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Biomedical subjects

I Florentin

Publications and source records attributed to I Florentin.

At least 19 recordsLinked to original sources
PubMed1992

Effects of interleukin-6 on cytochrome P450-dependent mixed-function oxidases in the rat.

Intravenous treatment of male rats with recombinant human interleukin-6 (rhIL6) at 50, 100 and 200 micrograms/kg (corresponding to 4, 8 and 16 x 10(4) U/animal, respectively) reduced the activities of hepatic microsomal cytochrome P450-dependent monoxygenases to varying degrees. Ethylmorphine-N-demethylase activity fell to 53% of control values, an effect similar to that induced by 2.5 mg/kg Escherichia coli lipopolysaccharide (LPS). Ethoxycoumarin-O-deethylase activity was also sensitive to inhibition, whereas IL6 had little effect on the activities of other P450-dependent enzymes, including ethoxyresorufin-O-deethylase. Pentoxyresorufin dealkylase activity, which is representative of the cytochrome P450 IIB 1/2 subfamily, was unaffected by IL6 whereas LPS reduced it to 33.7% of control values. Another hepatocyte-related parameter, serum concentration of alpha 1-acid glycoprotein (AGP), was increased by up to 3.5-fold over baseline by IL6 and 10-fold by LPS. Recombinant human interleukin-1 beta (rhIL1 beta) (10 micrograms/kg, corresponding to 5 x 10(4) U/rat) and recombinant human tumor necrosis factor alpha (rhTNF) (150 micrograms/kg corresponding to 24 x 10(4) U/rat) were both as potent as LPS (2.5 mg/kg) in increasing serum AGP levels and reducing hepatic microsomal monoxygenase activities. IL6 did not potentiate the effects of rhIL1 beta. Hepatic microsomal glucuronyltransferase activities were little affected by LPS and unaffected by rhIL6. Finally, rhIL6 was more potent after i.p. injection than after i.v. or s.c. injection. These results suggest that the effects of LPS, TNF and IL1 on the mixed-function oxidase system in vivo may be due partly to an induction of IL6 in vivo. The different sensitivities of the enzymes to IL6 but not to IL1 or TNF may be due to the involvement of two distinct mechanisms.

Animals↗
PubMed1992

Nitric oxide mediates the depression of lymphoproliferative responses following burn injury in rats.

Among the multiple biological activities of nitric oxide (NO) an immunoregulatory role consisting of the mediation of macrophage suppressive activity, has recently been evidenced. In the present work, we investigated whether NO was implicated in immunosuppression following burn injury. Thermal injury affecting 20-25% of the total body surface area in Wistar rats, provoked a biphasic depression of spleen cell proliferative responses to phytohemagglutinin (PHA) and concanavalin A (Con A). We show that these responses are fully restored on day 4 after burn and only by 55% on day 10 when spleen cells were stimulated in the presence of NG-monomethyl-L-arginine (NMMA), a potent inhibitor of the macrophage inducible NO synthase. Nitrite content in culture supernatant, as an indicator of NO release (in the absence of NMMA), was significantly augmented in Con A-stimulated spleen cells from burned rats as compared to normal spleen cells. These results show for the first time that NO is implicated, at least in part, in an immunosuppression state which is not linked to an infectious disease.

Animals↗
PubMed1991

Modification of inflammatory processes by phenobarbital in rats.

Enzyme-inducing drugs such as phenobarbital (PB) increase serum concentrations of an acute-phase protein, alpha 1-acid glycoprotein (AGP), in man, dogs, and rats via an unknown mechanism. We studied the effects of PB on components of an acute inflammatory reaction in rats in order to determine if PB acts only on this biological marker of inflammation or is capable of altering the clinical course of inflammatory processes. Local carrageenan injection induces a similar time-dependent plantar edema and increases serum AGP levels in Sprague-Dawley (SD) and Dark Agouti (DA) rats. Pretreatment with PB for seven days modified neither parameter in SD rats while plantar edema was aggravated and serum AGP levels were increased in DA rats. The sedative-hypnotic properties of PB were not involved, since a single administration of this drug had no action in DA rats. On the other hand, chronic PB administration reduced the severity of an autoimmune disease, type II collagen-induced arthritis, in DA rats. These data indicate that PB, a potent inducer a cytochrome P-450-dependent enzymes, modifies the course of the inflammatory process. Preliminary results with macrophage transfer experiments suggest that this response to PB could be mediated by stimulated macrophages.

Acute Disease↗
PubMed1991

When should the immune clock be reset? From circadian pharmacodynamics to temporally optimized drug delivery.

