Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice.

Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR(-/-) mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.

Wnt-induced secreted protein-1 is a prohypertrophic and profibrotic growth factor.

Wnt1-induced secreted protein-1 (WISP-1) is a member of the cysteine-rich 61, connective tissue growth factor, and nephroblastoma overexpressed (CCN) family of growth factors and is expressed in the heart at low basal levels. The purpose of this study was to investigate whether WISP-1 is upregulated in postinfarct myocardium and whether WISP-1 exerts prohypertrophic and mitogenic effects stimulating myocyte hypertrophy, cardiac fibroblast (CF) proliferation, and collagen expression. Male C57Bl/6 (25 g) mice underwent permanent occlusion of the left anterior descending coronary artery. mRNA and protein levels were analyzed by Northern and Western blot analyses. Cardiomyocyte hypertrophy was quantified by protein and DNA synthesis. CF proliferation was quantified by CyQuant assay, and soluble collagen release by Sircol assay. A time-dependent increase in WISP-1 expression was detected in vivo in the noninfarct zone of the left ventricle, which peaked at 24 h (3.1-fold, P < 0.01). Similarly, biglycan expression was increased by 3.71-fold (P < 0.01). IL-1beta and TNF-alpha expression preceded WISP-1 expression in vivo and stimulated WISP-1 expression in neonatal rat ventricular myocytes in vitro. WISP-1-induced cardiomyocyte hypertrophy was evidenced by increased protein (2.78-fold), but not DNA synthesis, and enhanced Akt phosphorylation and activity. Treatment of primary CF with WISP-1 significantly stimulated proliferation at 48 h (6,966 +/- 264 vs. 5,476 +/- 307 cells/well, P < 0.01) and enhanced collagen release by 72 h (18.4 +/- 3.1 vs. 8.4 +/- 1.0 ng/cell, P < 0.01). Our results demonstrate for the first time that WISP-1 and biglycan are upregulated in the noninfarcted myocardium in vivo, suggesting a positive amplification of WISP-1 signaling. WISP-1 stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and ECM expression in vitro. These results suggest that WISP-1 may play a critical role in post-myocardial infarction remodeling.

Early responses associated with chronic pathology in murine schistosomiasis.

Inbred male CBA/J mice infected with Schistosoma mansoni develop either hypersplenomegaly syndrome (HSS) or moderate splenomegaly syndrome (MSS) by 20 weeks of infection. Pathologically and immunologically, MSS and HSS closely parallel the intestinal and hepatosplenic clinical forms of schistosomiasis in humans, respectively. By 6 weeks after infection, mice that eventually will become MSS develop T cell-stimulatory, cross-reactive idiotypes (CRI) while HSS mice never produce CRI. Because presence of CRI is useful to predict degree of chronic pathology, we used this measure to investigate what other early immunological events occurred in animals destined to develop severe morbidity. At 8 weeks of infection, there was a strong inverse correlation between CRI and splenomegaly, egg counts, and liver hydroxyproline. Similarly, phorbol myristate acetate (PMA)- and ionomycin-stimulated intracellular cytokine expression of IL-4, IL-5, and GM-CSF in splenic CD4(+) T cells was inversely correlated with serum CRI and directly correlated with spleen size. In contrast, spleen cell intracellular TNF-alpha and peritoneal cell production of nitric oxide demonstrated positive correlations with CRI and inverse correlations with measures of morbidity. Surprisingly, IL-10 and IFN-gamma were not correlated with CRI levels. These studies link chronic pathology to certain immunological responses during the acute phase of schistosomiasis.

Comparison of Schistosoma mansoni irradiated cercariae and Sm23 DNA vaccines.

Immunization with defined antigens is generally less effective at inducing host protection against experimental infection with Schistosoma mansoni than vaccination with attenuated infective cercariae. We predicted that quantitative and/or qualitative differences existed between the immune responses generated to attenuated cercariae and those induced by defined antigens. Thus, we compared immune responses typically associated with protection in the murine model between animals vaccinated with attenuated cercariae and mice immunized with DNA encoding Sm23, a schistosome integral membrane protein that has previously been shown to confer protection. Mice vaccinated three times with attenuated cercariae demonstrated higher levels of protection than Sm23-vaccinated animals but spleen cells from Sm23 DNA vaccinated mice produced significantly higher levels of schistosome antigen-specific IFN-gamma. Both vaccines induced similar levels of Sm23-specific antibody and post-challenge dermal inflammation. However, the pulmonary inflammatory responses following challenge were much less pronounced in DNA immunized animals compared to those receiving irradiated cercariae. Thus, although Sm23 DNA vaccination effectively induced parasite-specific IFN-gamma and antibody responses, it failed to evoke other critical responses needed for optimal vaccine efficacy.

