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N Bloksma

Publications and source records attributed to N Bloksma.

At least 55 records · Page 3Linked to original sources
PubMed1988

Chemical-induced autoimmune reactions and Spanish toxic oil syndrome. Focus on hydantoins and related compounds.

Autoimmune diseases comprise a wide spectrum of overlapping, systemic and organ-specific disorders. Although, etiology and pathogenesis of such disorders are largely unknown, endogenous host factors and exogenous agents, such as viruses, bacteria, and small molecular weight chemicals, drugs and food components, are believed to be involved. The toxicological significance of low molecular weight compounds on induction of autoimmune disorders is illustrated by the toxic oil syndrome (TOS), a chemically induced epidemic, observed in Spain since 1981. The causative chemical(s) of TOS is still elusive, but an association between ingestion of refined aniline-adulterated rapeseed oil and the syndrome is well-documented. Epidemiological, clinical and immunopathological symptoms of TOS are briefly reviewed. The striking resemblance with immunological disorders, observed in man upon medication with hydantoins and related compounds, is demonstrated. The likeliness of formation of a hydantoin-related compound in the aniline-adulterated oil is evidenced and its role as possible toxic agent in TOS is proposed. Further, the presence of hydantoins and related compounds in food is briefly reviewed and it is suggested that these chemicals may account for a portion of idiopathic autoimmune diseases observed in man. The need for development of animal models to assess this kind of immunotoxicological effects is stressed.

Animals↗
PubMed1987

Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice.

Antitumor effects of i.v. injected human recombinant tumor necrosis factor (rTNF) against solid Meth A tumors in mice appeared to be critically dependent on the dose and were limited by its toxicity. Extensive necrosis and complete cures were only induced by doses having untoward effects, such as diarrhea, hypothermia, ruffled fur, and lethargy. Murine tumor necrosis serum (TNS, 0.5 ml) had about the same antitumor potential and induced all side effects except diarrhea. More extensive necrosis and approximate doubling of the incidence of complete regression in the absence of gross side effects were observed upon administration of a low dose of rTNF combined with detoxified endotoxin, nontoxic poly A:U, or submicrogram doses of toxic endotoxin. The separate constituents had little antitumor effects, if any at all. Increasing the dose of toxic endotoxin resulted in a further potentiation of necrosis, overt toxicity, but no cures. Muramyl dipeptide and interferon alpha/beta did not potentiate effects of rTNF. In vitro growth of Meth A cells was not inhibited by toxic endotoxin, rTNF or the combination, although TNS was highly inhibitory. Data show that therapeutic effects of rTNF and its synergy with endotoxin are not due to direct effects on the tumor cells and that the extent of prompt in vivo tumor necrosis does not predict the course of tumor growth. Therapeutic effects of both TNS and toxic endotoxin probably involve a synergy between low levels of TNF and other factors/effects induced by endotoxin. Detoxified endotoxin and poly A:U probably induce the latter effects and little or no TNF, so explaining the absence of side effects, their weak antitumor potential, and their powerful synergistic action with rTNF. A role for interferon alpha/beta as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Quantitative histology of muramyl dipeptide-potentiated induction of tumor necrosis by endotoxins.

Combinations of muramyl dipeptide (MDP) and toxic or detoxified endotoxin induced necrosis and subsequent disappearance of solid Meth A tumors in syngeneic mice. Toxic endotoxin alone was far less effective. MDP and detoxified endotoxin had negligible antitumor effects of their own. These observations were confirmed by histological examination. Neither MDP nor detoxified endotoxin induced significant changes in and around the tumor by 4, 24, and 48 h after intravenous administration when compared with saline treatment. MDP amplified various effects of toxic endotoxin such as the induction of hyperemia, mitotic arrest, mast cell depletion, non-hemorrhagic necrosis and reduction in lymphocyte infiltrates, but did not affect hemorrhagic necrosis or the influx of polymorphonuclear leukocytes. The combination of MDP and detoxified endotoxin lacked the latter two effects, but the other effects were similar to, although slightly less marked than those induced by the toxic combination. Because the degree of hyperemia was proportional to the degree of subsequent non-hemorrhagic necrosis, MDP seems to potentiate necrosis by enhancing mechanisms leading to hyperemia and mast cell mediators might be involved in the latter effect. Lymphocyte influx and the therapeutic outcome are likely to be related, since exclusively therapeutic treatments reduced the influx of these cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