Immune defenses are organized along both 24-h and yearly time scales. Two circadian systems have been isolated in man, which can be desynchronized: (1) the circulation of T, B, or NK lymphocyte subsets in peripheral blood and (2) the density of epitope molecules (CD3, CD4, ...) at their surface, which may relate to cell reactivity to antigen exposure. The in vitro response of murine splenocytes to interleukin 2, interferon (IFN), or cyclosporin A strongly depended upon circadian time of exposure. Temporally optimized delivery of biologic response modifiers (BRM) may be guided by immunologic marker rhythms. An alternative yet complementary strategy was sought with IFN: since high doses were shown as more effective than low doses against several malignancies, this drug was given at the presumed less toxic time, so that its dose could be increased. Continuous drug delivery was circadian modulated in 8 cancer patients. Dose intensities twice to fourfold higher than those usually recommended were safely infused to ambulatory patients. Chronotherapy with BRM may represent a necessary step for optimizing the immunologic control of malignancies.

Animals↗
PubMed1991

Acute non-immunological inflammation inhibits natural killer (NK) activity in the lungs and enhances metastatic development.

A non-immunological acute inflammatory reaction, induced in rats by intrapleural injection of calcium pyrophosphate microcrystals, decreased natural killer activity of lung intracapillary leucocytes (LICL), and, to a lesser extent, of spleen cells. NK activity was significantly depressed as early as 2 h after pleurisy induction, maximally suppressed at 72 h (when the inflammation had resolved) and returned to near-normal values by day 10. This decrease in NK activity was demonstrated using YAC-I lymphoma cells and syngeneic fibrohistiocytoma (P77) cells, as targets. The inhibition of NK activity of LICL was accompanied by an impaired destruction of P77 tumour cells injected i.v. 3 days after the onset of pleurisy. This was shown by an increase in the number of radiolabelled tumour cells surviving in the lungs at 24 h and of tumour nodules developed in lung parenchyma at 3 weeks. Suppression of NK activity was not due to a decrease in the proportion of large granular lymphocytes (LGL) in the LICL population. Suppressor macrophages may be involved, at least in part, since a partial restoration of LICL cytotoxicity was obtained after depletion of plastic-adherent cells. The effect of inflammation was reproduced in normal rats by injecting inflammatory serum or PGE2, suggesting a possible role of circulating mediators.

Animals↗
PubMed1990

Local and systemic effects of an acute inflammation on eicosanoid generation capacity of polymorphonuclear cells and macrophages.

Acute non-specific inflammation was induced in rats by injection of isologous serum into the pleural cavity. Pleural and peritoneal cells were collected at various times after pleurisy induction and tested for production of leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and prostacyclin (PGI2) after in-vitro stimulation with calcium ionophore A23187. Cells obtained by lavage of pleural and peritoneal cavities of normal rats were used as controls. Increased production of LTB4, PGE2 and PGI2 by pleural cells was observed 3 days after pleurisy induction, but with a significant depression of PGI2 release at 3 h. As the relative proportions of polymorphonuclear cells (PMN) and macrophages in the inflammatory exudate varied during the development of inflammation, these cells were examined separately for LTB4 production. PMN and macrophages contributed equally to the liberation of this mediator in normal and inflamed rats. Similar qualitative and quantitative changes in LTB4 production by pleural cells were observed, irrespective of the type of irritant used (isologous serum, dextran, carrageenan, microcrystals). In contrast, intrapleural injection of saline had no significant effect. In order to determine whether local inflammation may influence mediator release by phagocytic cells at remote sites, peritoneal cells were collected 3 or 72 after pleurisy induction. The production of LTB4, PGE2 and PGI2 was increased at 72 h. Mediator production by peritoneal macrophages was observed in both normal and inflamed rats. In conclusion, acute non-specific inflammation provoked increased arachidonic acid metabolite generation by phagocytes both locally and at a distance: this occurred more than 24 h after pleurisy resolution.

6-Ketoprostaglandin F1 alpha↗
PubMed1989

Imuthiol influences on cytotoxic T cells and NK activity in +/+ and athymic nude BALB/c mice.

The effects of imuthiol (sodium ditiocarb, DTC) on the expression of cytotoxic responses (CTL) and natural killer (NK) activity were evaluated in aged and young euthymic mice, and in nu/nu BALB/c mice. Imuthiol generated CTL and concomitantly reduced NK activity in nu/nu mice, suggesting that the agent can generate T cells in athymic nude animals. Treatment for up to 4 months augmented spleen NK and CTL activities in young or aged euthymic mice, but the generation of CTL in old animals was increased by long-term treatments better than by a single injection. The capacity of imuthiol to activate specific and nonspecific cytotoxic functions in euthymic mice may contribute to enhancement of resistance in vivo against transformed cells after treatment with this agent.

