Urbanization with reduced microbial exposure is associated with an increased burden of asthma and atopic symptoms. Conversely, environmental exposure to endotoxins in childhood can protect against the development of allergies. Our study aimed to investigate whether the renaturation of the indoor environment with aerosolized radiation-detoxified lipopolysaccharide (RD-LPS) has a preventative effect against the development of ragweed-induced Th2-type airway inflammation. To explore this, cages of six-week-old BALB/c mice were treated daily with aerosolized native LPS (N-LPS) or RD-LPS. After a 10-week treatment period, mice were sensitized and challenged with ragweed pollen extract, and inflammatory cell infiltration into the airways was observed. As dendritic cells (DCs) play a crucial role in the polarization of T-cell responses, in our in vitro experiments, the effects of N-LPS and RD-LPS were compared on human monocyte-derived DCs (moDCs). Mice in RD-LPS-rich milieu developed significantly less allergic airway inflammation than mice in N-LPS-rich or common environments. The results of our in vitro experiments demonstrate that RD-LPS-exposed moDCs have a higher Th1-polarizing capacity than moDCs exposed to N-LPS. Consequently, we suppose that the aerosolized, non-toxic RD-LPS applied in early life for the renaturation of urban indoors may be suitable for the prevention of Th2-mediated allergies in childhood.

Stem cell-based therapies raise hope for cell replacement and provide opportunity for cardiac regenerative medicine and tumor therapy. Extracellular vesicles are a membrane-enclosed intercellular delivery system with the potential to improve the therapeutic efficacy of the treatment of a variety of disorders. As the incidence of breast cancer continues to rise, radiotherapy has emerged as a leading treatment modality. Radiotherapy also increases the risk of coronary heart disease and cardiac mortality. In a chest-irradiated mouse model of cardiac injury, we investigated the effects of local irradiation. We found an increased lethality after 16 Gy irradiation. Importantly, radio-detoxified LPS (RD-LPS) treatment prolonged the survival significantly. By flow cytometry, we demonstrated that upon administration of RD-LPS, the number of bone marrow-derived endothelial progenitor cells increased in the bone marrow and, in particular, in the circulation. Furthermore, mass spectrometry analysis showed that RD-LPS altered the proteomic composition of bone marrow cell-derived small extracellular vesicles (sEVs). RD-LPS treatment increased interferon-induced transmembrane protein-3 (IFITM3) expression markedly both in bone marrow cells and in bone marrow cell-derived small extracellular vesicles. This is the first study to demonstrate that radio-detoxified LPS treatment induces an increase of circulating endothelial progenitor cells (EPCs) in parallel with a reduced radiotherapy-related mortality. While the total number of bone marrow-derived extracellular vesicles was significantly increased 24 h after treatment in the RD-LPS groups, the number of endothelial progenitor cells was reduced in animals injected with GW4896 (a chemical inhibitor of exosome biogenesis) as compared with controls. In contrast to these in vivo results, in vitro experiments did not support the effect of sEVs on EPCs. Our data raise the intriguing possibility that IFITM3 may serve as a marker of the radio-detoxified LPS treatment.

The observations on the protective effect of bacterial endotoxin in farm-derived cow’s milk on childhood asthma and allergy are contradictory. The aim of this study was to determine the endotoxin levels in ‘farm-derived whole raw’ and ‘processed shop’ sources of cow’s milk, and to test how the temperature and storing conditions might alter their endotoxin concentrations. Milk was collected from farms and shops. The level of endotoxin was measured by micro (gel-clot) Limulus amebocyte lysate test expressed as EU/ml. The concentration ranges of endotoxin were much higher and more widely scattered in the samples of whole raw farm milk than in the processed shop milk. Cold storage or heating increased the endotoxin concentrations in all samples of farm milk, but not in the processed shop milk. These results show that elevated levels of endotoxin in raw farm milk samples can occur from the cowshed or be formed during storage. In processed shop milk, storage does not cause any changes in the amount of endotoxin. Therefore, it is consistent that the handling and storage of raw milk alters the endotoxin concentrations, which may explain previous contradictory findings regarding the beneficial modulating effects on innate immunity toward allergy prevention in early childhood.

