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Biomedical subjects

G J Stanton

Publications and source records attributed to G J Stanton.

At least 19 recordsLinked to original sources
PubMed1996

Enhanced in vivo sensitivity of in vitro interferon-treated B16 melanoma cells to CD8 cells and activated macrophages.

Mouse B16 melanoma cells maintained in vitro in the presence of interferon (IFN)-alpha become resistant to the in vitro antiproliferative effects of IFN-alpha. However, IFN-alpha-treated mice inoculated with these in vitro IFN-treated cells (B16 alpha res cells) have significantly increased life spans (ILS) and significantly higher cure rates than IFN-alpha-treated mice inoculated with B16 cells. This unexpectedly greater sensitivity of B16 alpha res cells to the in vivo antitumor effects of IFN-alpha was evaluated by in vivo cell depletion experiments. Depletion of either activated peritoneal macrophages or cytotoxic T lymphocytes (CTL) reduced the ILS of IFN-treated B16 alpha res-inoculated mice to a level comparable to that of IFN-treated B16-inoculated mice. Depletion of natural killer (NK) cells did not affect the ILS for IFN-treated B16 alpha res-inoculated mice. These studies indicate that activated macrophage and CD8 cell function, but not NK cell function, is important for the enhanced antitumor effects induced by IFN-alpha against B16 alpha res cells. Macrophage killing was unlikely to be mediated by TNF-alpha or IL-1 as B16 and B16 alpha res cells were equally sensitive to TNF-alpha and insensitive to IL-1 in vitro. Further, H-2K antigen expression is significantly more readily inducible on B16 alpha res cells than on B16 cells, consistent with enhanced CD8-mediated killing due to increased MHC class I antigen expression.

Analysis of Variance↗
PubMed1995

Production of interferon gamma messenger RNA by cells of non-immune origin.

There is general agreement that IFN-gamma is produced only by cells of immune origin (T-cells, NK cells, and recently macrophages). However, indirect evidence has suggested that undetectable, low levels of IFN-gamma produced by cells of non-immune lineage, such as the murine line L-929, enhanced the antiviral activity of IFNs-alpha and/or beta following induction by agents such as the double stranded RNA poly ICLC. Since L-929 cells were one of the prototypic cell lines for studying murine IFN induction and action, we felt that it would be important to validate this observation by detection of the mRNA for IFN-gamma. If confirmed, it might indicate a role for IFN-gamma in non-immune cells. The present investigations revealed that mouse L-929 fibroblasts produce IFN-gamma message following exposure to conventional IFN-alpha/beta inducers such as poly ICLC or Newcastle disease virus. In addition, we found that IFN-gamma itself will induce its own message. We further show that this is not a phenomenon isolated to transformed cells since we found that normal mouse embryo fibroblasts also produced the message, however in a constitutive fashion.

Animals↗
PubMed1995

Modulation of immune responses by anabolic androgenic steroids.

Anabolic androgenic steroids (AS) have recently been placed on the Food and Drug Administration's (FDA's) list of controlled substances, because of the adverse effects seen in athletes taking accelerated dosages in attempts to enhance performance. Reported deleterious effects on abusers include sterility, gynecomastia in males, acne, balding, psychological changes, and increased risks of heart disease and liver neoplasia. Considering the roles of the immune and neuroendocrine systems and their interactions in many of these pathologies, it is important to determine the effects of these derivitized androgens on this connection. Little is known in this respect. We therefore determined the effects of anabolic steroids on certain immune responses and their effects on the extrapituitary production of corticotropin by lymphocytes. We present evidence that (1) both 17-beta and 17-alpha esterified AS, nandrolone decanoate and oxymethenelone, respectively, significantly inhibited production of antibody to sheep red blood cells in a murine abuse model; (2) the control androgens testosterone and dehydroepian-drosterone (DHEA) or sesame seed oil vehicle had no significant effects on antibody production; (3) nandrolone decanoate and oxymethenelone directly induced the production of the inflammatory cytokines IL-1 beta and TNF-alpha from human peripheral blood lymphocytes but had no effect on IL-2 or IL-10 production; (4) control androgens had no direct cytokine inducing effect; (5) nandrolone decanoate significantly inhibited IFN production in human WISH and murine L-929 cells; and (6) nandrolone decanoate significantly inhibited the production of corticotropin in human peripheral blood lymphocytes following viral infection. These data indicate that high doses of anabolic steroids can have significant effects on immune responses and extrapituitary production of corticotropin. Furthermore, the mouse model should provide an effective means by which to study other deleterious effects of anabolic steroid abuse in humans.

