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Biomedical subjects

E M Eugui

Publications and source records attributed to E M Eugui.

At least 55 records · Page 3Linked to original sources
PubMed1989

Insulin-like growth factor-1 increases the mitogenic response of human peripheral blood lymphocytes to phytohemagglutinin.

Receptors for insulin and insulin-like growth factor-1 (IGF-1) have been demonstrated on activated T-lymphocytes. The question is whether receptors for insulin or IGF-1 have any function in these cells. In this study we demonstrate that the concentration of IGF-1 in commercial samples of fetal calf serum is about 70 times that of insulin. Moreover, antibodies binding IGF-1 reduce responses of human peripheral blood mononuclear cells to PHA by about 50%, whereas antibodies to insulin have no demonstrable effect. These observations suggest that binding of IGF-1 to specific receptors contributes to the proliferative responses of activated T-lymphocytes.

Animals↗
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↗
PubMed1988

Dissection of the mechanisms of immune injury in rheumatoid arthritis, using total lymphoid irradiation.

Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation. After radiotherapy, there was a marked decrease in the number and function of peripheral blood helper/inducer (Leu-3+) T lymphocytes, in the spontaneous secretion of interleukin-1 by synovial biopsy specimens, and in the activity of the joint disease. In contrast, levels of IgM, IgA, and IgG rheumatoid factors and C3 concentrations in blood and synovial fluid samples did not change significantly after therapy with total lymphoid irradiation.

Arthritis, Rheumatoid↗
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↗
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↗
PubMed1983

The role of cell-mediated immune responses in resistance to malaria, with special reference to oxidant stress.

Asexual blood forms of malaria parasites are microaerophilic and sensitive to oxidant stress. Plasmodium falciparum and some other species of malaria parasites undergo schizogony attached to endothelial cells of postcapillary venules, where oxygen tensions are low. Acquired immune responses to all forms of malaria parasites so far investigated are thymus dependent. Animals deprived of T lymphocytes do not recover from the infections and cannot be immunized against malaria parasites. In contrast, animals unable to make antibodies recover normally from some primary infections, e.g. with Plasmodium chabaudi, and when rescued by chemotherapy from other species of malaria parasite develop lasting, nonsterile immunity. Immunity to malaria can be transferred in mice by T lymphocytes of the Ly1+ phenotype, but transfer of B lymphocytes together with this T-cell subset increases the effectiveness of immunity to Plasmodium yoelii. Thus, antibodies facilitate recovery from some primary malaria infections and increase the effectiveness of cell-mediated immune responses in these infections. Mice of the A strain are highly susceptible to malaria and are unable to increase the number of mononuclear cells in the spleen during the course of the infections. It is postulated that T lymphocytes responding to parasite antigens release factors that stimulate the proliferation of effector cell precursors and their recruitment into the red pulp of the spleen. In this site, the liver and probably the peripheral circulation, effector cells bind to the surface of parasitized erythrocytes and are activated to release superoxide (O2-). The consequent exposure to oxidant stress can lead to degeneration of parasites in erythrocytes. This effect on the parasites can be prevented by agents chelating metals, which suggests that iron-catalyzed lipid peroxidation and consequent K+ loss, or inactivation of metal-containing enzymes, may be the mechanism by which oxidant stress kills the intracellular parasites. Antibodies on the surface of schizont-infected cells could facilitate binding of effector cells and trigger O2- release, thereby acting synergistically with cell-mediated immunity. Inherited traits, such as abnormal hemoglobins and G-6-PD deficiency, and acquired cell-mediated immunity both subject malaria parasites to oxidant stress and may reinforce one another, increasing the chances of survival of children bearing these traits during the dangerous years of first exposure to malaria in areas where the disease is endemic.

Animals↗
PubMed1982

A radical interpretation of immunity to malaria parasites.

Asexual forms of malaria parasites in erythrocytes are sensitive to oxidant stress. Immunity to these parasites is thymus-dependent and may be mediated by the blinding of effector cells (macrophages or natural killer cells) to the surface of parasitised cells, with concomitant production of the superoxide anion (O2-). This can lead to degeneration of parasites in erythrocytes. Antibodies can facilitate the binding of effector cells to parasitised erythrocytes, reinforcing the effects of cell-mediated immunity. Plasmodium falciparum is more sensitive to oxidant stress in human erythrocytes with abnormal haemoglobins and glucose-6-phosphate-dehydrogenase deficiency than in normal erythrocytes. Thus cell-mediated immune responses, by producing oxidant stress, could act synergistically with these inherited traits to increase the chances of survival of children during the dangerous years of first exposure to malaria.

Antibody Formation↗
PubMed1981

Cell-mediated immune responses to Theileria parva (East Coast fever) during immunization and lethal infections in cattle.

Leucocytes from cattle with lethal or sub-lethal infections with Theileria parva were examined for responses in autologous mixed lymphocyte reactions (MLR) and for specific and non-specific cytotoxicity against cultured cell lines. During lethal infections, lymphoblasts isolated from central lymph from days 8 to 14 stimulated proliferation in autologous lymphatic lymphocytes and peripheral blood leucocytes (PBL), although cytotoxicity was not generated in such cultures. After day 14, non-specific cytotoxicity was exhibited by both lymphocyte populations and was maximal in moribund calves. Non-specific lytic activity was also noted in PBL from recovering calves, but disappeared after the elimination of the parasite. Calves immunized against T. parva by the concurrent administration stabilate and long-acting tetracycline showed macroschizont forms of the parasite in host lymphocytes from days 15 to 18 after infection. During this period, lymph node cells from infected calves stimulated MLR-type responses in autologous PBL. However, PBL from immunized calves lysed directly, autologous infected lymphoblasts in a genetically-restricted fashion from days 14 to 21, although additional cytotoxicity was not generated in the MLR. The results imply that when the parasitosis of T. parva is curtailed, specific cell-mediated responses are mounted against parasite-induced antigens in combination with polymorphic host antigens on the leucocyte membrane. These reactions are probably the major immune responses conferring to recovered cattle, immunity against rechallenge with the homologous isolate of T. parva.

