Detection of 'free' iron in biological systems by using bleomycin-dependent degradation of DNA.

Bleomycin in the presence of iron(II) degrades DNA to form a thiobarbituric acid-reactive product. This has been made the basis of a specific assay method for 'free' iron in biological fluids. Human synovial fluid, human cerebrospinal fluid and rat pleural-exudate fluid were found to contain micromolar concentrations of 'free' iron, which would be sufficient to allow formation of the hydroxyl radical from superoxide and hydrogen peroxide generated in vivo. This assay method does not detect iron bound to transport proteins or to enzymes.

Bleomycin↗
PubMed1981

Regulation by complementary idiotypes. Ig protects the clone producing it.

A/He mice actively producing complementary or anti-idiotypic antibody directed against a combining site structure for phosphorylcholine (PC) have profound and long-lasting suppression of their response to PC. B cells from unresponsive mice are unresponsive in vitro, and attempts to demonstrate suppressor cells in unresponsive mice were unsuccessful. Although the process ultimately responsible for suppression has not been defined, suppression can be initiated by anti-idiotypic antibody alone and prevented by complementary Ig; i.e., by anti-PC antibody. Furthermore, a suppressed anti-PC response can be rescued by sublethal irradiation and anti-PC antibody given passively. The recovery of the suppressed response is slow and presumably results from maturation from "stem" cells, which are protected from tolerization by the passively given antibody. Thus, by extrapolation, one of the functions of secreted Ig may be to protect the clone that produces it.

Animals↗
PubMed1980

An immunologic network.

The immune system is a complex network of molecules and cells specifically connected by the complementarity of receptors for antigen and receptors for receptors. The network includes multiple positive- and negative-feedback loops, which modulate the type, magnitude, and duration of responses. The great challenge is to devise ways to manipulate the system specifically to induce effective autoimmunity to cancer, to prevent allograft rejection, and to turn off undesirable responses in allergies and autoimmune diseases. Recognition of the immune system as a network helps to explain why these objectives are so difficult and why manipulation of multiple components to achieve desired regulation may be required. But presumably manipulation must be focused on connectivity between receptor for epitope and receptor for receptor to achieve a high degree of specific regulation.

Animals↗
PubMed1980

Suppression of tumor rejection by autologous anti-idiotypic immunity.

Autologous anti-idiotypic responses to tumorspecific lymphocytes altered the capability of mice to reject syngeneic tumors. This was shown by using two non-crossreacting fibrosarcoma lines, 1591 and 1316, induced by ultraviolet light. Cells from these tumor lines are regularly rejected when transplanted into normal syngeneic C3H mice but grow progressively in animals immunosuppressed by irradiation with ultraviolet light or by x-irradiation and thymectomy. Immunization of normal mice with 1591-specific lymphoblasts that had been generated in mixed lymphocyte-tumor cell cultures caused a loss of resistance to 1591 tumor cells, but the animals remained resistant to 1316 tumor cells. In vitro, spleen cells from animals immunized with 1591-specific lymphoblasts did not generate cytolytic T cells to 1591 fibrosarcoma cells, but spleen cells from the same animals responded normally to 1316 fibrosarcoma cells. Furthermore, spleen cells from animals immunized with 1591-specific lymphoblasts contained idiotype-specific T cells that lysed 1591-specific lymphoblasts, whereas 1316-specific lymphoblasts were unaffected. Immunization of normal animals with nonresponding lymphocytes from the same mixed lymphocyte-tumor cell cultures as the 1591-specific lymphoblasts showed normal responses to both tumors in vivo and in vitro. These results suggest that changes in the balance of tumor-specific and anti-idiotypic T lymphocyte clones can influence the capability of an individual to respond effectively to tumor antigens and can determine whether a tumor grows or regresses.

Animals↗
PubMed1979

Mechanism of action of nitroimidazole antimicrobial and antitumour radiosensitizing drugs. Effects of reduced misonidazole on DNA.