The immune system of higher animals comprised of two parts: Innate - or Natural -(INIM-NIM) and Adaptive Immunity (ADIM). Innate resistance includes physical barriers (e.g. skin, cornea, mucous membranes, the blood-brain barrier - BBB) chemical defense (HCl in the stomach, bile acids in the intestines, enzyme based protection) and Species Specific Resistance (SSR) to viruses and other pathogens. SSR may occur because of the lack of proper receptors for the pathogen to establish itself in the resistant animal species. Therefore, SSR is a phylogenetically determined property of various animal species. Innate immunity includes polyspecifc immune mechanisms with germ line gene based antigen receptors (INIR/NIR) that recognize phylogenetically preserved, highly cross-reactive (homologous) epitopes, or homotopes. Because both the antigen receptors (e.g. toll-like receptors - TLR) and the homotopes (e.g., lipid A in bacterial lipopolysaccharide - LPS) are constant, and fully differentiated immune (monocyte/macrophages and other leucocytes) and somatic cells express TLR, the entire organism is capable of responding instantaneously to infection or injury. Innate phagocytes, primarily monocyte/macrophages, support the development of adaptive immunity, by presenting antigen and by contributing cytokines for cell activation. If natural immunity is depressed, ADIM will be deficient. The natural immune system provides continuous protection for the host animals or men against the effects of stress, treatment of cytostatic drugs, septic shock, infectious diseases, and numerous other noxious agents. Neuroendocrine, nutritional and environmental factors regulate natural immunity. The maintenance of good NIM defense is most important in modern medicine. Radiodetoxified endotoxin (RD-LPS) stimulates NIM, and activates the bone marrow. Animal experiments and human studies showed that RD-LPS is a promising preparation for the elevation of natural immunity. RD-LPS is a potent immunological adjuvant in the case of inactivated virus vaccines (e.g. influenza).

It is well demonstrated that serial endotoxin injections produce endotoxin tolerance and elevate the natural immunity/resistance. However, such injections may also have harmful effects such as high fever, hypotension and abortion. For this reason endotoxin (LPS) injections are not suitable to enhance nonspecific resistance in endotoxin-sensitive species like man. Various techniques have been designed (physical, chemical, etc.) for the detoxification of endotoxins while the beneficial effects are maintained. Perhaps one of the best detoxification techniques is the treatment with ionizing radiation. The irradiation of LPS with 60Co (150 kGy) decreased its toxicity in a dose-dependent manner. Such radio-detoxified endotoxin (RD-LPS) preparations show decreased toxicity whereas the beneficial effects were preserved. Irradiation causes marked chemical alterations in LPS, such as a decrease of glucosamine, ketodeoxyoctonic and fatty acids. A single parenteral RD-LPS injection prevents various forms of shock in experimental animals. This preparation has a membrane-stabilizing effect, and thereby it can prevent the membrane-damaging effect of LPS and of some cytostatic agents. Unlike endotoxin, RD-LPS has little hypotensive effects, and the pretreatment with this preparation can prevent practically all the hemodynamic changes induced by LPS. LPS plays an important role in the pathogenesis of intestinal syndrome of radiation disease, which may be prevented by RD-LPS pretreatment up to 70% in rats. RD-LPS retains the adjuvant activity of LPS, and it serves as a good adjuvant for inactivated virus vaccines. RD-LPS can also evoke the regeneration of the immune system in irradiated animals. The decrease of nonspecific resistance in immunodeficient or immunosuppressed patients is the most important cause of opportunistic infections that may lead to sepsis like in endotoxaemia and pneumonia. Organ transplant recipients commonly die of septicaemia. Antilymphocyte serum (ALS) is used in such patients as an immunosuppressant. The augmentation of natural resistance and the induction of endotoxin tolerance are of major significance in such patients. In ALS-treated rats RD-LPS induces also tolerance against the lethal dose of LPS. This demonstrates that in spite of the suppressive effect of ALS on T-lymphocytes the induction of LPS tolerance (the enhancement of natural resistance) remains normal. Facultative pathogenic organisms may flourish and cause disease when specific and nonspecific resistance is impaired. RD-LPS can produce a significant proliferation of lymphoid cells in germ-free animals which are immunodeficient. Many other beneficial effects are preserved by RD-LPS preparations, such as the activation of macrophages and of the reticuloendothelial system and antitumor activity. On the basis of these favorable experimental results, RD-LPS has been tested on 350 surgical patients suffering from gastrointestinal tumors, patients suffering from acquired immunodeficiency syndrome (AIDS) and cancer patients treated with CYSPLATIN. RD-LPS treatment prevented sepsis and activated the bone marrow function in these patients.