Adjuvants, Immunologic↗
PubMed1994

Enhanced in vivo sensitivity to interferon with in vitro resistant B16 tumor cells in mice.

Mouse B16 melanoma cells rapidly develop resistance to the antiproliferative effects of interferon alpha (IFN alpha) and interferon beta (IFN beta) when they are exposed to the interferons in vitro. This resistance was characterized to be non-genetic and dose-dependent, and does not alter other IFN-induced effects such as antiviral effects and elevation of 2',5'-oligoadenylate synthetase activity in IFN-treated cells. The study of these IFN-resistant cells has been extended to an in vivo tumor model. Resistance, if it occurred in vivo, did not adversely affect the survival of IFN-treated mice. Further, IFN-treated mice inoculated with B16 cells that were resistant in vitro (B16 alpha res cells) survived significantly longer than IFN-treated mice inoculated with B16 cells that were sensitive in vitro. The IFN-treated B16 alpha res-inoculated mice had a significantly higher cure rate as well. The prolonged survival of the mice bearing B16 alpha res cell tumors did not seem to be caused by the slower growth rate of the B16 alpha res cells, since experiments performed with a tenfold higher B16 alpha res cell inoculum and a tenfold lower B16 cell inoculum did not show any change in the survival pattern. It is clear that in vitro resistant B16 alpha res cells are more sensitive to antitumor effects induced by IFN in vivo than in vitro sensitive B16 cells.

Animals↗
PubMed1991

The interferons. Mechanisms of action and clinical applications.

The interferons (IFN) are one of the body's natural defensive responses to such foreign components as microbes, tumors, and antigens. The IFN response begins with the production of the IFN proteins (alpha, beta, and gamma), which then induce the antiviral, antimicrobial, antitumor, and immunomodulatory actions of IFN. Recent advances have led to Food and Drug Administration approval of five clinical indications for IFN. Interferon alfa is approved for hairy-cell leukemia, condyloma acuminatum, Kaposi's sarcoma in the acquired immunodeficiency syndrome, and non-A, non-B (type C) viral hepatitis. Interferon gamma has properties distinctive from those of IFNs alpha and beta and is approved as an immunomodulatory treatment for chronic granulomatous disease. Promising clinical results with IFNs have also been reported for basal cell carcinoma, chronic myelogenous leukemia, cutaneous squamous cell carcinoma, early human immunodeficiency virus infection, hepatitis B, and laryngeal papillomatosis. Future clinical uses of IFNs may emphasize combination therapy with other cytokines, chemotherapy, radiation, surgery, hyperthermia, or hormones.

Humans↗
PubMed1991

Modulation of peripheral leukocyte counts in mice by oral administration of interferons.

The ability of interferons (IFN) to exert a systemic effect following their oral administration was evaluated. One systemic effect of parenteral interferon administration has been shown to be a suppression of the number of peripheral white blood cells both in man and in mouse models. Using the mouse model of peripheral white blood cell suppression, the relative systemic effects of orally and subcutaneously administered interferons were determined. Murine IFN-beta, murine IFN-gamma and cross-reactive recombinant human IFN-alpha A/D were examined. The oral administrations of each of the three interferons were found to cause a dose-dependent suppression of the peripheral white blood cell counts. Significant levels of suppression were seen with as little as 5 units/day of murine IFN-beta and with 500 units/day of recombinant human IFN-alpha A/D and murine IFN-gamma. The dose-response curves obtained with orally administered interferons were much more shallow than those obtained with subcutaneously administered interferons. The results demonstrate that oral administration of interferons can provide a significant systemic effect. Further, the results support the possibility that the oral administration of interferons may have therapeutic potential.

Administration, Oral↗
PubMed1989

Anti-mouse IgM immunoglobulin protects weanling mice from Coxsackievirus infection.

Mice treated from birth with rabbit anti-mouse IgM antiserum (anti-mu), although immunosuppressed in regard to B cell function, may paradoxically be protected when challenged with certain viruses. Our early studies indicated that short term treatment of weanling mice protected against Semliki forest virus, herpes simplex virus, and Coxsackievirus B1. For this study, the murine model of Coxsackievirus B1 infection was chosen to determine if specific anti-mu immunoglobulin (anti-mu Ig) would protect and whether protection could be correlated with antiviral activity in certain organs. Weanling Balb/c mice were treated intraperitoneally (i.p.) with either affinity purified anti-mu Ig or purified normal rabbit (NR) Ig two consecutive days prior to i.p. challenge with Coxsackievirus B1. Mortality of anti-mu Ig treated mice was significantly lower than controls (3.4% vs 89%, P less than 0.001). Importantly, this purified anti-mu-induced protection correlated well with reduced levels of virus in blood and certain organs, especially brain. This decrease was not attributed to interferon (IFN) or virus-specific neutralizing (NT) antibody or enhanced cellular cytotoxicity. Anti-mu treatment appears to inhibit virus replication and/or enhance clearance of virus from target organs. The data indicate that a unique antiviral activity is activated by anti-mu treatment, and can be passively transferred to and protect recipient mice. The murine model of Coxsackievirus disease appears to be well suited for use in the elucidation of the mechanism of this protection.