Adjuvants, Immunologic↗
PubMed1986

Early changes in immune parameters induced by an acute nonantigenic inflammation in mouse: influence of imuthiol.

Calcium pyrophosphate (CaPP)-induced pleurisy, may represent one of the simplest expressions of inflammation in that the irritant is a non-diffusible, non-antigenic and non-pyrogenic agent. Spleen or lymph node T or B cell numbers and activities, as well as NK activity, were modified at distance by CaPP-pleurisy. An intense increase in blood polymorphonuclear cells was also triggered by the inflammatory process. Treatment with imuthiol (sodium diethyldithiocarbamate), an agent known to be active on the T-cell lineage, restored towards control values the inflammatory response and tended to normalize white blood cell percentages altered by the inflammatory process. The findings suggest imuthiol could be employed as a virtually nontoxic and non-steroidal anti-inflammatory agent.

Animals↗
PubMed1986

In vivo immunopharmacological properties of tuftsin (Thr-Lys-Pro-Arg) and some analogues.

Tuftsin (Thr-Lys-Pro-Arg) is part of the Fc fragment of a leukophilic IgG and is a stimulator of the phagocytic activity of macrophages and polymorphonuclear cells (PMN) when cleaved from its carrier molecule. Tuftsin was shown to stimulate in vitro all PMN and macrophage functions examined through binding to specific cell surface receptors. In the present work, we provide further evidence that synthetic tuftsin administered to mice may act as an immunomodulator and that its effects on immune functions may result from a primary action on macrophages. After i.v. injection at a dosage of 25 micrograms/mouse, tuftsin stimulated effector (phagocytosis) and regulatory (IL1 production) functions of macrophages and potentiated DTH reaction. Lymphocyte functions (proliferative response to mitogens, T cell-mediated cytotoxicity, IL2 and gamma IFN production) were depressed at times at which macrophage activities were maximally enhanced, suggesting that negative regulatory functions of these latter cells were also stimulated. Tuftsin analogues were synthetized representing substitution or derivatization of the threonyl residue. The relative potencies of these analogues in augmenting phagocytosis-induced chemiluminescence of macrophages were tuftsin greater than or equal to (Gly1)-tuftsin greater than for-tuftsin greater than (for-Met1)-tuftsin greater than (Met1)-tuftsin. Concerning potentiation of DTH reaction the order was (Gly1)-tuftsin greater than or equal to (for-Met1)tuftsin greater than tuftsin greater than (Met1)-tuftsin greater than for-tuftsin. In contrast to tuftsin, none of the analogues induced depression of spleen cell reactivity to mitogens. In addition, (for Met1)-tuftsin administration resulted in an increased production of IL2 and IFN by ConA-stimulated spleen cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1985

Modifications of host defence mechanisms by an acute non-immunological inflammatory reaction.

Mice developing an acute non-immunological inflammatory reaction were examined for modification of specific and non-specific defence mechanisms on the basis of previous observations that these animals displayed an increased resistance to bacterial and parasitic infections but an impaired resistance to neoplasia. Local acute inflammation was induced by injection into the pleural cavity of a non-antigenic, endotoxin-free irritant--calcium pyrophosphate microcrystals or low-molecular-weight dextran. Effector functions of macrophages at remote sites from the inflammatory focus were markedly stimulated. This was shown by: (a) an accelerated elimination of Listeria monocytogenes in the liver and spleen of mice with inflammation; (b) the acquisition of cytostatic activity for tumour cells by peritoneal macrophages; and (c) an enhancement of chemiluminescence emission and superoxide production in response to phagocytosis. Natural killer activity of spleen and peritoneal cells was stimulated in a biphasic manner. In contrast, cytolytic T cell differentiation upon in vitro immunization of spleen cells against allogeneic tumour cells was impaired. All these effects were observed very early (2 h) after the onset of inflammation and were still detectable at least 3 days after the inflammatory process had disappeared.

Animals↗
PubMed1979

[Stimulation of proliferation of rat spleen cells, in vitro, by a nonspecific acute inflammatory exudate. Modulation of cell response to phytohemagglutinin (PHA)].

The effect of an acute non-specific inflammatory exudate with mitogenic activity on macrophages in culture has been tested on the spontaneous and PHA-induced DNA synthesis of spleen cells in vitro. Stimulatory effect of this exudate was observed on spontaneous DNA synthesis which was detectable over a range of 1 : 4 to 1 : 4,000 concentrations. After optimal PHA stimulation, an inhibition of mitogen-induced DNA synthesis was observed when the cells were exposed to the highest concentrations (up to 1 : 128) of the exudate. Thereafter, the phenomenon could be reversed and the stimulation was maximal at a concentration of 1 : 2,000. When a sub-optimal dose of PHA was used, the simulatory effect was more pronounced and detected from 1 : 8 up to 1 : 4,000 concentrations.