The toxic effects of endotoxin, the cell wall component of Gram negative intestinal bacteria, under experimental conditions, can be induced only when they are administered parenterally. However, in naturally occurring entero-endotoxaemic diseases (e.g., septic and various shocks, etc.), the endotoxin is absorbed from the intestinal tract. The cause and mode of translocation was unknown. The generally used experimental shock models differ from natural diseases only in the mode by which endotoxin enter the blood circulation. If the common bile duct of rats was chronically cannulated (bile deprived animals) orally administered endotoxin was absorbed from the intestinal tract into the blood circulation and provoked endotoxin shock. This translocation of endotoxins and the consequent shock can be prevented by sodium deoxycholate or natural biles. The bile acids split the endotoxin macromolecule into atoxic fragments. A similar detoxifying detergent action plays a significant role in host defence against infectious agents with a lipoprotein outer structure (e.g., so-called "big" viruses). This defence mechanism of macroorganisms based on the detergent activity of bile acids is called physico-chemical defence system. Since bile deficiency and the consequent endotoxaemia are important components in the pathogenesis of certain diseases (e.g., sepsis, intestinal syndrome of radiation disease, hepato-renal syndrome, parvovirus infection, herpes, psoriasis, atherosclerosis, etc.), bile acids may be used for the prevention and/or therapy of some clinical conditions such as the hepato-renal syndrome and psoriasis.

It is well demonstrated that serial endotoxin injections produce endotoxin tolerance and elevate natural resistance. However, such injections may also have harmful effects such as high fever, hypotension and abortion. For this reason LPS injections are not suitable to enhance nonspecific resistance in endotoxin-sensitive mammalian species including man. Various techniques have been designed (physical, chemical, etc.) for the detoxification of endotoxins while the beneficial effects were maintained. Perhaps one of the best detoxification techniques is treatment with ionizing radiation. The irradiation of LPS with Co-60 (100-200 kGy) decreased its toxicity in a dose-dependent manner. Such radiodetoxified endotoxin (RD-LPS) preparations showed decreased toxicity whereas the beneficial effects were preserved (150 kGy:TOLERIN (R)). These findings have been confirmed in other laboratories. Irradiation causes marked chemical alteration in LPS, such as the decrease of glucosamine, KDO and fatty acids. A single parenteral injection of TOLERIN (R) is capable of preventing the various forms of shock in experimental animals. This preparation has a membrane-stabilizing effect and thereby can prevent the membrane-damaging effect of LPS and of some cytostatic agents. Unlike endotoxin, TOLERIN has barely any hypotensive effect and pretreatment with this preparation can prevent practically all the haemodynamic changes induced by LPS. LPS plays an important role in the pathogenesis of the intestinal syndrome of radiation disease, which may be prevented by up to 70% in rats with RD-LPS pretreatment. TOLERIN retains the adjuvant activity of LPS and it is a good adjuvant for inactivated virus vaccines. TOLERIN can also evoke the regeneration of the immune system in irradiated animals. The decrease of nonspecific resistance in immunodeficient or immunosuppressed patients is the most important cause of opportunistic infections that may lead to sepsis, endotoxaemia, pneumonia and so on. Organ transplant recipients commonly die of septicaemia. Antilymphocyte serum (ALS) is used in such patients as an immunosuppressant. The augmentation of natural resistance and the induction of endotoxin tolerance are of major significance in such patients. We found that in ALS-treated rats RD-LPS induced tolerance against the lethal dose of LPS. This experiment demonstrated that in spite of the suppressive effect of ALS on T lymphocytes the induction of LPS tolerance (the enhancement of natural resistance) was normal. Facultative pathogenic organisms may flourish and cause disease when specific and nonspecific resistance is impaired. RD-LPS could produce significant proliferation of lymphoid cells in germ-free animals which are immunodeficient. Many other beneficial effects are preserved by RD-LPS preparations, such as the activation of macrophages and of the reticuloendothelial system, antitumour activity, etc. On the basis of these favourable experimental results, TOLERIN was tested on 350 surgical patients suffering from gastrointestinal tumours, on other patients suffering from AIDS and on cancer patients treated with CYSPLATIN(C). TOLERIN treatment prevented sepsis and activated bone marrow function in these patients.

