Immune responses during human Schistosomiasis mansoni. XI. Immunologic status of patients with acute infections and after treatment

Sixteen patients, 8 to 30 yr of age, with acute (toxemic) phase schistosomiasis mansoni were studied immunologically within 2 to 3 mo of their exposure to Schistosoma mansoni cercariae, and were monitored after chemotherapy. Total leukocyte levels and peripheral blood eosinophilias were higher in these patients than in similar individuals with chronic schistosomiasis mansoni. In contrast to chronic patients, the eosinophilias of the acute cases were decreased rather than elevated upon treatment. Total lymphocyte population (T and B cell) percentages were not altered during acute infection. Lymphoid subset (T3+, T4+, and T8+) analysis revealed elevated levels of both T4+ and T8+ cells. In vitro blastogenic responses of peripheral blood mononuclear cells (PBMN) to heterogeneous schistosome-derived antigens (eggs, SEA; adult worms, AW; and cercariae, CERC) were evaluated. SEA responsiveness was considerably higher than that of patients with chronic S. mansoni infections. The ratios of SEA to AW responses in acute cases gave a mean of 2.0, as opposed to 0.5 for a comparable group of chronically infected patients. The sera of most acute patients already contained suppressive factors that specifically decreased schistosomal antigen-induced PBMN blastogenesis. Chemotherapy of acute cases lead to a diminution of PBMN responsiveness to SEA and CERC. Treatment of patients with chronic infections lead to the elevation of such responses. PBMN from patients with acute infections produced lymphokine leukocyte inhibition factor upon exposure of the cells to SEA but not AW. A similar pattern was true for production of the lymphokine activity mitogenic factor. Levels of antibody in sera of acutely infected patients against SEA, CERC, and AW were considerably higher than levels in sera of chronically infected patients matched for age and intensity of their infections. These high antibody titers persisted for at least 6 mo after treatment, and were unrelated to the intensity of infection. The immunologic status of these patients with acute schistosomiasis mansoni differed considerably from patients with chronic infections. These findings re-emphasize the immunoregulatory events that apparently develop upon continued exposure to schistosomes and their products during chronic infection.     

Immune responses during human schistosomiasis mansoni. VI. In vitro nonspecific suppression of phytohemagglutinin responsiveness induced by exposure to certain schistosomal preparations.

Simultaneous in vitro exposure of human peripheral blood mononuclear cells to phytohemagglutinin-P (PHA) and either soluble schistosomal egg antigenic preparation (SEA) or soluble cercarial antigenic preparation (CAP) obtained from Schistosoma mansoni resulted in decreased responsiveness as compared to exposure to PHA alone. The addition of a soluble adult worm antigenic preparation (SWAP) did not predictably alter PHA responses in this system. The suppression due to in vitro exposure to either SEA or CAP was expressed whether the lymphocyte donors were S. mansoni patients (early infection, chronic, or treated), or uninfected subjects. The degree of suppression was related to the concentration of SEA used, and the timing of exposure. Preexposure to SEA for 3 days before the addition of PHA resulted in more potent suppression. However, a delay in the time of the addition of SEA of 6 and 24 hr after PHA exposure decreased and eliminated, respectively, its suppressive capacity. SEA and CAP were not directly toxic to responding cells, and appeared to exert their nonspecific suppressive influences through T lymphocyte-related mechanisms. It was observed that although these suppressive events could be induced and observed in vitro, the responsiveness of S. mansoni patient lymphocytes to PHA was equal with that of uninfected controls.     

Histamine-induced suppressor factor (HSF): effect on migration inhibitory factor (MIF) production and proliferation.

