Homeostasis is the maintenance of equilibrium in a biological system by means of positive and negative feedback control mechanisms that counteract influences tending toward physiological dissonance. At the molecular level, homeostasis is controlled by the network of the neuro-endocrine-immune system, in which lactoferrin plays a central role. The purpose of this review is to provide a comprehensive summary of a collaborative study established between the Hirszfeld Institute of Immunology and Experimental Therapy (Wroclaw, Poland) and the University of Texas Health Science Center (Huston, USA) regarding lactoferrin and its role in homeostasis. In our studies we focused on the immunoregulatory functions of lactoferrin, both in vitro and in vivo. We investigated the immune status of individuals subjected to different insults, including experimental endotoxemia in mice and surgery in humans. We also studied a lactoferrin-dependent delayed type hypersensitivity (DTH) response to evaluate some of the mechanisms by which lactoferrin can effectively substitute an adjuvant in vaccine.
The aim of this study was to investigate the effects of bovine lactoferrin on the proliferative response of human blood lymphocytes induced by PHA and alloantigens in two-way mixed lymphocyte culture at a broad range of BLF concentrations (1.5 - 50 mug/ml). We found that the effects of BLF in both experimental models were differential and depended on an individual reactivity of lymphocytes with respect to mitogen or alloantigen and BLF concentration. Generally, lymphocytes from donors reactive to BLF exhibited higher proliferation indices compared to nonreactive individuals. Low BLF doses were regulatory and higher ones mostly inhibitory. MLR was in most cases inhibited by all doses of BLF, some MLR stimulated and other not affected by BLF. We conclude that basis for the differential action of BLF is its ability to sense the activation status of lymphocytes. The resultant effects of BLF are probably mediated by monocytes and cytokines.
The aim of this study was to evaluate the effect of lipopolysaccharide (LPS) administration, which mimics a surgical intervention, on the immune status of obstructive jaundiced (OJ) and sham-operated control rats. Rats were given 20 mug LPS intraperitoneally on day 13 following bile duct ligation or sham surgery. We determined serum levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) on day 14 after surgery, and spontaneous as well as LPS-induced production of these cytokines in splenocyte and peritoneal exudate cell cultures (PEC). We found that IL-6, but not TNF-alpha, serum concentrations were significantly elevated (4-fold) in OJ rats treated with LPS compared with LPS-untreated OJ rats. In sham-operated rats the differences between the respective groups were not significant. The production of TNF-alpha by splenocyte and PEC cultures was depressed in OJ rats treated with LPS; in particular, a very deep decline was observed in the case of spontaneous TNF-alpha production in PEC cultures. In contrast, TNF-alpha production in LPS-untreated and LPS-treated sham-operated rats did not differ. In the case of IL-6 production by splenocytes and PEC cultures, we observed a significant suppression of this cellular function in both OJ and sham-operated rats treated with LPS when compared with the respective controls. In conclusion, the results indicate that the already depressed cytokine production in OJ rats leads to even deeper hyporeactivity following LPS challenge. Lack of TNF- alpha suppression upon LPS treatment in sham-operated rats suggests that surgery-elicited hyporeactivity is mediated by a different mechanism than that leading to immune hyporesponsiveness in OJ. Our findings may explain the relatively high mortality rates of OJ patients subjected to surgery.
In this report we describe immunostimulatory properties of RM-11 in several in vivo and in vitro tests in the murine model. We found that RM-11 significantly stimulated the humoral immune response to sheep erythrocytes (SRBC) when given intraperitoneally (i. p.) at doses of 10 and 100 mug or per os (doses of 20 and 200 mug) 3 h before immunization. The compound was also stimulatory with regard to generation of delayed type hypersensitivity (DTH) to SRBC when given i. p. or per os (doses of 10, 100 and 500 mug/mouse). The described immunostimulatory activities of RM-11 were higher compared to that of the reference drug, levamisole. RM-11 stimulated, in addition, concanavalin A (ConA) -induced splenocyte proliferation. Lastly, we showed that RM-11 was not toxic when given to mice per os at doses 250 mg/kg body weight. Taken together, RM-11 appeared to be a universal stimulator of the immune response in mice. Lack of toxicity and the ability to stimulate the immune response, when administered per os, predispose the compound for further preclinical studies.