Animals↗
PubMed1989

Protection of mice from Semliki Forest virus infection by lymphocytes treated with low levels of interferon.

These studies provide the first evidence that adoptive transfer of syngeneic mouse (BALB/c) lymphocytes treated with low levels of mouse interferon (IFN)-alpha/beta can result in sufficient protection to protect mice from Semliki Forest virus (SFV) infection. Specifically, intraperitoneal inoculation of noncytotoxic lymphocytes treated exogenously with IFN (3 to 50 U/ml), washed exhaustively, and mixed with antibody to IFN-alpha/beta to neutralize any residual or early produced IFN, resulted (after repeated studies) in a 35% to 40% reduction in mortality of mice challenged with SFV (P less than or equal to .01), while inoculation of control lymphocytes had no effect. Direct administration of relatively high levels of IFN-alpha/beta (2,000 U/d) only moderately reduced the mortality (by 20%) in mice. Passive transfer of IFN-treated BALB/c mouse embryo cells also did not protect. The protection could not be attributed to carryover of IFN by the lymphocytes, endogenous IFN induction, enhanced cytotoxicity of endogenous splenocytes or peritoneal leukocytes, or early appearance of antiviral neutralizing antibody. Thus, the most likely cause of the observed protection is consistent with a unique mechanism that can be activated by the IFN-treated lymphocytes.

Animals↗
PubMed1988

Immunoreactive ACTH, beta-endorphin, and cortisol levels in plasma following spinal manipulative therapy.

This study examines the possibility of a humorally mediated analgesic response to spinal manipulative therapy by determination of plasma levels of beta-endorphin, adrenocorticotropic hormone (ACTH), and cortisol before and after intervention. Forty male subjects (20 symptomatic, 20 asymptomatic) were allocated into four equal groups. Two treatment groups were given spinal manipulative therapy, and two groups underwent a sham procedure. Blood samples were taken via indwelling butterfly needles pre- and postintervention in all four groups, and levels of immunoreactive ACTH, immunoreactive beta-endorphin, and cortisol determined by radioimmunoassay. No differences in ACTH or beta-endorphin were found between sham and treated groups, or between pre- and postintervention in any group; cortisol levels fell over the course of the study in all groups. The findings thus appear to exclude a humoral role for beta-endorphin in mediating the analgesic response to spinal manipulative therapy; in addition, they suggest that such therapy is not a stressor that activates the hypothalamo-pituitary-adrenal axis.

Adolescent↗
PubMed1987

Nondetectable levels of interferon gamma is a critical host defense during the first day of herpes simplex virus infection.

Previous studies have demonstrated the importance of IFN alpha/beta in resistance to primary viral infections. However, the role of IFN gamma in primary infections is unclear. The present studies were undertaken to determine whether IFN gamma induction was an important early host defense against primary HSV infection. The approach was to block the IFN gamma response with antibodies to IFN gamma prior to infection and at various times post-infection (p.i.). The data indicates that treatment of mice with anti-IFN gamma prior to infection enhanced mortality (89% vs 37%). Anti-IFNs given at various times post HSV challenge proved most effective within the first 24 h of infection. The above results suggest for the first time that IFN gamma mediates important host defense(s) early during primary HSV infection. Similar results were obtained using antibody to IFN alpha/beta.

Animals↗
PubMed1987

Antibodies to the carboxyl terminus of mouse interferon-gamma neutralize its immunoregulatory and antiviral activities.

Antibodies to a synthetic carboxy-terminal peptide (Cys-Ser-Leu-Arg-Lys-Arg-Lys-Arg-Ser-Arg-Abu) (gamma-C-TP) of mouse interferon-gamma (MuIFN-gamma) were produced in rabbits. They neutralized the antiviral activity of MuIFN-gamma but not that of MuIFN-alpha/beta or human (Hu) IFN-alpha/beta or -gamma. They also inhibited the IFN-dependent enhancement of natural cytotoxic cells (NCC) and the in vivo plaque-forming cell (PFC) response to sheep red blood cells (SRBC). Thus, our results indicate that polyclonal antibodies specific for the nine carboxy-terminal amino acids of MuIFN-gamma can specifically inhibit the antiviral and immunoregulatory activities of this IFN in vitro. In addition, our findings indicate that endogenous production of MuIFN-gamma in vivo plays a role in development of the full antibody response to SRBC surface antigens.