In vivo effects of toxic and detoxified endotoxin alone or in combination with muramyl dipeptide on lymphoid and non-lymphoid cells in the spleen of Meth A sarcoma-bearing mice.

In this study we confirmed that combinations of toxic or detoxified endotoxin with muramyl dipeptide (MDP) induced much more necrosis of transplanted Meth A sarcoma in mice than toxic endotoxin alone. Detoxified endotoxin and MDP alone had little antitumor effects. We investigated whether these divergent antitumor effects could be related to histopathological changes in the white pulp of the spleen of Meth A sarcoma-bearing mice. Toxic endotoxin reduced the T:B cell compartment ratio in the splenic white pulp by increasing the size of the B-cell compartment while leaving the size of the T-cell dependent inner PALS unaffected. The number of the T-lymphocytes in this area, however, was reduced. The border of B-lymphocytes in the marginal zone was markedly narrowed and the number of marginal metallophils along the inner border of the marginal sinus was decreased. None of these changes were observed after treatment with detoxified endotoxin or MDP. Addition of MDP to either endotoxin did not change their effects. The histopathological changes in the lymphoid and non-lymphoid compartments of the splenic white pulp are apparently exclusively induced by toxic endotoxin. As the antitumor activity of both toxic and detoxified endotoxin combined with MDP are about equal and more powerful than the activity of toxic endotoxin alone, it is concluded that these antitumor effects cannot be related to changes in the white pulp of the spleen.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1985

Effects of endotoxin-treatment on inflammatory cell infiltrates in murine Meth A sarcoma.

The effect of intravenously injected endotoxin on inflammatory cells within solid Meth A tumours was studied and central hyperaemia, necrosis and early collapse were observed macroscopically at 4, 24 and 48 h, respectively. The effects were studied in semithin sections and cytocentrifuge preparations of the tumours. The inflammatory cell reaction evoked by the tumours in untreated animals was relatively slight. It was located predominantly around the lateral margins of the tumours and only a few inflammatory cells were found inside the tumour. Prominent effects of endotoxin included a transient increase of mononuclear inflammatory cells in the centre of the tumour by 4 h and a reduction of the influx of lymphocytes, observed in and around the margin of control tumours, by 48 h. Mast cells formed an important part of the inflammatory cell infiltrate, but no distinct changes in number and appearance were observed with time or following treatment. Total host cell numbers within tumours did not increase significantly upon endotoxin-treatment. Results suggest that a direct cytotoxic action of host cells cannot account for the extensive tumour damage observed. Rather, endotoxin-induced regression seems to be related to decreased lymphocyte numbers.

Animals↗
PubMed1985

Muramyl dipeptide analogues as potentiators of the antitumor action of endotoxin.

The potentiation of endotoxin-induced necrosis and regression of solid syngeneic Meth A tumors in mice previously observed following administration of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP) was investigated further by use of various muramyl peptide analogues and two unrelated synthetic adjuvants, viz. the pluronic polyol L121 and dimethyldioctadecylammonium bromide (DDA) instead of MDP. All agents were administered in aqueous solution by the IV route. None of the muramyl peptide analogues nor L121 or DDA had any strong antitumor action of their own. Two 6-O-acylated muramyl peptides (L2-MDP and B30-MDP) and muramyl dipeptide stearoyllysine [MDP-Lys (L18)] clearly potentiated endotoxin-induced necrosis and regression. In contrast, MDP with L- instead of D-isoglutamine was completely inactive. Optimal activity of B30-MDP and MDP-Lys (L18) was only achieved by adding of suitable amounts of a nonionic surfactant. L121 and DDA could not replace muramyl peptides as potentiating agent. The combination of endotoxin, MDP, and L121 caused complete tumor regression in all mice, but was highly toxic. On the basis of the data in the literature on the biological response-modifying activities of the agents used it is concluded that the potentiating activity of muramyl peptides cannot yet be related to their immunoadjuvant action or their capacity to activate macrophages or to enhance nonspecific bacterial resistance.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Muramyl dipeptide is a powerful potentiator of the antitumor action of various tumor-necrotizing agents.