Animals↗
PubMed1981

Theileriosis: cell-mediated and humoral immunity.

The protozoan parasite of cattle Theileria parva transforms lymphoid cells into permanently proliferating cell lines. Antibodies reacting with parasite antigens can be detected by several methods, but there is no evidence that they are protective. Two cellular responses to infection have been found. In immune animals powerful cytotoxicity restricted to syngeneic infected cells rapidly appears; this is thought to be mediated by T-lymphocytes and to play a major role in resistance to reinfection. In primary infections cytotoxicity against allogeneic infected and xenogeneic cells is observed late. This is thought to be due to activation of a nonspecific cytotoxic system, which contributes to the lymphocytolysis and panleukopenia, a prominent feature of the disease. If mounted early enough, the nonspecific effector mechanism could also contribute to recovery from a primary infection, when it occurs.

Animals↗
PubMed1980

Differences in susceptibility of various mouse strains to haemoprotozoan infections: possible correlation with natural killer activity.

Striking differences in the susceptibility to P. chabaudi and B. microti infections among different strains of mice are described. In most of the strains, both parasites induce a moderate, transient parasitaemia, followed by recovery. However, in the A strain P. chabaudi is rapidly lethal and B. microti induces a parasitaemia which persists for life in most animals. In contrast B10.A mice, which have the same H-2q haplotype as the A strain, recover from both infections. In first crosses (A X B10.A)F1 mice are uniformly resistant. Among other correlates, NK cells activity may be relevant. This activity is known to be high in strain of mice which are resistant to both of the parasites studied, such as C57B1 and CBA mice, and low in the susceptible A strain. We have examined the spleen weight, total cell number and NK activity at different times after infection. In the resistant strains there is a rapid increase in size and cell number which is still more marked during recovery. NK activity increases greatly during the infection; this is especially remarkable considering the dilution of nucleated cells with erythrocytes precursors. In contrast, in A mice cell numbers of NK activity remain almost unchanged. Thus, marked activation of NK cells occur, in resistant strains but not in susceptible ones. Possible mechanisms of activation of these cells and their effect in haemoprotozoan infections are discussed.

Animals↗
PubMed1979

Separation of erythrocytes infected with murine malaria parasites in metrizamide gradients.

Density gradients with metrizamide, a tri-iodinated benzamido derivative of glucose, have been used to separate erythrocytes infected with 3 species of murine plasmodia. Good separations were obtained of uninfected erythrocytes from erythrocytes containing parasites in different developmental stages. With metrizamide solutions, the densities required for isopyenic separation can be obtained without hypertonicity or high viscosity, and the viability and those aspects of the metabolism of parasites and erythrocytes that we measured are not detectably modified by exposure to these solutions. This type of separation has many possible applications to biochemical and immunological investigations.

Animals↗
PubMed1979

Metrizamide density gradients for separation of different developmental stages of malarial parasites.

Density gradients with metrizamide, a tri-iodinated benzamido derivative of glucose, have been used to separate erythrocytes infected with three species of murine plasmodia. Uninfected erythrocytes separated well from erythrocytes containing parasites in different developmental stages. With metrizamide solutions, the densities required for isopyknic separation can be obtained without hypertonicity or high viscosity, and the viability and metabolism of parasites and erythrocytes are not detectably modified by exposure to these solutions. This type of separation has many possible applications to biochemical and immunological investigations.

Animals↗
PubMed1979

Malaria infections in different strains of mice and their correlation with natural killer activity.

Different mouse strains show marked variation in susceptibility to murine malaria parasites. Of those studied, strain A mice showed the highest susceptibility, most animals dying from Plasmodium chabaudi infections. In contrast, C57Bl and CBA mice all recovered from P. chabaudi infections and were then resistant to challenge with a virulent strain of P. yoelii. BALB/c mice recovered from P. chabaudi infections but were not uniformly resistant to P. yoelii challenge. B10.A mice, which share haplotypes (H-2(a)) with strain A mice, were resistant to P. chabaudi infections. Of all the correlates of resistance, one appears to be of special interest: natural killer (NK) activity. This was high in C57Bl mice and in malaria-infected mice considerable increases in spleen cell numbers and in NK activity were observed. In contrast, strain A mice showed low NK activity and in malaria-infected animals spleen cell numbers and NK activity showed little or no increase. It is suggested that NK cells, recruited and activated by T lymphocyte-mediated immune responses to parasite antigens, recruit and activate NK cells and macrophages, and that a product of the reacting cells may produce death of parasites within circulating erythrocytes.

Animals↗
PubMed1975

Passive transfer of unresponsiveness by lymph node cells. Studies on adjuvant disease.

Pretreatment of rats with subarthritogenic doses of mycobacterial adjuvant suppresses the arthritogenic reaction induced by this adjuvant. This unresponsiveness can betransferred to normal syngeneic recipients by viable lymph node cells from unresponsivedonors. Serum from the same donors did not prevent the arthritis. Abrogation ofunresponsiveness was obtained by injecting normal lymph node cells together with the challeging inoculation and also with sensitized lymphoid cells. In agreement with the concept of tolerance as an active immune reaction, the data suggest that in this experimental model lymphoid cells actively suppress the immune response induced by microbacterial adjuvant. Thus, arthritis or unresponsiveness may result from the predominance of either sensitized or suppressor cells.

Animals↗