Role of 4-hydroxynonenal in modification of cytochrome c oxidase in ischemia/reperfused rat heart.

Mitochondrial dysfunction is a characteristic of ischemia/reperfusion (I/R) injury in the heart. While oxidative stress has been implicated in mitochondrial damage in I/R injury, the underlying mechanisms are unclear. 4-Hydroxynonenal (HNE) is a toxic aldehyde generated by lipid peroxidation. The purpose of the present study was to assess the role of HNE in I/R-induced damage of a crucial component of the mitochondrial electron transport chain, cytochrome c oxidase (COX). I/R was induced in male WKY rats by 15 mins of ischemia followed by reperfusion for up to 3 h. COX activity was measured spectrophotometrically at 550 nm. HNE adducts with COX subunits were detected by Western Blot using an HNE-histidine antibody. HNE and reduced glutathione (GSH) contents were measured in mitochondria by HPLC. Following 3 h of reperfusion, COX activity was reduced to 59% of control, accompanied by increases in HNE adducts with COX (P<0.05). Mitochondrial HNE content in reperfused hearts was increased to 165% of control, whereas GSH was decreased to 62% of control (P<0.05). After purified COX was incubated with HNE in vitro, COX activity was decreased progressively with increasing concentrations of HNE, accompanied by concentration-dependent formation of HNE adducts with COX. GSH prevented HNE adduct formation as well as COX inhibition by HNE. These results suggest that HNE, via adduct formation with COX subunits, plays an important role in COX dysfunction caused by reperfusion. The findings also indicate that decreases in mitochondrial GSH stores in reperfused myocardium could potentiate HNE-mediated COX damage.

Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine.

BACKGROUND: Mechanisms by which neutrophils are attracted to the myocardium in ischemia/reperfusion are not fully defined. Lipopolysaccharide-induced CXC chemokine (LIX), cytokine-induced neutrophil chemoattractant (KC), and macrophage inflammatory protein-2 (MIP-2) are rodent chemokines with potent neutrophil-chemotactic activity. The goals of the present study were to evaluate the roles of these chemokines in a rat model of ischemia/reperfusion and to examine the mechanisms of chemokine induction by oxidative stress and cytokines in cultured cardiomyocytes. METHODS AND RESULTS: Male Wistar-Kyoto rats underwent 45 minutes of ligation of the left anterior descending coronary artery, followed by reperfusion for various periods. Compared with sham-operated controls, myocardium from reperfused animals had higher levels of free radicals, increased neutrophil infiltration evidenced histologically and by elevated myeloperoxidase activity, and increased nuclear factor (NF)-kappaB DNA binding activity. Ischemia-reperfusion also induced the expression of interleukin-1beta, tumor necrosis factor (TNF)-alpha, LIX, KC, and MIP-2 mRNA and protein. LIX expression was localized to resident myocardial cells, whereas KC and MIP-2 were expressed only in infiltrating inflammatory cells. Neutralization of LIX inhibited 79% of neutrophil infiltration into previously ischemic myocardium. In contrast, neutralization of KC and MIP-2 reduced neutrophil infiltration by only 28% and 37%, respectively. In cultured cardiomyocytes, LIX expression was induced by oxidative stress or TNF-alpha and was blocked by the NF-kappaB inhibitor pyrrolidinedithiocarbamate. CONCLUSIONS: LIX is expressed by resident myocardial cells during ischemia-reperfusion and is induced in cultured cardiomyocytes by oxidative stress or TNF-alpha via NF-kappaB activation. Although KC and MIP-2 are expressed by inflammatory cells infiltrating the myocardium during reperfusion after ischemia, neutrophil recruitment to reperfused rat myocardium is mainly due to cardiomyocyte expression of LIX.

Differential Vbeta T-cell receptor usage during chronic experimental schistosomiasis corresponds with distinct pathological presentations.

CBA/J male mice with chronic Schistosoma mansoni infections display either moderate splenomegaly syndrome (MSS) or hypersplenomegaly syndrome (HSS). As MSS and HSS mice differ in several immunologic characteristics, we investigated T-cell receptor Vbeta usage. The groups had significantly different expression of several Vbetas, suggesting a relationship between the T-cell repertoire and schistosomiasis pathology.