Histamine added in vitro to cultures of sensitized lymphocytes suppresses antigen-induced production of migration inhibitory factor (MIF) and proliferation by these cells. Recent studies have suggested that lymphocytes bearing histamine type-2 receptors play a regulatory role in these in vitro responses. The present studies were undertaken to determine if suppressor function by cells having histamine receptors was mediated through a soluble product. It was found that lymph node cells from nonimmune or immune strain 2 guinea pigs elaborate a nondialyzable factor into the culture supernatant when incubated with 10(-3) to 10(-5) M histamine (histamine-induced suppressor factor of HSF). HSF, when cocultured with sensitized lymphocytes, suppressed their MIF and proliferative responses to antigen. HSF was made by lymphocytes but not macrophages. Its production could be blocked by an H2 receptor antagonist (burimamide) but not an H1 receptor antagonist (chlorpheniramine). Furthermore, the inhibitory effect of HSF was reversible as lymphocytes washed free of the factor after 24 hr and recultured with fresh medium and antigen were able to produce MIF. Gel filtration by Sephadex G-100 chromatography indicated that HSF had an approximate m.w. of 23,000 to 40,000. These results suggest that the release of histamine at the sites of immediate hypersensitivity reactions, possibly by generating HSF activity, may play a regulatory role in the subsequent development of cellular-immune reactions at the same site.     

Immunoregulation in experimental schistosomiasis: in vitro induction and assay of spleen cell suppressor activity

Spleen cells from normal CBA/J mice or mice infected with Schistosoma mansoni were exposed for 48 to 72 hr to either concanavalin A (Con A), soluble egg antigen (SEA), or soluble worm antigenic preparation (SWAP), treated with mitomycin C to prevent further DNA synthesis, and admixed with either normal or sensitized syngeneic spleen cells exposed to a concentration gradient of phytohemagglutinin (PHA) or SEA, respectively. Both nonspecific (by Con A) and "antigen-specific" (by SEA and SWAP in infected mice only) induction of suppression was observed when using PHA-induced blastogenesis as the final assay. The number of mice with inducible splenic suppressive activity and the degree of PHA suppression induced by exposure to SEA appeared to decline between 8 and 20 weeks of infection. In contrast, when the response of spleen cells from mice infected for 8 weeks to SEA served as the final assay, strong suppressive activity was induced from the spleen cells of all chronically infected mice (20 weeks of infection). This model permits parallel analysis of the induction of suppressor activity by nonspecific and schistosome antigen-specific signals during the course of this chronic, immunoregulated condition, schistosomiasis mansoni.     

Phenotypic and functional evaluation of suppressor cells in normal pregnancy and in chronic aborters

To evaluate the potential role of immunoregulatory cells modulating the maternal immunologic response during pregnancy, we carried out phenotypic and functional studies in patients with normal obstetrical histories during each trimester and in patients with chronic idiopathic spontaneous abortions. Using monoclonal antibodies (Ortho), total numbers of T cells (T3+) and T4+ cells progressively increased during pregnancy (compared to nonpregnant controls) and then declined in the third trimester. Increased percentages of T8+, T10+, and Ia+ cells were found in the third trimester. The relative decline in numbers of T4+ cells, with increased numbers of T8+ cells, led to a significantly reduced T4/T8 ratio in the third trimester. Histamine receptors on T cells were quantitated by an immunofluorescent technique. Significantly reduced numbers of H1-type receptors were noted during the second trimester of pregnancy and this was associated with a decreased H1/H2 ratio. Functionally, histamine-induced suppression was measured in a lymphocyte proliferation assay. Patients in the first and second trimester of pregnancy had greater histamine-induced suppression of phytohemagglutinin (PHA)-stimulated proliferation at high concentrations of histamine (10(-3) to 10(-7)) but less suppression at the lower concentrations (10(-9) to 10(-11) M), compared to nonpregnant controls. In contrast, patients studied in the third trimester failed to respond to any concentration of histamine. MLC-induced suppressor activity was generated by incubating the maternal cells with either paternal or third-party mononuclear cells for 2 or 6 days and assaying the cell-free supernatant for its suppressive effects on PHA-stimulated proliferation. Maternal responses to paternal cells did not result in significant suppression in 2-day supernatants during any trimester but by 6 days the suppressive activity was equivalent to non-pregnant controls in patients during the first and second trimester. Maternal responses to third party cells was greater during the second trimester than either the first or third trimesters in both 2- and 6-day supernatants. Patients with histories of chronic idiopathic spontaneous abortions, who were not pregnant at the time of study, exhibited normal numbers of T-cell subsets and T4/T8 ratios. Numbers of both H1 and H2 receptor bearing T cells were proportionally reduced, resulting in a normal H1/H2 ratio. Despite having decreased numbers of H1 and H2 receptor bearing cells, histamine-induced suppression of PHA-stimulated proliferation was comparable to nonpregnant controls over the concentration range (10(-3) to 10(-11) M) employed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Selective stimulation of histamine H3 autoreceptors