The previously observed potentiation of necrosis and regression of solid immunogenic Meth A sarcoma transplants in mice after IV administration of endotoxin by addition of muramyl dipeptide (MDP) in saline was investigated further by varying time and route of administration of both agents. Equal potentiation was observed when MDP was administered 4 h before or after endotoxin, but administration 48 h or 24 h before or 24 h after endotoxin had no effect. Simultaneous administration of both agents enhanced tumor damage considerably, regardless of the route of administration of either agent. A strong potentiation of necrosis and regression was also observed upon addition of MDP to concanavalin A, poly I:C or poly A:U and, to a lesser degree, to a radio-detoxified endotoxin, purified L cell interferon, or Propionibacterium acnes. No consistent relationship could be seen between the degree of potentiation of necrosis and of regression. It was suggested that distinct mechanisms underlie the augmenting action of MDP on necrosis and regression and that enhanced production and/or action of vasoactive agents might play a role in the potentiation of necrosis. Whether the capacity of MDP to stimulate specific and nonspecific immune defense is involved in the enhancement of tumor regression remains uncertain at present.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

Role of histamine in the antitumour activity of endotoxin.

The role of histamine in the antitumour activity of endotoxin against solid syngeneic Meth-A sarcoma in BALB/c mice was studied. Endotoxin induces haemorrhagic necrosis and regression of this tumour. Histamine and the selective H1 receptor agonist 2-pyridylethylamine mimicked the induction of necrosis but did not cause regression. The selective H2 receptor agonist dimaprit did not cause any tumour damage. The effect of histamine could be inhibited by the H1 receptor antagonists diphenhydramine and promethazine but not by the H2 receptor antagonist cimetidine. Endotoxin-induced necrosis was slightly affected by diphenhydramine, and the incidence of regression was reduced by both H1 antagonists. Cimetidine potentiated endotoxin-induced regression. Similar effects were observed concerning the effects of H-receptor antagonists on necrosis and regression induced by tumour necrosis serum (TNS). Histological examination revealed no marked additional effects of diphenhydramine or cimetidine on endotoxin-induced hyperaemia, haemorrhagic necrosis, and mitotic arrest of the tumour cells. Only cimetidine increased the extent of nonhaemorrhagic necrosis. The endotoxin-induced release of tumour necrosis factor and cytostatic activity in TNS was clearly reduced by diphenhydramine, but hardly affected by cimetidine. Data indicate that intact H1 receptors are required for the induction of tumour regression and antitumour factors by endotoxin. Concomitant H2 blockade may facilitate this by stimulating H1 receptor-mediated processes upon endotoxin-induced histamine release, although a cimetidine-induced inhibition of T-suppressor cell activation might also be involved.

Animals↗
PubMed1984

Role of vasoactive amines in the antitumor activity of endotoxin.