Acute Disease↗
PubMed1979

In vitro effect of an acute nonspecific inflammatory exudate on tritiated-thymidine incorporation by unstimulated and PHA-stimulated spleen cells.

The effect of an acute nonspecific inflammatory exudate with mitogenic activity for macrophages in culture has been tested on the spontaneous and PHA-induced DNA synthesis by spleen cells in vitro. Stimulatory effect of this exudate was observed on the spontaneous DNA synthesis which was detectable over a range of 1:4 to 1:4096 concentrations. After optimal PHA stimulation, an inhibition of mitogen-induced DNA synthesis was observed when the cells were exposed to the highest concentrations (up to 1:128) of the exudate. Thereafter, the phenomenon could be reversed and the stimulation was maximal at the concentration of 1:2048. When a suboptimal dose of PHA was used, the stimulatory effect was more pronounced and detected from 1:8 up to 1:4096 concentrations.

Animals↗
PubMed1979

Comparative study of the histologic reactions to intravenous injections of heat-killed Pseudomonas aeruginosa and of BCG.

Intravenous injection (i.v.) of heat-killed Pseudomonas aeruginosa in mice produced histologic changes in the thymic cortex, some of which resembled, while others differed from, those produced by i.v. injection of living BCG. The changes that were similar consisted of pyroninophilia of cortical lymphocytes and hyperplasia of epithelial cells in the medulla and at the corticomedullary junction with increased PAS positive cells and secretions. Major differences, however, in the sequence and nature of the histologic events were observed. Pseudomonas injections produced thymic epithelial cell hyperplasia with increased PAS positive cells and secretions and pyroninophilia of thymic cortical lymphocytes earlier than did i.v. BCG (day 1 versus day 7). Corticomedullary inversion of thymic structure and early transient hyperplasia of the thymus dependent areas in the lymph nodes and spleen occurred after Pseudomonas but not after BCG injections. Hyperplasia in the B cell areas and germinal centers started to appear at day 10 after injection of Pseudomonas and persisted up to day 21 (compared to day 7 and day 14, respectively, for BCG). In contrast to i.v. BCG, Pseudomonas injections did not produce granulomas or macrophage proliferations.

Animals↗
PubMed1979

Restoration of impaired immune functions of aged animals by chronic bestatin treatment.

An attempt to correct the state of immunodeficiency in old age was made by repeatedly injecting a chemically defined immunostimulating agent, bestatin, to 16 month old (C57Bl/6 x BALB/c) F1 mice. Aged mice were found to have depressed T-cell and B-cell responses but increased ADCC activity. Weekly injections of bestatin over a period of 6 months resulted in varying effects depending on the dose administered. Small doses (10 microgram per injection) were more effective in restoring humoral responses to SRBC rather than delayed-type hypersensitivity reactions, whereas large doses (100 microgram per injection) acted in the opposite way. Macrophage activation was only obtained after the administration of the high doses of bestatin. Continuous treatment with bestatin did not prevent the appearance of suppressor cells induced by ageing. It led to a significant reduction of ADCC activity in aged animals near to the base line value of young animals. Animals were examined for the presence of spontaneous tumours from the end of the treatment until the age of 28 months. A significant reduction of spontaneous tumour incidence was observed in mice given repeated injections of 100 microgram bestatin when compared to untreated aged mice and to mice given the low doses of bestatin.

Aging↗
PubMed1978

Pharmacologic factors and manipulation of immunity systemic adjuvants in cancer therapy.

Because of the experimental and clinical studies which have been extensively conducted with bacillus Calmette-Guérin (BCG) as a systemic adjuvant in cancer immunotherapy, we have analyzed the main factors and conditions which determine its beneficial action and have underlined some of these (eg, the dose factor which controls the amplification of suppressor cells which is probably responsible for failures and even the possible tumor-enhancing effect of immunotherapy). Knowing those factors and conditions, we have been able to establish a systematic immunopharmacologic study of systemic immunity adjuvants, which has resulted in the discovery of agents whose actions are more rapid than that of BCG on one or a few populations of cells involved in immunity and which, unlike BCG, do not induce suppressor cell amplification. This amplification may explain the difference in the results obtained with this mycobacterium in various clinical immunotherapy trials in which it was applied differently. It is proposed to combine these mono- or pauc-functional adjuvants in order to try to obtain all of the beneficial effects of BCG without the amplification of suppressor cells.

Adjuvants, Immunologic↗