A simple derivative of histamine, alpha-methylhistamine i.e. 4-(2-aminopropyl)-imidazole, was shown to potently inhibit the K+-induced release of [3H] histamine from slices of rat cerebral cortex previously incubated in the presence of [3H] histidine. The maximal inhibition elicited by alpha-methylhistamine was of about 60% i.e. similar to that elicited by exogenous histamine. The effect occurred with an EC50 value of 4.3 +/- 1.1 X 10(-9) M about 10 times lower than that of histamine and was reversed by a H3-receptor antagonist. Since alpha-methylhistamine is known to display negligible potency at H1- and H2-receptors, this compound appears to be the first highly potent and selective H3-receptor agonist to be identified.     

Histamine H2-receptor-mediated regulation of human natural killer cell activity

We have investigated effects of histamine on the spontaneous cytotoxic activity of human natural killer (NK) cells in vitro. Addition of histamine (10(-3) to 10(-7) M) to assay cultures of Percoll-fractionated mononuclear cells (MNC) and erythroleukemic K 562 target cells resulted in a strong enhancement of the cytotoxicity of low-density MNC, enriched for NK cell cytotoxicity (NKCC). No enhancing or suppressing effects of histamine could be detected after removal of monocytes/adherent cells from the effector cell suspensions. When unfractionated MNC were used as NK effectors, similar results were obtained, i.e., dose-dependent enhancement of NKCC by histamine in the presence of monocytes and lack of effect in nonadherent effector cells. Freshly isolated monocytes displayed low spontaneous cytotoxicity against K 562 targets and were not induced by histamine. The histamine-induced enhancement was mimicked by dimaprit, a specific histamine H2-receptor agonist, but not by N-methyldimaprit, a chemical control for H2-receptor agonist activity of dimaprit. Furthermore, the enhancement was completely antagonized by the specific histamine H2-receptor antagonists cimetidine and ranitidine. The effect of histamine could not be ascribed to endogenous interferon (IFN) production, since no IFN activity could be detected in histamine-treated MNC effectors. Also, the enhancing effects of histamine and human leukocyte IFN-alpha were clearly additive. On the basis of these findings, we suggest that histamine, via specific activation of H2 receptors, may be an important regulator of human NK cell activity.     

日本血吸虫病患者血清对血吸虫卵和成虫抗原的免疫反应

用免疫印渍术分析了33例确诊为日本血吸虫病患者血清对日本血吸虫虫卵抗原(SEA)和成虫抗原(SWAP)的免疫反应,发现患者血清对虫卵和成虫抗原的敏感性分别为100％和97％,而正常人血清则无反应,大多数病例(28/33)血清和SEA抗原反应后,印渍谱上于180,54和32kD处显现较宽区带;对SWAP而言,多数病例(26/32)则在190及64kD处显现区带;而急性患者(21/24)还可在34kD处检出一条较宽区带。这些结果提示了免疫印渍术在日本血吸虫病临床诊断上的价值。     

Histamine modulation of eosinophil migration.