Calorie restriction attenuates inflammatory responses to myocardial ischemia-reperfusion injury.

The life-prolonging effects of calorie restriction (CR) may be due to reduced damage from cumulative oxidative stress. Our goal was to determine the long-term effects of moderate dietary CR on the myocardial response to reperfusion after a single episode of sublethal ischemia. Male Fisher 344 rats were fed either an ad libitum (AL) or CR (40% less calories) diet. At age 12 mo the animals were anaesthetized and subjected to thoracotomy and a 15-min left-anterior descending coronary artery occlusion. The hearts were reperfused for various periods. GSH and GSSG levels, nuclear factor-kappaB (NF-kappaB) DNA binding activity, cytokine, and antioxidant enzyme expression were assessed in the ischemic zones. Sham-operated animals served as controls. Compared with the AL diet, chronic CR limited oxidative stress as seen by rapid recovery in GSH levels in previously ischemic myocardium. CR reduced DNA binding activity of NF-kappaB. The kappaB-responsive cytokines interleukin-1beta and tumor necrosis factor-alpha were transiently expressed in the CR group but persisted longer in the AL group. Furthermore, expression of manganese superoxide dismutase, a key antioxidant enzyme, was significantly delayed in the AL group. Collectively these data indicate that CR significantly attenuates myocardial oxidative stress and the postischemic inflammatory response.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors.

OBJECTIVE: To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors. METHODS: Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25-65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index. RESULTS: Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25-65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86-8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33-6.36). CONCLUSION: The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

Validation of a mouse conductance system to determine LV volume: comparison to echocardiography and crystals.

The application of left ventricular pressure-volume analysis to transgenic mice to characterize the cardiac phenotype has been problematic due to the small size of the mouse heart and the rapid heartbeat. Conductance technology has been miniaturized for the mouse and can solve this problem. However, there has been no validation of this technique. Accordingly, we performed echocardiography followed by simultaneous ultrasonic crystals, flow probe, and conductance studies in 18 CD-1 mice. Raw conductance volumes were corrected for an inhomogenous electrical field (alpha) and parallel conductance (G(pi)) yielding a stroke volume of 14.1 +/- 3.7 microliter/beat, end-diastolic volume of 20.8 +/- 6.5 microliter, and end-systolic volume of 9.0 +/- 5.8 microliter. The mean conductance volumes were no different from those derived by flow probe and echocardiography but did differ from ultrasonic crystals. G(pi) was determined to be 14.9 +/- 8.7 microliter. However, hypertonic saline altered dimension and pressure in the mouse left ventricle. Although G(pi) can be determined by the hypertonic saline method, saline altered hemodynamics, questioning its validity in the mouse. Although mean measures of absolute volume may be similar among different techniques, individual values did not correlate.

Development of a multifrequency conductance catheter-based system to determine LV function in mice.

Transgenic mice offer a valuable way to relate gene products to phenotype, but the ability to assess the cardiovascular phenotype with pressure-volume analysis has lagged. Conductance measurement offers a method to generate an instantaneous left ventricular (LV) volume signal in the mouse but has been limited by the volume signal being a combination of blood and LV muscle. We hypothesized that by developing a mouse conductance system that operates at several simultaneous frequencies, we could identify and correct for the myocardial contribution to the instantaneous volume signal. This hypothesis is based on the assumption that mouse myocardial conductivity will vary with frequency, whereas mouse blood conductivity will not. Consistent with this hypothesis, we demonstrated that at higher excitation frequency, greater end-diastolic and end-systolic conductance are detected, as well as a smaller difference between the two. We then empirically solved for LV blood volume using two frequencies. We combined measured resistivity of mouse myocardium with an analytic approach and extracted an estimate of LV blood volume from the raw conductance signal. Development of a multifrequency catheter-based system to determine LV function could be a tool to assess cardiovascular phenotype in transgenic mice.

Induction of nuclear factor kappaB but not kappaB-responsive cytokine expression during myocardial reperfusion injury after neutropenia.