The term natural resistance refers to the capacity of living organisms to withstand injury caused by physical, chemical and biological agents that may be present in the external or internal environment. This protection is mediated by the natural, or innate, immune system, a multi-factorial and polyspecific defence system. Evolutionarily preserved germ-line receptors mediate the activation of natural immune cells that recognize genetically preserved, cross-reactive homologous epitopes (homotopes) in micro-organisms, cancer cells, virus-infected cells and distressed cells. In general, protection is based on balancing the defence mechanisms of the organism with the damaging effects of harmful agents. This defence comprises epithelial, secretory and endogenous mechanisms in addition to the cellular and humoural components of the natural immune system. In recent years, a continuing surge of exploration and discussion has helped to crystallize our appreciation of the molecular mechanisms of this innate system, their basis in evolution, physiological, pathological and behavioural significance and their regulation, in particular their intimate connection with the neuroendocrine system. In higher animals natural immune mechanisms are boosted profoundly during acute febrile illness leading to the release of pro-inflammatory cytokines, IL-1, TNF-alpha and IL-6, which in turn activate the neuroimmune regulatory network. The HPA axis and the sympathetic nervous system is activated and catabolism prevails. IL-6, glucocorticoids and cathecolamines induce the production of acute phase proteins permitting a rapid activation of phagocytic and cytotoxic mechanisms under the command of natural antibodies and other recognition molecules (e.g. C-reactive protein, endotoxin binding and mannose binding proteins). The acute phase response is a highly co-ordinated emergency defence reaction, which relies on the interaction of neuroendocrine, immune and metabolic mechanisms in the interest of maximum host defence during emergency situations, such as sepsis. In most cases febrile illness leads to healing and recovery, which attests to the effectiveness of the natural immune system and excites the desire for the benefits which should accrue from mastering the manipulation of this system.

The discovery of the physico-chemical host defence is closely connected with the endotoxin research. It is well known that the toxic effects of endotoxins under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring entero-endotoxemic diseases (e.g. septic and various shocks, etc.), the endotoxin is absorbed from the intestinal tract. The cause and mode of translocation have been unknown. The generally used experimental shock models differ from natural diseases only in the mode by which endotoxin enters the blood circulation. If the common bile duct of rats was chronically canulated (bile-deprived animals) orally administered endotoxin was absorbed from the intestinal tract into blood circulation and provoked endotoxin shock. This translocation of endotoxins and the consequent shock can be prevented by sodium deoxycholate or natural biles. The bile acids split the endotoxin macromolecule into atoxic fragments. A similar detoxifying detergent action plays a significant role in host defence against infectious agents with outer lipoprotein structure (e.g. so-called 'big' viruses). This defence mechanism of macroorganisms based on the detergent activity of bile acids (end-products of the cholesterol metabolism) is called as physico-chemical defence system. Therefore, bile deficiency and the consequent endotoxemia are important components in the pathogenesis of certain diseases (e.g. sepsis, intestinal syndrome of radiation disease, hepato-renal syndrome, parvovirus infection, herpes, psoriasis, atherosclerosis, etc.). Bile acids may be used for the prevention and/or therapy of the above mentioned clinical conditions.

The authors have tested the hypothesis that the deficiency of bile acids and the consequent endotoxin translocation might play a role in the pathogenesis of psoriasis. Under normal conditions the bile acids act as detergents (physico-chemical defense) and can protect the body against enteric endotoxins by splitting them into nontoxic fragments and thus preventing the consequent release of cytokines [Persp. Biol. Med. 21 (1977) 70]. A total of 800 psoriasis patients participated in the study and 551 were treated with oral bile acid (dehydrocholic acid) supplementation for 1–8 weeks. The efficacy of the treatment was evaluated clinically and also by means of the Psoriasis Area Severity Index (PASI score). During this treatment, 434 patients (78.8%) became asymptomatic. Of 249 psoriatics receiving the conventional therapy, only 62 (24.9%) showed clinical recovery during the same period of time (P<0.05). The curative effect of bile acid supplementation was more pronounced in the acute form of psoriasis (95.1% of the patients became asymptomatic). Two years later, 319 out of the 551 acute and chronic psoriasis patients treated with bile acid (57.9%) were asymptomatic, compared to only 15 out of the 249 patients (6.0%) receiving the conventional treatment (P<0.05). At the end of the 2-year follow-up, only 10 out of 139 acute psoriasis patients (7.2%) receiving the conventional therapy and 147 out of 184 bile acid treated patients (79.9%) were asymptomatic (P<0.01).

The plasma level of endotoxin was determined in 116 healthy blood donors. After a routine physical and laboratory investigations the endotoxin level was determined with Limulus amebocyte lysate assay (LAL-test) by the chromogenic kinetic method of Bio-Whittaker Co. (USA). Its sensitivity was 0.005-50 EU/ml. The plasma level of endotoxin in most of the healthy donors was less than 1 EU/ml (in the range of 0.01-1.0 EU/ml), but always measurable. The average +/- S.D. was 0.128 +/- 0.215 EU/ml. Because of the high standard deviation and high range of values, the data were distributed into two groups with the means of 0.05 +/- 0.022 EU/ml and 0.294 +/- 0.186 EU/ml. The difference between the groups was significant (p < 0.001). In conclusion, endotoxin can be measured in plasma of healthy individuals.