The aim of this study was to investigate the effect of phagotherapy on tumor necrosis factor (TNF-) and interleukin 6 (IL-6) serum levels and the ability of blood cells to produce these cytokines in culture. Fifty one patients with long-term, suppurative infections of various tissues and organs were enrolled. The ability of cells to secrete cytokines was tested using whole blood cell cultures, unstimulated or stimulated with lipopolysaccharide (LPS) from E. coli. In addition, cytokine serum levels were determined. Measurement of cytokine activity was performed using bioassays. We showed that TNF-, but not IL-6 serum levels, were regulated upon division of patients into categories exhibiting initial: low, moderate and high cytokine levels. The low spontaneous production of IL-6 by blood cell cultures was elevated significantly on day 21 of phage therapy, whereas high release of this cytokine was inhibited. No such correlation was observed with LPS-induced IL-6 production in cell cultures when cells from low-, moderately- or highly-reactive patients were studied. Phage therapy modified TNF release according to the initial ability to produce that cytokine: it reduced TNF production in high responders and increased it in low responders. Patients infected only with Gram-positive bacteria demonstrated analogous changes in the spontaneous and LPS-induced TNF- production as in the whole studied group. A similar kind of regulation was observed in TNF- and LPS-induced production, i. e. low production was significantly elevated, high strongly inhibited, and moderate only slightly affected. In summary, we demonstrated for the first time that effective phage therapy can normalize TNF- serum levels and the production of TNF- and IL-6 by blood cell cultures.
The effect of oral administration of lactoferrin (LF) was studied to determine if it could modify post-surgical immune response. The action of lactoferrin was evaluated in 18 LF-treated patients versus 28 placebo counterparts. Patients (women and men, mean age 50 years) were given daily oral doses (20 mg each) of LF for 5 consecutive days prior to thyroid surgery. The following immune response parameters were determined in blood samples taken from the patients one day before, one day after, and 5-7 days following surgery: cell morphology, the proliferative response of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), and the spontaneous and lipopolysaccharide (LPS)-induced production of tumor necrosis factor alpha (TNF-) and interleukin 6 (IL-6). As a consequence of the thyroid surgery, the total leukocyte count increased on the postoperative day by about 50% in all patients and the percentage of lymphocytes fell by 26 and 35% in the control vs LF-treated group. The content of neutrophils, on the other hand, elevated on day 1 post-operation by 51 and 68%, respectively. The percent of neutrophil precursors was markedly higher in LF-treated patients, particularly on the day before and the day after surgery (4.1 and 4.8 vs 2.5 and 3.7%, respectively). The post-surgical values were, however, comparable in both groups for neutrophils. The proliferative response of lymphocytes showed a slight decrease in the control group and an increase in the LF-treated patients on day 5 post-operation (20% over control group). LPS-induced TNF- production was higher in LF-treated patients in both one day before and one day following surgery (28 and 24% respectively). LPS-induced IL-6 production was comparable in both placebo and LF-treated patients before surgery, however, on day 1 and 5 following surgery, the production of IL-6 was higher in LF-treated patients by 65 and 27%, respectively. Taken together, the data presented in this study revealed increased immune responsiveness in all patients treated with lactoferrin subjected to the thyroid surgery. This suggests that treatment with lactoferrin could constitute an effective protective measure against post-surgical complications.
We have previously shown that bovine lactoferrin (BLF) given intravenously (i.v.) protected mice against a lethal dose of E. coli and strongly stimulated both the clearing and killing activities in liver, lungs, spleen and kidney. Since some studies indicated a reduction of the manifestation of experimental pancreatitis with lactoferrin, we decided to examine the protective activity of BLF against lethal E. coli infection in animals with alloxan (Alx)-induced diabetes. It appeared that 48 h diabetes substantially lowered the killing activity in all four organs as well as the clearing rate of E. coli from the circulation. BLF given i.v. o reduced this undesirable effect of diabetes. However, in 10- and 20-day diabetic animals, the diabetes alone stimulated the killing activity in the organs investigated, and upregulated the clearing rate of E. coli from the circulation. Lactoferrin (LF) significantly increased both the killing and the clearing activity in these long-term diabetic animals. In some cases the stimulating effect of BLF was very high, suggesting a concerted action of BLF and diabetes in that category of mice. Despite these beneficial effects of BLF and diabetes on the killing process in the investigated organs, the survival time of animals from all the diabetic groups ( 48 h, 10 and 20 days) was not prolonged by BLF. The protective properties of BLF did not depend on the blood glucose levels in the diabetic animals. BLF partly delayed the development of experimental Alx-induced diabetes, measured by the glucose level, but only if administered shortly after Alx injection. In conclusion, we demonstrated that the state of diabetes alone could increase killing of bacteria in the investigated organs and LF enhanced this process. However, LF had no protective effect against the mortality of diabetic mice infected with a lethal dose of E. coli.
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