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Biomedical subjects

N K Day

Publications and source records attributed to N K Day.

At least 73 records · Page 4Linked to original sources
PubMed1991

Immune suppression induced by protoscoleces of Echinococcus multilocularis in mice. Evidence for the presence of CD8dull suppressor cells in spleens of mice intraperitoneally infected with E. multilocularis.

Immunoregulatory states induced by i.p. inoculation with the metazoan parasite Echinococcus multilocularis in the murine system were investigated. Proliferative responses and IL-2 production induced by Con A in spleen cells from BALB/c mice were significantly depressed at an early stage after infection with E. multilocularis protoscoleces (PSC). Addition of plastic-adherent cells from normal syngeneic mice to the nonadherent spleen cells from infected mice did not restore the depressed Con A responsiveness. On the other hand, exogenous IL-2 reconstituted completely the proliferative responses to Con A. Flow cytometry analysis revealed that CD4- CD8+ cells with a low density of CD8 Ag (CD8dull cells) increased in spleens from infected mice 2 weeks after inoculation. Addition of the spleen cell subpopulation containing the CD8dull cells, but not that depleted of the CD8dull cells, to normal spleen cells resulted in marked suppression of the Con A responses. These findings suggest that the CD8dull cells detected in spleens of mice inoculated with E. multilocularis PSC may play a key role in the suppressive regulation of immune responses. The relevance of the immune suppression seen in the early stages of experimental infection with E. multilocularis PSC to the eventual establishment of a host-parasite relationship is discussed.

Animals↗
PubMed1991

Two populations of guinea pig erythrocyte-rosetting cells in the cat: evidence for their T-helper function in mitogen-induced synthesis of Ig and interleukin-2.

Studies in our laboratory have shown that T-helper (T-H) and T-suppressor (T-S) cells in cat peripheral blood leukocytes (PBL) rosette with guinea pig (GP) and gerbil (G) erythrocytes (E), respectively. Removal of GE-rosetting cells leads to an enhanced (two- to threefold) synthesis of Ig in a pokeweed mitogen (PWM)-driven system as measured by plaque-forming cells (PFC) to protein A-coated sheep RBC, while depletion of GPE-rosetting cells yields a PFC response only 10-15% of the control. Surprisingly, removal of both GE- and GPE-rosetting cells gave a response equivalent to 40-100% of the control PBL. Analysis of the mixed GE/GPE rosette depleted cultures revealed the reappearance of GPE- but not GE-rosetting cells, reaching maximum values within 12-18 hr after in vitro culture. Cultures of control PBL and those following the mixed rosette depletion showed two populations of GPE-rosetting cells; the GPE-1 cells, present on Day 0 before culture, and the GPE-2 cells, those appearing on Day 1. Addition of cycloheximide prevented development of the GPE receptor while colchicine and mitomycin C were without effect. The development of PFC after the mixed GE/GPE rosette depletion was interpreted as being due to the GPE-2 cells functioning as T-H cells in the absence of any T-S (GE-rosetting) cells. This thesis was supported by showing a marked decrease in the PWM-induced Ig response when both the GPE-1 and GPE-2 populations were removed on Day 1. Additional evidence for functional T-H cells in the GPE-rosetting population was obtained by analyzing interleukin-2 (IL-2) production. Removal of the GPE-rosetting cells (GPE-1 and/or GPE-2) from PBL led to a marked decrease in Con A-induced IL-2 synthesis while removal of the GE-rosetting cells yielded a normal or slightly greater than normal response.

Animals↗
PubMed1991

The interaction of cryoimmunoglobulins with a model surface.