To estimate a possible role of vasoamines in the antitumor action of endotoxin, effects of isoproterenol, serotonin and adrenaline on subcutaneously transplanted murine Meth A sarcoma and the capacity of these agents to elicit antitumor factors were studied. Macroscopically all agents induced tumor necrosis and a temporal tumor growth stop, but only endotoxin was capable of induction of complete tumor regression. Histology showed that all agents induced hyperemia by 4 h and hemorrhagic necrosis by 24 h. The latter was located superficially at the outside of tumors. Only serotonin and especially endotoxin induced substantial non-hemorrhagic necrosis in the remaining part of the tumors. Endotoxin induced a profound inhibition of the mitotic activity within the tumor, the effect of other agents was considerably less. Only endotoxin induced high levels of tumor necrosis factor, heat stable cytostatic factors and interferon in the circulation of mice treated with Corynebacterium parvum 14 days earlier. It is concluded that these and other data provide indirect but circumstantial evidence for a role of vasoamines in the induction of hyperemia and hemorrhagic necrosis by endotoxin. The latter two effects are probably causally related. It is suggested that non-toxic vasoamines may be useful adjuvants to other treatments of cancer.

Animals↗
PubMed1984

Role of mononuclear phagocyte function in endotoxin-induced tumor necrosis.

The temporal susceptibility of tumors to induction of necrosis and regression by endotoxin was investigated further with a focus on the role of the putative mediator, tumor necrosis factor (TNF). Production of this factor was shown earlier to require prior activation of the mononuclear phagocytic system (MPS). Transplants of Meth A sarcoma or MOPC315 plasmacytoma had no consistent effect on parameters of MPS function such as hepatosplenomegaly, carbon clearance and non-specific antibacterial resistance at times that they were sensitive to induction of necrosis. Moreover, TNF, quantified by its necrotizing and regressing activity in vivo, could not be detected in the serum of tumor hosts after a necrotizing dose of endotoxin, while much smaller volumes of serum with TNF (TNS) of appropriately treated donor mice showed activity. As repeated incubation of TNS with Meth A cells at 37 degrees C hardly removed its in vivo activity against Meth A, immediate absorption of produced TNF to the tumor cell mass seems a less likely cause. Cytostatic activity, another property attributed to TNF, was hardly increased in post-endotoxin tumor host serum, while TNS is highly cytostatic. It is concluded that induction of tumor necrosis is not dependent on MPS activation. A role of TNF as mediator of the effects of endotoxin still remains uncertain. Furthermore, the present and other data suggest that TNF, like endotoxin, probably acts by an indirect mechanism against tumors in vivo.

Animals↗
PubMed1984

Endotoxin-induced antitumor activity in the mouse is highly potentiated by muramyl dipeptide.

The ability of aqueous solutions of various endotoxin preparations, muramyl dipeptide (MDP) and combinations of endotoxin and MDP, to induce necrosis and regression of subcutaneous Meth A transplants in mice and their toxicity were studied. While intravenously injected toxic endotoxins, in contrast to a detoxified preparation and to MDP, induced considerable necrosis and regression of their own, addition of MDP potentiated the antitumor potential of both toxic and detoxified endotoxins to the same high degree. Detoxified endotoxin combined with MDP, however, was far less toxic than toxic preparations alone or combined with MDP. This indicates that toxicity is not directly related to therapeutic potential.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1983

Antitumour activity of endotoxin, concanavalin A and poly I: C and their ability to elicit tumour necrosis factor, cytostatic factors, and interferon in vivo.

Concanavalin A, endotoxin, poly I: C, and tumour necrosis serum (TNS) were compared for antitumour activity against Meth A sarcoma transplanted in syngeneic BALB/c mice and their capacity to induce tumour necrosis factor (TNF), heat-stable cytostatic factors, and heat-labile interferon in the blood of normal and Corynebacterium parvum-pretreated mice. All the agents induced hyperemia and inhibition of mitosis at 4 h, and by 24 h many tumours had a dark necrotic centre. Subsequent tumour growth was inhibited and in some of the treated mice tumours regressed completely. Poly A: U and normal mouse serum did not induce regression and their effects were less marked in all other respects, suggesting that these events may be linked. The necrotizing effects of concanavalin A and poly I: C are unlikely to be mediated by TNF, because neither agent could mimic endotoxin in eliciting RNase-resistant necrotizing and regressing activity in the serum of mice pretreated with C. parvum. Poly I: C did not induce strong cytostatic activity in the sera of C. parvum-treated mice, and for this and other reasons these factors are unlikely to be responsible for the observed effects. Concanavalin A, endotoxin, and poly I: C induced high levels of serum interferon but purified interferon had only weak antitumour activity in the Meth A system, suggesting that interferon may not be the mediator. From these and other data it is concluded that there is no clear relationship between the capacity of the agents to induce tumour necrosis and their capacity to elicit TNF, cytostatic factors, and interferon.