Animals↗
PubMed1987

Interferon review.

Although IFN proteins were recognized first for their potent antiviral properties, it has now been established that they may profoundly affect other vital cellular functions. The IFNs are divided into three main classes, alpha, beta, and gamma, and are defined by their differences in amino acid sequences, physicochemical properties, and induction by different agents from different cell types. The inducing agents include viruses, bacteria, bacterial products, polymers, low molecular weight compounds, and antigens or mitogens. Studies on the mechanisms of action of IFNs have mainly been focused on their antiviral actions. However, many of the facts revealed by these studies are equally relevant for understanding other actions of IFN. IFNs are extremely potent, they interact with specific receptors, and they induce the expression of specific genes, the products of which mediate their various actions. There is almost a complete lack of knowledge of what happens between the interaction of IFN with its receptor and induction of new RNA synthesis. However, we are beginning to understand how some of the IFN-inducible enzymes impair viral replication. The discovery of the dsRNA-dependent enzymes has implications beyond the IFN system. It is quite possible that they are used for other physiologic regulatory systems as well. The identities and functions of many other IFN-inducible proteins remain to be elucidated. Principally, IFNs alpha and beta are cytokines in that they may be produced by the cellular components of the immune system and have immunoregulatory effects on the cells of the immune system. These effects include enhancement of surface structures such as histocompatibility antigens, pleiotropic hormone-like effects, and stimulation or inhibition of the activities of a number of different effector cells such as B cells, T cells, macrophages, and natural killing cells. IFN levels may be below detection and yet mediate important biologic functions. Perhaps the most interesting IFN subtype regarding immunoregulation is IFN gamma, which is a product of T lymphocytes. Few drugs have stimulated as much research interest or clinical promise as the IFNs. Clinical trials in patients have shown most promise in coryza, herpes virus infections, papilloma virus tumors, hairy cell leukemia, multiple myeloma, and renal cell carcinoma. IFN gamma employed alone and in combination with IFN alpha may dramatically increase IFN's activity. IFN treatment combined with chemotherapy also may give enhanced antitumor activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Histamine releasing activity (HRA) produced by leukocytes co-cultured with tumor cells.

Human stomach adenocarcinoma (AGS), astrocytoma (AST) and myelogenous leukemia (K562) cells were co-cultured with human peripheral blood leukocytes (PBL) through four days. Histamine releasing activity (HRA, lymphokines that stimulate degranulation of basophilic leukocytes with the release of histamine) and interferons alpha and gamma (IFN alpha and IFN gamma) were detected in the culture fluids. Maximal levels of HRA were detected by 24 hr in AST and K562-leukocyte co-culture fluids. Notably, only low levels of HRA was detected in AGS-leukocyte cultures. HRA was separated into two molecular weight species (60,000 and 25,000) by column chromatography. The IFN activity was shown to be a mixture of IFN alpha and IFN gamma (IFN alpha greater than IFN gamma). IFN did not cause histamine release from human PBL or affect HRA. Our results indicate that PBL from normal individuals produce HRA in response to tumor antigen and suggest that the basophilic leukocyte response to certain cancers may be related to HRA production.

Astrocytoma↗
PubMed1986

Pretreatment of human lymphocytes with interferon enhances the synthesis of interferon in cocultures with allogeneic cells.

Human lymphocytes pretreated with interferon (IFN) alpha, beta, or gamma produced 17 times more IFN alpha (600-10,000 units/ml) than nontreated lymphocytes when cocultivated with allogeneic cells. Significant increases in IFN production (500-3,000 units/ml) were observed when lymphocytes were treated with IFN for just 2 h, and peak levels (10,000 units/ml) were produced after a 4-h treatment. The amount of IFN required to show the maximum priming effect was between 100 and 1,000 units; higher levels of IFN were inhibitory. The levels of IFN increased as the lymphocyte-to-target-cell ratio increased from 2:1 to 10:1 and decreased at higher ratios. The decrease in IFN production at higher ratios of lymphocytes to target cells could not be attributed to the presence of a soluble suppressor substance. The additional IFN found in supernates was attributed to enhanced production of IFN by the same cells, rather than recruitment of more cells to produce IFN. This conclusion is based on the fact that no increase in the number of cells staining positive for IFN production was observed in primed lymphocytes. The increased amount of IFN due to priming enhanced both nonsensitized cytotoxic activity and the transfer of antiviral activity, which could be prevented by antibody to IFN. The data suggest that priming may be an important biological mechanism for obtaining significant levels of IFN more rapidly in the vicinity of transformed cells or virus-infected tissues.