Cryoimmunoglobulins are associated with numerous clinical problems ranging from collagen vascular disorders (rheumatoid arthritis and systemic lupus erythematosus) to infectious processes including HIV infection. The precise role of cryoglobulins in the pathophysiology of these disorders remains unresolved. Although cold insolubility may account for some of the observed processes, it cannot explain the entire array of findings in cryoglobulinemia. An alternative hypothesis suggests that the subtle differences responsible for cold precipitation of these proteins renders them intrinsically more sticky, resulting in deposition of cryoimmunoglobulins on vascular surfaces. We have explored this hypothesis by characterizing the binding of monoclonal cold soluble and cryoimmunoglobulins to silica beads as a model biological surface. It is found that monoclonal, type I, IgM and IgG cryoglobulins have only a slight tendency to bind to a greater extent to this surface than cold soluble immunoglobulins. Physical studies utilizing front surface fluorescence measurements and differential scanning calorimetry show surface interaction leads to partial thermal destabilization of the proteins. To a limited extent, this destabilization is more pronounced with the cryoglobulins compared to cold-soluble control homologues. Surface bound IgM cryoimmunoglobulin was also found to fix complement less efficiently than their cold soluble surface bound counterparts. These studies do not strongly support the hypothesis that pathological mechanisms of cryoimmunoglobulins primarily involve abnormal surface interactions, although surface effects could play a limited role in some situations.

Calorimetry, Differential Scanning↗
PubMed1991

Specific association of retroviral envelope protein, p15E, with human cell surfaces.

Experiments were carried out to analyze the binding sites on human cells for highly purified retroviral protein p15E isolated from Feline Leukemia Virus, Rickard Strain. Binding of 125I-labeled p15E was tested with surfaces of human peripheral blood lymphocytes and 3 cell lines, Raji, MOLT-4, and U-937. 125I-labeled p15E showed specific binding to human peripheral blood lymphocytes. In addition, all of the cell lines tested showed binding of 125I-labeled p15E. Using U-937 cells, we characterized the interaction between p15E and the surface of these cells, and showed that the binding was specific by the following 3 different sets of evidence: (i) in equilibrium binding experiments, 18,000 binding sites with a dissociation constant of 2 x 10(-9) M were present on U-937 cells; (ii) trypsin or N-glycanase treatment decreased the binding sites of 125I-labeled p15E; and (iii) by affinity chromatography using p15E or BSA Sepharose columns, the isolated membranes of 125I-labeled U-937 cells previously treated with Triton X-100 showed a significantly higher binding to the p15E column than to the BSA column.

Amidohydrolases↗
PubMed1991

In vitro immunomodulation and in vivo immunotherapy of retrovirus-induced immunosuppression.

Early studies with the Gross passage A leukemia virus demonstrated that retroviral infection suppresses cellular and humoral immune responses. In extensive studies of the feline leukemia (FeLV) virus, which can induce profound immunodeficiency disease, are generative anemia and lymphoid, myeloid and erythroid neoplasia, the immunosuppressive effects of this retrovirus could be attributed to the actions of the retroviral envelope protein p15E. We found that a highly conserved, synthetic 17 amino acid peptide synthesized by Cianciolo and co-workers that is homologous to the hydrophilic portion of the otherwise hydrophobic transmembrane envelope protein can suppress polyclonal activation of B-cells, impair production of gamma- and alpha-interferon, inhibit production of interleukin-2, inhibit expression of IL-2 receptors, and suppress responses of cytotoxic lymphocytes. In analyses with inactivated preparations of the human immunodeficiency virus, with Pahwa et al. we demonstrated that purified non-infectious retrovirus and also retroviral proteins, in particular gp120, appeared to produce some of the immunosuppressive properties of HIV, particularly suppression of B-cell activation in response to known B-cell stimulants irrespective of T-cell influence, suppression of T-helper cell functions essential to B-lymphocyte responsiveness, and impaired function of immunoglobulin-secreting cells. Other investigators have also reported strong immunosuppressive or immunostimulatory influences for components of the HIV retrovirus and also gp120 through yet poorly elucidated but certainly complex actions on both T- and B-lymphocyte-mediated immune functions.