Annals of the New York Academy of SciencesVolume 851, Issue 1 p. 404-405 Introduction: Endotoxin as Stressor and Endotoxemia as Stress LÓRÁND BERTÓK, Corresponding Author LÓRÁND BERTÓK “Frédéric Joliot Curie” National Research Institute for Radiobiology and Radiohygiene, Anna u. 5, H-1221 Budapest, HungaryAdditional correspondence information: Telephone: (36-1) 226-6736; Fax: (36-1) 226-6736.Search for more papers by this author LÓRÁND BERTÓK, Corresponding Author LÓRÁND BERTÓK “Frédéric Joliot Curie” National Research Institute for Radiobiology and Radiohygiene, Anna u. 5, H-1221 Budapest, HungaryAdditional correspondence information: Telephone: (36-1) 226-6736; Fax: (36-1) 226-6736.Search for more papers by this author First published: 07 February 2006 https://doi.org/10.1111/j.1749-6632.1998.tb09014.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Citing Literature Volume851, Issue1STRESS OF LIFE: FROM MOLECULES TO MANJune 1998Pages 404-405 RelatedInformation

Annals of the New York Academy of SciencesVolume 851, Issue 1 p. 1-2 Stress and Nonspecific Resistance LÓRÁND BERTÓK, Corresponding Author LÓRÁND BERTÓK “Frédéric Joliot Curie” National Research Institute for Radiobiology and Radiohygiene, Anna u. 5. H-1221, Budapest, HungaryAdditional correspondence information: Telephone: (36-1) 226-6736; Fax: (36-1) 226-6736.Search for more papers by this author LÓRÁND BERTÓK, Corresponding Author LÓRÁND BERTÓK “Frédéric Joliot Curie” National Research Institute for Radiobiology and Radiohygiene, Anna u. 5. H-1221, Budapest, HungaryAdditional correspondence information: Telephone: (36-1) 226-6736; Fax: (36-1) 226-6736.Search for more papers by this author First published: 07 February 2006 https://doi.org/10.1111/j.1749-6632.1998.tb08968.xCitations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL REFERENCES 1 Selye, H. 1936. A syndrome produced by diverse nocous agent. Nature 138: 32. 2 Virchow, R., Ed. 1854. Handbuch der speziellen Pathologie und Therapie. Verlag von Ferdinand Euke. Erlangen. 3 Selye, H. 1955. Stress and disease. Science 122: 625– 631. 4 Bertók, L. 1983. Stimulation of nonspecific resistance by radiation-detoxified endotoxin (pp. 213-226) In Beneficial Effects of Endotoxins. A. Nowotny. Ed: Plenum Publishing Corporation. New York. 5 Bertók, L. 1980. Radiodetoxified endotoxin as a protent stimulator of nonspecific resistance. Persp. Biol. Med. 24: 61– 66. 6 Selye, H., B. Tuchweber & L. Bertók. 1966. Effect of lead acetate on the susceptibility of rats to bacterial endotoxins. J. Bacteriol. 91: 884– 890. 7 Bertók, L. 1985. Lead acetate induced endotoxin hypersensitivity. Experientia 41: 575– 576. 8 Bertók, L. & U. Nagy Zs. 1984. The effect of endotoxin and radio-detoxified endotoxin on the serum T4 level of rats and response of their thyroid gland to exogenous TSH. Immunpharmacology 8: 143– 146. 9 Bertók, L. 1977. Physico-chemical defense of vertebrate organisms: the role of bile acids in defense against bacterial endotoxins. Persp. Biol. Med. 21: 70– 76. 10 Bertók, L. Jr., L. B. Sztanyik & L. Bertók. 1992. Possibile role of bile deficiency in the development of intestinal syndrome of acute radiation disease. Acta Physiol. Hung. 79: 29– 32. 11 Bertók, L. 1990. Stimulation of nonspecific resitance by radio-detoxified endotoxin In Endotoxin. H. Friedman, T. W. Klein, M. Nakano & A. Nowotny, Eds.: 677-680. Plenum Publishing Corporation. New York. Citing Literature Volume851, Issue1STRESS OF LIFE: FROM MOLECULES TO MANJune 1998Pages 1-2 ReferencesRelatedInformation