Cells, Cultured↗
PubMed1986

Role of interferon in streptococcal infection in the mouse.

In previous studies, we have shown the rapid in vitro induction of IFN gamma from human T cells by highly purified peptic extracts of M proteins from Streptococcus pyogenes. The present report extends these in vitro studies and shows that a mixture of both alpha/beta and gamma IFN were present in spleen cell homogenates after in vivo treatment with M protein wild-type (M+) or mutant (M-) S. pyogenes strains. The levels of bacterial-induced IFN were found to be greater in M+ treated animals. Additional studies in vivo showed that pretreatment of mice with heat-killed M+ S. pyogenes organisms significantly protected mice to pneumococcal infection compared to similarly treated M- or control animals (P less than 0.001). Further, antibodies to mouse IFN alpha/beta and antibodies specific to a synthetic N-terminal peptide of mouse IFN gamma enhanced the death of animals due to pneumococcal infection and blocked the protection observed in animals previously treated with heat-killed M+ organisms. Most importantly, treatment of mice with either type of IFN alone enhanced the survival of mice to levels similar to that observed by treatment with M+ organisms (P less than 0.05). The results strongly suggest that IFN can play a crucial role, directly or indirectly, in controlling infection by Streptococcus pneumoniae and perhaps other streptococci.

Animals↗
PubMed1986

Conjunctivitis in rabbits caused by enterovirus type 70 (EV70).

A rabbit enterovirus 70 (EV70) model infection that closely mimics human enteroviral conjunctivitis was developed. Conjunctivitis occurred 24 hr following topical application of EV70. The conjunctivitis was characterized by tearing, redness, swelling of the eye lids, follicles in the superior palpebral conjunctiva, and dilatation of subconjunctival blood vessels. Histologic examination of conjunctival and corneal tissue taken 1 and 2 days after infection revealed numerous punctate areas devoid of squamous epithelium on the upper palpebral conjunctiva. Also, follicles without germinal centers were observed microscopically in the palpebral and tarsal conjunctiva. Fibroblast infiltration characteristic of wound healing and a sparse mononuclear infiltration was noted by the second day. Peak levels of virus [10(3) to 10(6.2) plaque forming units (PFU)/ml] were detected 1 to 2 days after infection and declined to undetectable levels after 3 to 5 days. Interestingly, antiserum to parental EV70 was less effective (8-10-fold) in neutralizing EV70 adapted to animal and tissue culture systems. This finding suggests that an antigenic variant of EV70 arose during adaptation. Fibroblast interferon (IFN beta), which is indicative of viral infection, was detected in tears from 6 of 16 rabbits and declined to undetectable levels 3 days after infection. Serum antibody to EV70 was detectable 8 to 10 days after infection. However, the level of serum antibody was highly variable. The results indicate that the clinical disease, virologic and immunologic courses were similar to that of the human infection. Results suggest that this animal model provides a system for studying the natural antigenic variation of EV70, the natural host defenses of the eye, and antiviral treatments against enteroviral conjunctivitis.

Animal Diseases↗
PubMed1985

Streptococcus pneumoniae cocultured with fibroblasts enhances both interferon production and cytotoxic activity by lymphocytes.

Cell-mediated cytotoxicity against normal human fibroblasts was dependent on treatment of the fibroblasts with Streptococcus pneumoniae. Both spontaneous and interferon (IFN)-enhanced lymphocytes killed human foreskin (HFS) or skin muscle cells cocultured with S. pneumoniae five- to eightfold more than control nontreated cells. Based on Percoll gradient centrifugation, the cytotoxic effector cell migrated like a large granular lymphocyte. The human IFN produced from mixtures of HFS cells, lymphocytes, and S. pneumoniae was observed to be both a mixture of IFN-alpha and IFN-gamma and in an amount 500 times greater than that observed with lymphocytes on HFS cells alone, and it was in an amount 12 times greater than when lymphocytes and bacteria were cultured together. A mixture of antibodies to IFN-alpha and -gamma added to cocultures of fibroblasts and bacteria blocked the killing of fibroblast targets by lymphocytes (47 versus 13%). Thus, endogenously produced IFN was essential for the effective killing of the fibroblasts. Treatment of HFS cells with IFN before bacterial treatment protected the HFS cells from lysis by lymphocytes. The observation that normal diploid cells exposed to bacteria can be killed by lymphocytes suggests that natural cytotoxic cells are active at the site of bacterial infection and conceivably play roles in defense or pathogenesis.

Bacterial Infections↗