Preincubation of eosinophils with 10(-5) M or higher concentrations of histamine inhibited the eosinophil chemotactic response to endotoxin-activated serum whether by using the nucleopore filter assay and counting the cells migrating through the filter, or by using the Zigmond-Hirsch assay and counting the cells at each 10-mum interval. When the H2-receptor sites on the eosinophils were blocked by metiamide, the inhibitory capacity of histamine was prevented. Preincubation of eosinophils with 10(-6) M histamine increased the number of responding eosinophils to endotoxin-activated serum and this enhancement was blocked by an H1-receptor antagonist. Isoproteronol and aminophylline inhibited eosinophil movement and increasing concentrations of dibutryl cyclic AMP inhibited eosinophil migration. Concentrations of histamine that consistently resulted in inhibition of eosinophil movement stimulated an increase in cyclic AMP that was prevented by blocking the H2-receptor but not the H1-receptor. Thus, histamine-dependent inhibition of the eosinophil chemotactic response to other agents is mediated through the H2-receptor and is associated with an increase in the intracellular level of cyclic AMP whereas histamine dependent enhancement of eosinophil migration to other agents appears to be mediated through the H1-receptor. Eosinophils behave as a heterogeneous population as assessed by the ability of histamine to augment or inhibit cell migration. This may reflect differences in H1 to H2 receptor density or cell responsiveness to receptor stimulation. The chemoattractant activity of histamine itself is not influenced by H1 or H2 receptor antagonists, thus it is possible that an eosinophil has a third type of histamine receptor.     

A calmodulin antagonist inhibits histamine-stimulated acid production by isolated rat parietal cells

The role of calmodulin in the regulation of histamine-stimulated parietal cell function was studied in isolated rat parietal cells using [14C]aminopyrine uptake as a quantitative index of acid production. In enriched (77-87%) intact parietal cells the calmodulin antagonist naphthalene sulfonamide W 7 dose-dependently inhibited the response to 10(-4) M histamine (IC50: 2 X 10(-6) M). The mechanism of this inhibition was examined further with two other stimuli of H+-production: forskolin which directly activates the parietal cell adenylate cyclase without interacting at the histamine H2-receptor and dbcAMP which mimics the biological action of cAMP without preceding activation of adenylate cyclase. W 7 effectively inhibited the responses to 10(-4) M forskolin (IC50: 6 X 10(-7) M), 10(-3) M dbcAMP (IC50: 10(-6) M) and to 10(-2) M K+ (IC50: 3 X 10(-6) M). The action of W 7 followed non-competitive kinetics since the antagonist reduced the entire range of the concentration-response curves without shifting them rightwards towards higher concentrations of the respective stimulants. The effect of W 7 was reversed by washing the cells. ATP-induced [14C]aminopyrine uptake into digitonin-permeabilized oligomycin-inhibited parietal cells reflects H+-production independent of oxidative phosphorylation and was also inhibited by W 7 (IC50: 10(-5) M). Inhibition of K+-stimulated H+/K+-ATPase activity required even higher W 7-concentrations (IC50: 1.4 X 10(-4) M). Our data suggest that calmodulin might be involved in the intracellular mediation of the response to histamine. Between histamine-induced cAMP-generation and the H+-secreting tubulovesicular system W 7 seems to inhibit an intracellular step that finally activates the H+/K+-ATPase. Yet, direct inhibition of the ATPase requires W 7 concentrations of questionable specificity and is unlikely to be the mechanism behind the action of W 7 on the parietal cell response to histamine.     

Effect of synthetic cyclic nucleotides on immunologic histamine release from calf granulocytes.