Neutrophils may contribute to myocardial ischemia/reperfusion (I/R) injury by generating reactive oxygen intermediates (ROIs). ROIs activate nuclear factor (NF)-kappaB, which regulates genes for cytokines with negative inotropic effects (interleukin [IL]-1beta, IL-6, and tumor necrosis factor [TNF]-alpha). We investigated the impact of neutrophil depletion on NF-kappaB DNA binding activity, and expression of these cytokines during myocardial I/R injury. Male WKY rats (n = 28) received a single dose of antineutrophil antiserum (i/v). Twenty two hours later, when the peripheral blood neutrophil counts were profoundly decreased (94% reduction), the animals underwent 15 min of left anterior descending coronary artery ligation followed by reperfusion for 0.25, 0.5, 1, 2, 3, and 6 h (n = 4/group). Saline-treated animals underwent a similar protocol, and served as controls (n = 28, 4/group). Neutrophil accumulation, defined by myeloperoxidase activity, was present in controls, but not in anti-PMN antisera-treated animals (at least p <0.05 at 1, 2, 3, and 6 h R). Despite this difference, in both saline- and antiserum-treated animals, the GSH levels were very similar and fell significantly (p < 0.0001) at 15 min R; the levels increased gradually over time. In contrast, GSSG levels rose at 15 and 30 min R (p < 0.05), and declined thereafter. NF-kappaB DNA binding activity increased in both groups at 15 min and again at 3 h of R. Both NF-kappaBp50 and p65 subunits were detected by supershift assay. In saline-injected controls both mRNA and protein for IL-1beta, IL-6, and TNF-alpha were detected at 1 h R; levels remained high until 3 h, then fell (except IL-6, which was elevated at 6 h). In neutropenic animals, however, a significant decrease in mRNA (at least 1.7-fold, p < 0.05) as well as protein levels (at least 2. 3-fold, p < 0.01) for all three cytokines was observed. Thus, while neutrophils had minimal effects on oxidative stress (GSH/GSSG) and oxidative stress-responsive NF-kappaB activity, they contributed significantly to myocardial cytokine expression.

Differential regulation of nitric oxide synthase isoforms in experimental acute chagasic cardiomyopathy.

We have previously demonstrated induction and high level expression of IL-1beta, IL-6 and tumour necrosis factor-alpha in the myocardium during the acute stage of experimental Trypanosoma cruzi infection (Chagas' disease). The myocardial depressive effects of these cytokines are mediated in part by the induction of nitric oxide synthase (NOS), production of nitric oxide (NO) and formation of peroxynitrite. In this study we investigated the expression, activity and localization of NOS isoforms, and the levels of NO, malondialdehyde (a measure of oxidative stress), and peroxynitrite in rats at 1.5, 5, 10 and 15 days after infection with T. cruzi trypomastigotes. The myocardial inflammatory infiltrate and number of amastigote nests increased over the course of infection. A significant increase in tissue nitrate + nitrite levels, NOS2 mRNA, and NOS2 enzyme activity was observed at all time points in the infected compared with uninfected animals. The enzyme activity of constitutive NOS, tissue malondialdehyde levels, and NOS3 mRNA levels was only transiently increased after infection. The protein levels of the NOS isoforms paralleled their mRNA expression. While no positive nitrotyrosine immunoreactivity was detected in control myocardium, its levels increased in infected animals over time. Thus, by 1.5 days post-infection, when no parasite or immune cell infiltration could be detected, the myocardium expressed high levels of NOS and NO metabolites. Nevertheless, the early production of NO in the myocardium was not sufficient to clear the parasites.

beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling.

BACKGROUND: Whether beta-adrenergic blockade modulates myocardial expression of inflammatory cytokines and nitric oxide (NO) in heart failure is unclear. METHODS AND RESULTS: We administered oral metoprolol or no therapy to rats for 12 weeks after large myocardial infarction and subsequently examined left ventricular (LV) remodeling; myocardial tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 expression; and NO. In untreated rats, echocardiography revealed significant (P<0.001) LV dilatation and systolic dysfunction compared with sham. Papillary muscle studies revealed isoproterenol hyporesponsiveness to be unaltered by NO synthase (NOS) inhibition. Circulating NO metabolites were undetectable. In noninfarcted myocardium, although inducible NOS (iNOS) mRNA was absent, TNF-alpha, IL-1beta, and IL-6 mRNA and protein were markedly elevated compared with sham (P<0.001), with 2-fold higher expression (P<0.025) of IL-6 compared with TNF-alpha or IL-1beta. Metoprolol administration starting 48 hours after infarction (1) attenuated (P<0.02) LV dilatation and systolic dysfunction, (2) preserved isoproterenol responsiveness (P<0.025) via NO-independent mechanisms, and (3) reduced myocardial gene expression and protein production of TNF-alpha and IL-1beta (P<0. 025) but not IL-6, which remained high. CONCLUSIONS: During heart failure development, adrenergic activation contributes to increased myocardial expression of TNF-alpha and IL-1beta but not IL-6, and one mechanism underlying the beneficial effects of beta-adrenergic blockade may involve attenuation of TNF-alpha and IL-1beta expression independent of iNOS and NO.