Animals↗
PubMed1991

Detection of human factor B biosynthesis in culture supernatants and cell lysates by ELISA.

We report here on the development of a simple, sensitive, convenient, and quantitative enzyme-linked immunosorbent assay for human factor B, a protein of the alternative complement pathway, by the sandwich method using goat anti-human factor B antibody. The assay described herein is reproducible and highly specific for human factor B. The assay was used to determine biosynthesis (cell lysates or extracts) and secretion (supernatants) of human factor B using human monocyte cell line U937. Phorbol myristate acetate strongly enhanced (10- to 20-fold) biosynthesis of factor B by U937. The combination of a sensitive enzyme-linked immunosorbent assay and phorbol myristate acetate enabled us to use a microculture system.

Antimetabolites↗
PubMed1991

Phenotypic markers for the feline monocyte: rosette formation with human erythrocytes and a monoclonal antibody which binds myeloid cells.

A small population of cells with the ability to form rosettes with human erythrocytes was found in feline peripheral blood leukocytes (PBL) (10%) and bone marrow (9%), but not in purified granulocyte preparations, thymus, and lymph node tissues. The morphologic appearance and ability to phagocytize latex beads indicated these cells were monocytes. A monoclonal antibody, CM277, with a binding specificity for feline peripheral blood phagocytes was also characterized. Immunofluorescent microscopy revealed CM277 to bind specifically to monocytes and polymorphonuclear neutrophils. The binding of CM277 to monocytes was also shown by human erythrocyte-rosette formation wherein there was a high degree of correlation between these two phenotypic markers for cells ingesting latex beads. Monocytes, polymorphonuclear neutrophils, and T lymphocytes of the cat rosette with guinea pig erythrocytes (GPE) and using CM277 we were able to determine the contribution of the former two cell types to the GPE-rosetting population. Monocytes and polymorphonuclear neutrophils comprised the majority of the GPE-rosetting cells in fresh PBL (greater than 60%), but after culturing overnight, there was a substantial decrease in these cells (less than 35%). In contrast, GPE-rosetting T lymphocytes comprised approximately 10% of the cells in fresh PBL, and after in vitro culture for 1 day they constituted 35-45% of all cells. The removal of monocytes by human erythrocyte-rosetting did not affect the pokeweed mitogen-induced synthesis of Ig, but did lead to an increased production of interleukin 2. Removal of the GPE-rosetting population from PBL resulted in a marked decrease in interleukin 2 production, pointing to a positive contribution of GPE-rosetting T lymphocytes to the synthesis of this lymphokine.

Animals↗
PubMed1991

The suppressive effect of a synthetic retroviral peptide on the human IFN gamma production is abrogated by the combined stimulation with IL-1 and IL-2.

Certain retroviral envelope proteins and peptides have been shown to be highly immunosuppressive. Recently, we have demonstrated that a synthetic 17 amino acid peptide (CKS-17*) homologous to a highly conserved region in the transmembrane portion of the envelope of several human or animal retroviruses suppresses the production of human interferon-gamma (IFN gamma) by human peripheral blood leukocytes (PBL). In the present investigation, we studied the role of exogenous IL-1 or IL-2, and IL-1 plus IL-2 on the suppressive action of CKS-17* in the production of IFN gamma. The results showed that preculture of PBL with CKS-17* reduced the production of IFN gamma in a dose-dependent manner. The addition of IL-1 or IL-2 reduced, in part, this suppression of IFN gamma production. Full abrogation of the inhibition attributable to CKS-17, however, occurred only when PBL precultured with CKS-17* were recultured with staphylococcus enterotoxin A (SEA) together with exogenous IL-1 plus IL-2. These results show that the inhibition of IFN-gamma production by CKS-17* is reversible. The findings indicate that cytokines can modulate certain of the immunosuppressive actions attributable to retroviruses or their components and suggest that some cytokines influence immunosuppressive consequences of retroviral infection.