Sensitized bovine granulocytes release histamine when exposed to specific antigens. A unique modulation of histamine release by adrenergic agents has been shown in the bovine; beta-adrenergic agonists enhance and alpha-adrenergic agonists inhibit histamine release. This is an opposite response to that reported in other species. The present study was undertaken to determine the possible relationship between cyclic nucleotides and adrenergic agents in this species. Dibutyryl cAMP enhanced antigen-induced histamine release over the complete concentration range tested (10(-6)--10(-3)M); it also overcame, in a dose-dependent manner, the inhibition of antigen-induced histamine release produced by 10(-4) M phenylephrine. The 8-bromo cGMP AND 0-MONOBUTYRYL CGMP had no significant effect on antigen-induced histamine release nor did 8-bromo-cGMP have any significant effect on the enhancement of histamine release produced by 10(-4) M dibutyryl cAMP. These findings suggest that only cAMP has a role in the modulation of antigen-induced histamine release from bovine granulocytes.     

Effects of histamine on contractile activity of lymphatic node capsules. The NO role

Effects of histamine (10(-9)--5 x 10(-5) M) on the phase and tonic contractile activity of capsular smooth muscles of isolated bovine mesentery lymph node were investigated. Dual dose-depended effect of histamine was found. Low concentrations of histamine less than 10(-7) M caused a decrease of contractile activity, whereas higher concentrations of histamine (more than 5 x 10(-7) M) resulted in increase of the phase and tonic contractions. Both H1- and H2-receptors of smooth muscle cells are involved in the response. Much of the relaxing histamine-induced response is produced by the stimulation of the endothelial cells. We believe that activating effect of histamine is due to the excitation of H1-receptors located on the membrane of myocytes, whereas its inhibitory effect occurs in two ways: 1) via excitation of H2-receptors located on the membrane of myocytes; 2) via stimulation of the NO production by the endothelial cells of lymph node sinus.     

Bronchial vasodilation by histamine in sheep: characterization of receptor subtype.

Histamine has been shown to mediate features of pulmonary allergic reactions including increased tracheobronchial blood flow. To determine whether the increase in blood flow was due to stimulation of H1- or H2-histamine receptors, we gave histamine base (0.1 micrograms/kg iv) or histamine dihydrochloride as an aerosol (10 breaths of 0.5% "low dose" or 5% "high dose") before and after H1- or H2-receptor antagonists. Blood velocity in the common bronchial branch of the bronchoesophageal artery (Vbr) was continuously measured using a chronically implanted Doppler flow probe. Pretreatment with H2-receptor antagonists cimetidine, ranitidine, or metiamide did not affect the increase in Vbr induced by intravenous histamine [106 +/- 45% (SD)]. Addition of the H1-receptor antagonists diphenhydramine or chlorpheniramine, however, reduced the Vbr response to 16 +/- 22, 21 +/- 28, 23 +/- 23, and 37 +/- 32% of the unblocked responses (P less than 0.05) when intravenous histamine was given at 3, 10, 20, and 30 min, respectively, after the H1 antagonist. At 40, 50, and 60 min the H1-receptor blockade appeared to attenuate, but subsequent continuous infusion of chlorpheniramine (2 mg.kg-1.min-1) then blocked the histamine response for 60 min. Low-dose histamine aerosol did not change mean arterial or pulmonary arterial pressures, cardiac output, or arterial blood gases but increased Vbr transiently from 15.2 +/- 3.4 to 37.6 +/- 8.4 (SE) cm/s. After chlorpheniramine, the Vbr response to histamine, 16.3 +/- 2.2 to 22.6 +/- 3.6 cm/s, was significantly reduced (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of adenosine and verapamil on histamine vascular contractions

The present study was undertaken to compare the effects of adenosine and verapamil on histamine-induced contractions in rabbit vascular smooth muscle. Ring segments of rabbit femoral artery were isometrically mounted and contractile responses to histamine (10(-7) to 10(-4) M) were recorded. Verapamil (10(-5) to 10(-4) M) and adenosine (10(-5) to 10(-4) M) produced significant (P less than 0.05) shifts to the right of the histamine dose-response curve in normal physiological salt solution (PSS). Adenosine (10(-4) M) had no effect on the contractile responses to histamine in calcium-deplete PSS but significantly (P less than 0.01) increased the rate of relaxation (-dT/dt, 16.1 +/- 2.3 mg/s before adenosine, 53.7 +/- 7.0 mg/s during adenosine). In calcium-free PSS, verapamil (10(-4) M) had no effects on histamine-induced contractions, nor did it affect the spontaneous rate of relaxation. These findings suggest that the relaxant responses to adenosine, like verapamil, are partially mediated through blockade of external calcium influx, while adenosine, unlike verapamil, appears to have an additional intracellular mode of action.     