Animals↗
PubMed1983

Impaired macrophage functions as a possible basis of immunomodification by microbial agents, tilorone and dimethyldioctadecylammonium bromide.

Four microbial and two chemically defined immunomodulating agents namely viable BCG, killed Mycobacterium butyricum, killed Lactobacillus plantarum, zymosan, tilorone, and dimethyldioctadecylammonium bromide (DDA) were studied for their effects on macrophage functions in vitro and in vivo. All agents induced a dose-dependent mortality of macrophages as determined by trypan blue exclusion. DDA and especially tilorone were rather toxic for macrophages in vitro. All agents except tilorone and DDA inhibited phagocytosis of yeast cells and uptake of acridine orange in vitro at doses which killed up to about 30% of the macrophages. DDA and tilorone had no effect at similar doses. All agents but zymosan inhibited the spreading of macrophages. No interference with the fusion of lysosomes and yeast cell-containing phagosomes could be observed. The activity of the mononuclear phagocytic system (MPS) in vivo as measured by carbon clearance was stimulated by all substances within twenty-four hours. All agents but DDA and tilorone enhanced non-specific bacterial resistance. As demonstrated previously for DDA, tilorone could serve as adjuvant for induction of specific resistance to Listeria monocytogenes. The results are discussed in relation to other data on influencing of macrophage functions and on immunomodification. It is concluded that hampered antigen destruction by local macrophage suppression attended with MPS stimulation might be a basic mechanism for adjuvanticity exerted by these agents.

Adjuvants, Immunologic↗
PubMed1982

Endotoxin-induced release of tumour necrosis factor and interferon in vivo is inhibited by prior adrenoceptor blockade.

The effect of alpha- and beta-adrenoceptor blocking agents on endotoxin-induced release of tumour necrosis factor (TNF), and of interferon in the circulation of Corynebacterium parvum-treated mice was the subject of this study. TNF was quantified after injection of TNF containing heated serum (TNS) into Meth A sarcoma-bearing mice by determining colour, extent, and incidence of haemorrhagic necrosis. The release of TNF was weakly inhibited by the competitive alpha-blocker phentolamine and the beta-blocker propranolol. The non-competitive alpha-blocker phenoxybenzamine inhibited to a higher degree. Endotoxin-induced elicitation of growth-inhibiting principles into TNS was antagonized by propranolol and phenoxybenzamine. Administration of adrenaline before endotoxin inhibited the elicitation of TNF and growth-inhibitory activities, which indicates tachyphylaxis. The release of interferon was effectively inhibited by both alpha-adrenoceptor blockers but not by propranolol. The interferon was heat-labile. The results indicate that endotoxin-induced TNF and interferon are separate factors, elicited in different ways. As both alpha-blockers do not only inhibit reactions at the alpha-adrenergic receptor but also reactions at the serotonin receptor and in the case of phenoxybenzamine also at the choline receptor, it is suggested that endotoxin-induced release of the anti-tumour factors is controlled by reactions mediated by one or more of these receptors. It is suggested that the inhibition of TNF release by propranolol may be due to the membrane-stabilizing activity of this agent.

Animals↗
PubMed1982

Effect of adrenoceptor blockade on hemorrhagic necrosis of meth A sarcomata induced by endotoxin or tumor necrosis serum.