Cells, Cultured↗
PubMed1990

Sugar competition assays reveal high affinity receptors for Erythrina cristigalli lectin on feline monocytes.

An examination of fluorescein-labelled Erythrina cristigalli lectin (FITC-ECL) staining on feline mononuclear cells (MNC) using fluorescent microscopy and a novel sugar titration competition assay revealed that monocytes (MO) were stained brighter by FITC-ECL than were lymphocytes (LYM). When MNC were stained with FITC-ECL in the presence of 400 mM or greater D-galactose, analysis by flow cytometry revealed continued MO staining while LYM were negative. MO expressed a larger quantity of carbohydrate receptors (CHO-R) for ECL than did LYM. The CHO-R expressed on MO were mostly protease-insensitive and uncapped by sialic acid residues. All of the CHO-R on LYM were protease-sensitive and many were capped by sialic acid residues. A combined labelling of MNC for non-specific esterase staining, latex bead ingestion and FITC-ECL staining in the presence of 400 mM D-galactose confirmed that FITC-ECL specifically stains MO in the presence of high sugar competitor concentrations.

Animals↗
PubMed1990

Inhibition of murine cytotoxic T lymphocyte activity by a synthetic retroviral peptide and abrogation of this activity by IL.

A synthetic 17 amino acid peptide (CKS-17) homologous to a highly conserved region of human and animal retroviral transmembrane proteins was investigated for its influence on the generation of murine alloantigen-specific CTL activity in vitro. CKS-17 coupled to a carrier protein, BSA or human serum albumin, inhibited the generation of anti-allo CTL in a dose-dependent manner. Controls consisting of BSA and human serum albumin, which had undergone the coupling procedure or neurotensin, an unrelated peptide, coupled to BSA in an identical manner as CKS-17 showed no such inhibitory action. The suppression was not restricted to the Ag specificity of the CTL activity. CKS-17 exerted inhibitory effects on the early afferent phase of CTL induction. Kinetic studies showed that the suppressive activity occurred when CKS-17 was introduced to the immunologically stimulating culture concomitant with or up to 48 h after initiation of culture. Analysis of the frequency of CTL precursor cells using limiting-dilution assays revealed that CKS-17 did act to reduce the number of precursor cells. Abrogation of the inhibition of CTL activity was observed when IL-2 was introduced to the culture together with the stimulator cells. Other lymphokines, such as IL-4, exerted a similar influence to counteract this suppression.

Animals↗
PubMed1990

Experimental approaches to nutrition and cancer: fats, calories, vitamins and minerals.

Chronic energy intake restriction (CEIR) inhibits lymphoproliferative disease, autoimmune-based renal disease and mammary adenocarcinoma in mice of numerous short-lived strains (MRL/lpr, C3H/Bi, C3H/Ou). Doubling and tripling of life span and health span and inhibition of development of diseases associated with aging could be attributed to restriction of calories but not to restriction of dietary fat in the absence of calorie restriction. In mice of both long- and short-lived strains, CEIR dramatically prevents the waning of immunologic vigor that commonly occurs with aging, delays thymic involution, impairs formation of circulating immune complexes, prevents the renal injury that accompanies autoimmune disease, and significantly forestalls development of genetically determined lymphoproliferative or neoplastic disease. Evidence suggests that CEIR may exert these beneficial influences in part through regulation of cellular proliferation. Trace elements, particularly zinc, as well as vitamins may play important roles in maintaining immunocompetence and also appear to be of significance in the dietary prevention of certain experimental cancers.

Animals↗
PubMed1990

Prolactin effects on the dietary regulation of mouse mammary tumor virus proviral DNA expression.