Altered LV inotropic reserve and mechanoenergetics early in the development of heart failure.

To test the hypothesis that alterations in left ventricular (LV) mechanoenergetics and the LV inotropic response to afterload manifest early in the evolution of heart failure, we examined six anesthetized dogs instrumented with LV micromanometers, piezoelectric crystals, and coronary sinus catheters before and after 24 h of rapid ventricular pacing (RVP). After autonomic blockade, the end-systolic pressure-volume relation (ESPVR), myocardial O(2) consumption (MVO(2)), and LV pressure-volume area (PVA) were defined at several different afterloads produced by graded infusions of phenylephrine. Short-term RVP resulted in reduced preload with proportionate reductions in stroke work and the maximum first derivative of LV pressure but with no significant reduction in baseline LV contractile state. In response to increased afterload, the baseline ESPVR shifted to the left with maintained end-systolic elastance (E(es)). In contrast, after short-term RVP, in response to comparable increases in afterload, the ESPVR displayed reduced E(es) (P < 0.05) and significantly less leftward shift compared with control (P < 0.05). Compared with the control MVO(2)-PVA relation, short-term RVP significantly increased the MVO(2) intercept (P < 0.05) with no change in slope. These results indicate that short-term RVP produces attenuation of afterload-induced enhancement of LV performance and increases energy consumption for nonmechanical processes with maintenance of contractile efficiency, suggesting that early in the development of tachycardia heart failure, there is blunting of length-dependent activation and increased O(2) requirements for excitation-contraction coupling, basal metabolism, or both. Rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.

Short report: prevention of Schistosoma mansoni infections in mice by the insect repellents AI3-37220 and N,N-diethyl-3-methylbenzamide.

N,N-diethyl-3-methylbenzamide (DEET) has recently been reported to kill cercariae of Schistosoma mansoni in vitro. In addition, it blocked cercarial entry into mouse tail skin. We confirmed these results and compared the efficacy of DEET to a second insect repellent, 1-(3-Cyclohexen-1-yl-carbonyl)-2-methylpiperidine (AI3-37220), in preventing S. mansoni infections in mice. Both AI3-37220 and DEET conferred 100% protection against S. mansoni infection via percutaneous exposure to cercariae.

Neonatal exposure to idiotype induces Schistosoma mansoni egg antigen-specific cellular and humoral immune responses.

Exposure of neonatal mice to appropriate, cross-reactive Id (CRI) preparations alters immune responsiveness, ameliorates pathology, and prolongs survival of animals upon subsequent Schistosoma mansoni infection. However, because schistosome infections profoundly affect host immunobiology, which responses are effected by neonatal Id exposure alone and which responses are influenced by infection is unclear. To directly examine the schistosome soluble egg Ag (SEA)-specific immune responses altered by CRI exposure, neonatal mice were injected with CRI-expressing (CRI+) SEA-specific Ab preparations, SEA-specific Abs that did not express CRI (CRI-), or normal mouse Ig. At 9 wk of age, only mice that were neonatally exposed to CRI+ anti-SEA Abs displayed significant SEA-specific IgG serum levels and spleen cell proliferative responses. SEA-stimulated spleen cells from these CRI+-exposed mice also produced IFN-gamma, although not at significantly higher levels than mice receiving CRI- Id or normal mouse Ig. If CRI+-exposed mice were also injected with SEA at 8 wk of age, the 9-wk IFN-gamma responses were significantly higher than those of the other neonatal injection groups. The presence of both CRI and anti-CRI in the sera of animals neonatally injected with CRI, but receiving no exposure to S. mansoni Ags or infection, suggested a functional idiotypic network led to these responses. These data demonstrate that appropriate idiotypic exposure induces B and T cell responsiveness to the Ag recognized by the Id and support the hypothesis that neonatal idiotypic exposure can be an important immunoregulatory factor in schistosomiasis.