An intravenous injection of endotoxin into BALB/c mice bearing subcutaneous Meth A sarcomata caused hemorrhagic necrosis and reduced growth of the tumors. In a number of instances this was followed by regression. alpha-Adrenergic blockade with phentolamine prior to endotoxin did not influence tumor growth, but tended to reduce the incidence of regression when compared to mice merely treated with endotoxin. The frequency of hemorrhagic necrosis was not changed, although the extent of necrosis was somewhat reduced. The alpha-adrenoceptor blocking agent phenoxybenzamine nullified the growth retardation induced by endotoxin and reduced the frequency of regression. Moreover both incidence and extent of necrosis were diminished. Beta-adrenoceptor blockade with propranolol seems to potentiate the effect of endotoxin on tumor growth in the highest dose, but had no substantial effect on the necrotizing activities of endotoxin. Both alpha-blocking agents impaired induction of hemorrhagic necrosis and nullified tumor growth inhibition by tumor necrosis serum (TNS). beta-Adrenoceptor blockade decreased only the incidence of necrosis induced by TNS. Regressing tumors had considerably more hemorrhagic necrosis irrespective of pretreatment, excepted phenoxybenzamine. A single injection of the latter agent caused a dose-dependent stimulation of tumor growth, while the other agents exerted no effect. It is suggested that both normal and endotoxin-modified tumor growth are under alpha-adrenergic control and that induction of hemorrhagic necrosis is possibly mediated by release of adrenal catecholamines.

Animals↗
PubMed1982

Influence of adrenoceptor blockade on endotoxin-induced histopathological changes in murine Meth A sarcoma.

Histological examination of subcutaneous murine Meth A sarcomata 4 h after administration of endotoxin revealed an overt but superficial vasodilation, which had largely disappeared after 24 h. At this time hemorrhagic necrosis could be observed in that region mainly featured by degenerating tumour cells, diffuse hemorrhage and blood vessels filled with a yellow substance probably derived from disintegrated erythrocytes. Administration of the alpha-adrenoceptor antagonist phenoxybenzamine or the beta-adrenoceptor antagonist propranolol caused decrease of vasodilation at 4 h but an increase at 24 h especially after phenoxybenzamine. Only the latter agent prevented the induction of hemorrhagic necrosis by endotoxin. Endotoxin reduced tumour size within 24 h, which was prevented by both adrenoceptor blocking agents. Administration of these agents alone even enhanced tumour size. Mitotic activity of Meth A sarcoma was greatly reduced already 4 h after endotoxin injection. This was not significantly changed by both adrenoceptor antagonists, while these agents alone probably stimulate tumour cell division between 4 and 24 h after administration. The histological data are discussed in relation to earlier data on the influence of adrenoceptor blockade on endotoxin-induced hemorrhagic necrosis and tumour regression.

Adrenergic alpha-Antagonists↗
PubMed1981

Effects of lactobacilli on parameters of non-specific resistance of mice.

The viability of Lactobacillus plantarum in vivo and the effects of viable and heat-killed lactobacilli on parameters of non-specific resistance were studied. After intravenous administration of 10(8) viable lactobacilli, which is a dose with optimal adjuvant activity, viable lactobacilli could be isolated from spleens for more than 1 week and from livers and lungs for more than 3 weeks. Both viable and heat-killed lactabacilli stimulated the clearance of colloidal carbon, viable bacteria stimulated initially to a higher extent. Doses of 10(8) viable and heat-killed lactobacilli, but not less, stimulated non-specific resistance to Listeria monocytogenes and caused splenomegaly. Doses as small as 10(5) viable and heat-killed lactobacilli induced substantial natural killer (NK) cell activity in the peritoneal exudate 4 days after i.p. administration. Higher doses generally caused a dose-dependent increase of NK cell activity. Viable lactobacilli injected in the paw and to a lesser extent heat-killed bacteria caused a proliferative response in the draining popliteal lymph node, which peaked at day 5. Results are discussed in relation to adjuvanticity and comparisons are made with bacterial agents already used in immunotherapy.

Adjuvants, Immunologic↗