Chronic energy-intake restriction inhibits mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice by greater than 90%. We have shown that associated with suppression of mammary tumorigenesis there is a reduction or inhibition of circulating prolactin, MMTV particles expressed, and MMTV mRNA transcription in mammary glands (and in most organs tested). To understand the concerted action of prolactin, energy-consumption level, and MMTV on inducing mammary tumors, experiments were designed to control prolactin and energy levels in order to evaluate their effects on MMTV mRNA expression. Mice on restricted diets were grafted with adenohypophyses, and mice fed ad libitum were treated with the dopaminomimetic agent octahydrobenzo [g]quinoline. Adenohypophyseal grafting significantly increased prolactin in dietary (energy)-restricted mice, and this effect was associated with an increase in MMTV mRNA expression within the mammary gland; a linear correlation between prolactin levels and MMTV mRNA expression in the mammary gland was found. Conversely, elimination of the nocturnal peak of circulating prolactin by i.p. injection of dopaminomimetic octahydrobenzo [g]quinoline to mice fed ad libitum delayed (by 8 weeks) and reduced (even as long as 25 weeks) mammary gland MMTV mRNA expression. These findings associate prolactin influences with MMTV mRNA production in mice and help explain the link between chronic energy-intake restriction and reduced MMTV gene expression.

Aminoquinolines↗
PubMed1990

Suppression of mouse mammary tumor proviral DNA and protooncogene expression: association with nutritional regulation of mammary tumor development.

Chronic energy intake restriction (CEIR) reduces mouse mammary tumor virus (MMTV)-induced mammary tumors in C3H/Ou mice. Fewer than 10% of C3H/Ou mice developed mammary tumors during 88 wk of study when subjected to CEIR regardless of calorie source (fat vs. carbohydrate). By contrast, 100% of mice fed ad libitum diets relatively high in fat or carbohydrate or a commercial diet developed tumors by 35-40 wk. MMTV proviral DNA transcription was shown to be activated in spleen, liver, lung, kidney, small intestine, and mammary gland of mice consuming these diets ad libitum. By contrast, these messages were suppressed by CEIR in all tissues analyzed except spleen. MMTV proviral messages in liver and mammary gland increased with age in full-fed mice and were suppressed by CEIR. These findings suggest that the nutritional regulation of MMTV proviral DNA expression is tissue-specific. In CEIR mice the suppressed MMTV proviral DNA transcripts in mammary gland and liver increased with time in association with the delayed onset of mammary tumors. Mammary tumorigenesis in C3H mice is associated with integration of MMTV proviral DNA, which appears to activate a putative mammary tumor protooncogene, int-1. CEIR apparently decreases the frequency of viral reintegration adjacent to the int-1 gene and thus inhibits expression of int-1 and probably an initiation step in mammary tumorigenesis. Expression of other putative protooncogenes, int-2 and ras, in liver tissue was also reduced by CEIR. These findings indicate that both initiation and promotion of mammary tumorigenesis are influenced by CEIR in C3H/Ou mice.

Animals↗
PubMed1990

Calorie consumption level influences development of C3H/Ou breast adenocarcinoma with indifference to calorie source.

To analyze simultaneously the influence attributable to calorie consumption level and percentage of dietary fat on the spontaneous development of mammary adenocarcinoma, virgin female C3H/Ou mice were separated into five dietary groups. Four groups of mice were fed purified diets either ad libitum (16-18 kcal/mouse/day) or restricted 40% in calorie consumption (10-11 kcal/mouse/day), and diets contained either 4.5%, 7.5%, 67%, or 68% calories from fat. Mice that consumed isocaloric diets developed breast malignancy at a comparable pace. Consuming a diet in which fats were present only at levels sufficient to satisfy the threshold requirement of essential fatty acids, 4.5-7.5% of the total calories, or alternatively where dietary fat represented greater than 67% of the total calories consumed, did not significantly alter the tendency for breast tumor development. The pace and frequency with which tumors occurred reflected the host's level of calorie consumption. Mice consuming a high caloric diet, low or high in fat, tended to have a shortened latency to breast tumor formation, an increased incidence of breast tumors, elevated serum prolactin levels, elevated levels of antibodies to mouse mammary tumor virus, and elevated circulating immune complex levels.