Mechanism of histamine-induced inhibition of lymphocyte response to mitogens in mice

Histamine induced, in mice, an inhibition of lymphocyte response to PHA and LPS, at molar concentrations ranging from 10^?3 to 10^?9M. This inhibition occurs as a specific interaction between histamine and T lymphocytes bearing H2-type receptors for this hormone (H + cells) and Ly 2 membrane antigens. Two features of the suppressive activity of this T-cell subpopulation were observed: (i) when histamine is added at the beginning of the culture period with PHA or LPS, it activates the suppressor activity of H + cells which act on the lymphocyte population responding to PHA and LPS; (ii) preincubation of spleen lymphocytes with histamine for 24 hr induces suppressor cells which inhibit the response to PHA, but not to LPS, of syngeneic lymphocytes in a coculture system, and which are radiosensitive. The role of PHA as a second stimulus of histamine-induced suppressor cells, and the relation between these cells and PHA or Con A-induced suppressor cells, are discussed.     

Histamine H1- and H2-receptors in canine renal artery in vivo and in vitro

The present work investigates (a) the modification by pretreatment with selective H1- and H2-receptor antagonists on the dose-response curves (DRC) to histamine for heart rate, blood pressure, renal arterial blood flow and renal vascular resistance in anesthetized dogs, and (b) the characteristics of the DRC to histamine in canine isolated renal artery. In vivo, pretreatment with metiamide (10 mg/kg i.v.) did not modify the DRC to histamine. In contrast, significant rightward shift of the DRC to histamine for all the hemodynamic parameters was observed after diphenhydramine (5 mg/kg i.v.). Combined pretreatment with metiamide and diphenhydramine resulted in further rightward displacement of the DRC to histamine. Analysis of the DRC to the relaxant effect of histamine in depolarized (K+ 67 mM) isolated canine renal artery yielded an ED50 of 3.3 x 10(-4) M and a Hill coefficient of 1.74. The results demonstrate the existence of the two types of histamine receptors, H1 and H2, in the renal artery of the dog, both mediating dilator responses, although the H1-receptor appears to predominate.     

Multiple signaling pathways of histamine H2 receptors. Identification of an H2 receptor-dependent Ca2+ mobilization pathway in human HL-60 promyelocytic leukemia cells

In order to analyze the complex activities of histamine H2 receptor activation on neutrophils, human HL-60 promyelocytic leukemia cells were differentiated into neutrophils by incubation with dimethyl sufoxide, loaded with the Ca2+-sensitive indicator dyes, indo-1 or fura-2, and the levels of intracellular Ca2+ ([Ca2+]i) measured in a fluorescent-activated cell sorter and fluorimeter, respectively. Histamine increased [Ca2+]i in a dose-dependent manner with a half-maximal concentration (EC50) of approximately 10(-6) to 10(-5) M, which exhibited H2 receptor specificity. Prostaglandin E2 and isoproterenol also induced [Ca2+]i mobilization in HL-60 cells, whereas the cell permeable form of cAMP and forskolin failed to increase [Ca2+]i. Since H2-receptor mediated [Ca2+]i mobilization was not inhibited by reducing the concentration of extracellular Ca2+ nor by the addition of Ca2+ channel antagonists, LaCl3 and nifedipine, [Ca2+]i mobilization is due to the release of Ca2+ from intracellular stores. Furthermore, both 10(-4) M histamine and 10(-6) M fMet-Leu-Phe increased the levels of 1,4,5-inositol trisphosphate. However, histamine-induced mobilization of [Ca2+]i was inhibited by cholera toxin but not by pertussis toxin, whereas the action of fMet-Leu-Phe was inhibited by pertussis toxin but not by cholera toxin. These data suggest that H2 receptors on HL-60 cells are coupled to two different cholera toxin-sensitive G-proteins and activate adenylate cyclase and phospholipase C simultaneously.     