Electrolytic reduction of the hypoxic tumour cell radiosensitizing drug misonidazole was carried out at a controlled potential under anaerobic conditions in the presence of Escherichia coli DNA. During the reduction process the DNA was examined by viscometry, thermal hyperchromicity, melting and renaturation profiles, hydroxyapatite chromatography, agarose gel electrophoresis and alkaline sucrose density gradient centrifugation. The reduced drug decreases the viscosity, hyperchromicity and renaturation of DNA. These effects are consistent with strand breakage of the molecule which was corroborated by finding an increase in the single-strand content of DNA, increased migration and loss of fluorescence intensity on agarose gels and sedimentation to a less dense region in alkaline sucrose density gradients. The results are discussed in relation to postulated mechanisms of the selective toxicity of the drug towards anaerobes and cytotoxicity of electron affinic radiosensitizers of hypoxic tumour cells.

Antibiotics, Antineoplastic↗
PubMed1978

Simultaneous complementary idiotypic responses: absence of reciprocal regulation.

Complementary antibodies, i.e. antibodies having combining site structures which are at least partially directed against each other, were induced in A/He mice by immunization with phosphorylcholine (Pc) coupled to keyhole limpet hemocyanin or with the Pc-binding IgA myeloma protein, HOPC-8 (H8). Both responses were monitored by enumerating plaque-forming cells and assaying serum antibody levels to Pc and H8. Prior immunization with H8 markedly suppressed subsequent immunization with Pc and vice versa; neither plaque-forming cell response was diminished, however, when mice were immunized simultaneously with Pc and H8. Experiments were designed to determine if the absence of reciprocal regulation was due to change in idiotypes. This was determined by measuring inhibition of plaque formation using complementary antibody. Plaque formation by cells was equally inhibited by high dilutions of the appropriate complementary antibody whether cells were from mice immunized with one, the other, or both antigens. Thus, the absence of regulation could not be accounted for by emergence of different idiotypes. Interestingly, sera from mice immunized to have high responses to both antigens were relatively ineffective in inhibiting plaque formation or suppressing immunization to Pc. However, such sera contained complexes of the complementary antibodies; apparently antibody to Pc in such sera quenches or neutralizes the activity of anti-H8 antibody. But the formation of complexes, at least measurable levels of circulating complexes, must be a result rather than the cause for the absence of reciprocal regulation, since regulation was also absent when immunization to Pc was manipulated so that responses were too low to result in detectable levels of circulating antibody to Pc. It is proposed that simultaneous complementary responses may occur in nature to other antigens and antibodies, and that such simultaneous responses may cause pathologic changes.

Animals↗
PubMed1978

Time-dependent resistance or susceptibility of tumor cells to cytotoxic antibody after exposure to a chemotherapeutic agent.

We report that a chemotherapeutic agent (melphalan) can affect the sensitivity of tumor cells to cytotoxic antibody. Depending on the time interval between drug treatment and subsequent exposure to antibody and complement, the tumor cells can be either more resistant or more susceptible to antibody when compared to control cells. The number of tumor cells surviving the combined treatment was determined by a colony inhibition assay. The two antisera used in this study were directed against either virus-specific or myeloma protein-specific antigens on the surface of S107 murine myeloma cells; identical results were obtained with both sera. Twenty-four hours after exposure to the drug, the number of tumor cells surviving the antibody treatment increased. During this period of increased resistance, the tumor cells were temporarily arrested in the G(2) phase of the cell cycle. After this period of maximal resistance, the effect of cytotoxic antibody on the cells changed such that 4 days after melphalan treatment the cells were significantly more susceptible to the antibody than were the sham-treated control cells. The period of increased susceptibility correlated with an increased density of S107 myeloma protein and viral antigens on the surface of the tumor cells. Eight days after the drug treatment, the susceptibility of the tumor cells and the density of surface antigens both returned to normal levels. This study shows that the correct time interval between exposure to a drug and subsequent treatment with antibody is critical for maximal killing of the tumor cells. The basis for the differential sensitivity of the tumor cells to anti-body may be related to the drug-induced changes in the cell cycle and in antigen expression on the cell surface.

Antibodies, Viral↗
PubMed1977

Complementary idiotypy in the regulation of the immune response.

A new concept is presented for the interactions of two complementary antibodies in the immune response. These antibodies bind to each other by means of their variable sequence determinants and therefore are designated as complementary idiotypes. Under certain conditions, both complementary idiotypes are produced by the same animal at the same time. An idiotype can drastically affect the expression of the complementary idiotype in the animal, inducing a peripheral quench effect of antibody-binding activity and a central effect on the immunocompetent cell, which produces the complementary idiotype. It is proposed that complementary idiotypes might be induced during every immune response, thus playing an essential role in the regulation of the immune response.

Animals↗