Adenocarcinoma↗
PubMed1990

Dietary manipulation of mammary tumor development in adult C3H/Bi mice.

Chronic energy intake restriction (CEIR) in virgin female mice is one of the most effective ways of reducing significantly mammary adenocarcinoma in C3H/Bi mice, a strain which develops mammary adenocarcinoma associated with the murine mammary tumor virus spontaneously and at high incidence. In this study, the influence of chronic energy intake restriction imposed on fully mature (4- to 5-month-old), breeding female C3H/Bi mice was addressed, and the influence of energy intake where energy was derived largely from fat versus diets in which energy was derived largely from carbohydrates on tumor development and survival rate was investigated. The results show that chronic energy intake restriction can be delayed until full maturation and successful reproduction and still reduce significantly the incidence of mammary tumor development in this relatively short-lived strain of mice. Our findings demonstrate that the overriding dietary factor controlling mammary tumor development in these experiments in C3H/Bi mice was the level of energy intake, regardless of the primary source of energy (fat or carbohydrates).

Adenocarcinoma↗
PubMed1990

Immunosuppressive actions of retroviruses.

The immunosuppressive properties of retroviruses were first demonstrated by Old et al. We later showed that Gross Passage A retrovirus superinfection in mice resulted in decreased antibody production and diminished allograft rejection. We have studied in some detail the immunosuppression which occurs subsequent to infection with feline leukemia virus (FeLV) as characterized by profoundly depressed T and B lymphocyte responses and decreased production of gamma-interferon. Injection of staphylococcal protein A (SPA) corrected these deficient immune responses, cleared circulating FeLV from blood and produced a regression of FeLV-induced lymphomas and leukemias. The immunosuppressive properties of FeLV and certain other retroviruses have been linked to the transmembrane viral envelope peptide, p15E. Cianciolo et al synthesized a 17-amino acid viral component which shares sequence homology with a highly conserved region of p15E. In vitro analyses have shown that this synthetic retroviral peptide suppresses T and B cell functions, inhibits the generation of cytotoxic lymphocyte (CTL) responses and dramatically alters the morphology and distribution of monocytes. The latter finding, along with reports that cells of the monocyte/macrophage lineage play a critical role in the initiation of human immunodeficiency infection, suggests that monocytes and macrophages may play a crucial role in retroviral infection and some of the associated immunodeficiencies associated with retroviral infection.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Recombinant interleukin 2 therapy in severe combined immunodeficiency disease.

Severe combined immunodeficiency disease (SCID) is a congenital disorder of severe B- and T-lymphocyte dysfunction in which several pathogenic mechanisms have been identified. The present study describes a female child with SCID who had a primary defect in the ability of T cells to secrete interleukin 2 (IL-2). B- and T-cell numbers were normal, but their functions were severely deficient. Mitogen and antigen-driven lymphoproliferative responses were diminished but were correctable in vitro with recombinant IL-2 (rIL-2). The patient's phytohemagglutinin-stimulated lymphocytes expressed IL-2 receptors normally. Despite the presence of the gene for IL-2, the patient's cells were grossly deficient in messenger RNA for IL-2 and endogenous IL-2 production. Pokeweed mitogen-driven B-cell differentiation was decreased and was not corrected by the addition of normal T cells to the B cells. Two attempts at immune reconstitution by haploidentical bone marrow transplantation failed. Therapy with rIL-2 (30,000 units/kg, given daily i.v.) resulted in marked clinical improvement as well in improved T-cell functions. The child, now 3 yr old, has been on rIL-2 therapy for 2 yr and receives rIL-2 (30,000 units/kg) three times weekly at home. This case study points to a new direction in the treatment of such disorders with rIL-2.

B-Lymphocytes↗