Immune responses to a soluble schistosomal egg antigen preparation during chronic primary infection with Schistosoma mansoni.

Murine schistosomiasis mansoni is characterized by an intense, predominantly cell-mediated, anti-egg, granulomatous response to schistosomal egg antigens (SEA). Anti-SEA responses include lymphocyte blastogenesis, the production of the lymphokine eosinophil stimulation promoter (ESP), hemagglutinating antibody, heat-labile and heat-stable, 72-hr passive cutaneous anaphylaxis (PCA) antibodies, and pronounced peripheral blood eosinophilia. These responses were followed during the course of chronic (1 year) infection and analyzed with specific reference to the observed diminution of granuloma formation, in the presence of continued antigenic exposure, which occurs by 10 to 12 weeks after infection and persists during long-term schistosomiasis. Lymphocyte blastogenesis and peripheral blood eosinophilia were positive from the 8th week of infection until the 50th. Lymphokine production and circulating heat-labile PCA antibody were only positive for a few weeks after 8 weeks of infection. In contrast, hemagglutinating antibody and heat-stable, 72-hr PCA antibody increased during weeks 10 to 14 and remained high throughout chronic infection. The development and regression of these various immune responses to SEA indicate that there are several potential mechanisms that could explain the immunoregulatory interactions that result in specifically diminished lesion formation in this chronic infection.     

Cytokine profile associated with chronic and acute human schistosomiasis mansoni

The production and regulation of interleukin (IL) IL-13, IL-4 and interferon-gamma (IFN-gamma) was evaluated in 43 schistosomiasis patients with different clinical forms. Whole-blood cultures cytokine production in response to soluble egg antigen (SEA), soluble worm adult preparation (SWAP), mitogens, neutralizing antibodies or recombinant IL-13 were measured by ELISA. After SWAP stimulation, chronic patients, particularly hepatointestinals, produced higher levels of IL-4 in comparison with acute patients, suggesting the presence of a type 2 cytokine profile in these patients. Following SEA and SWAP stimulation, hepatosplenic (HS) patients showed increased levels of IFN-gamma when compared with acute patients, indicating that HS disease in humans is associated with a type 1 cytokine response. The mechanisms of immune regulation are apparently different between the clinical stages of the disease, some of which are antigen-specific.     

Neuronal histamine release elicited by hyperthermia mediates tracheal dilation and pressor response

Whether brain histaminergic neurons contribute to the regulation of tracheal tone and peripheral vascular tone under hyperthermia was investigated in anesthetized rabbits. Histamine release from the rostral ventrolateral medulla (RVLM), the raphe nuclei, and the solitary nucleus of the medulla oblongata was significantly increased by hyperthermia. The increased histamine was significantly suppressed by 10(-6) M tetrodotoxin microdialyzed in each area. Tracheal pressure and mean arterial pressure were significantly decreased and increased by hyperthermia, respectively. An H(1)-receptor antagonist, 5 x 10(-6) M (+)-chlorpheniramine, bilaterally microdialyzed in the RVLM significantly enhanced histamine release in the RVLM as well as significantly suppressed tracheal dilation and pressor response caused by hyperthermia. These data indicate that histamine release in the medulla oblongata is enhanced by hyperthermia. The enhanced histamine is the neuronal origin and the cause of tracheal dilation and pressor response at least via H(1) receptors in the RVLM. Brain histaminergic neurons play important roles in tracheal tone and peripheral vascular tone via H(1) receptors in the RVLM and homeostasis on body temperature.