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Biomedical subjects

C L King

Publications and source records attributed to C L King.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cytokine control of the granulomatous response in Schistosoma mansoni-infected baboons: role of exposure and treatment.

Variations in exposure and treatment may contribute to heterogeneity in immunity and granuloma-induced pathology in human schistosomiasis. To examine this hypothesis, olive baboons were either repeatedly infected with Schistosoma mansoni cercariae or received an equivalent dose in a single infection. They were then cured with praziquantel and reinfected with a single exposure. Serial liver biopsies were obtained throughout the course of the experiment, and cytokine responses by peripheral blood mononuclear cells were measured every 2 to 3 weeks. Reinfection after treatment resulted in a twofold-smaller granuloma size at 6 and 9 weeks after infection compared to the size for the same period after primary infection (P < 0.001) but had no effect at 16 or 19 weeks postinfection. The pattern of exposure did not influence granuloma size. During primary infection schistosome-soluble egg antigen (SEA)-induced cytokine production correlated with granulomatous inflammation. Cytokine levels peaked during the acute infection, declined with chronic infection, and became undetectable after treatment. Reinfection after treatment stimulated a two- to three-fold increase in SEA-specific interleukin-4 (IL-4), IL-5, IL-10, IL-2, and transforming growth factor beta (TGF-beta) production and a marked rise in SEA-specific immunoglobulin E (IgE) and IgG regardless of the type of exposure. Cytokine production was significantly greater in repeatedly exposed animals (P < 0.001). SEA-induced gamma interferon production, however, did not increase with reinfection after treatment. SEA-induced TGF-beta was the only cytokine that remained elevated as the infection become chronic and correlated with diminished hepatic granuloma size, implying its participation in down-modulation. These studies demonstrate that baboons partially retain their ability to down-modulate the granulomatous response after treatment.

Animals↗
PubMed1999

Role of adult worm antigen-specific immunoglobulin E in acquired immunity to Schistosoma mansoni infection in baboons.

Allergic-type immune responses, particularly immunoglobulin E (IgE), correlate with protective immunity in human schistosomiasis. To better understand the mechanisms of parasite elimination we examined the immune correlates of protection in baboons (Papio cynocephalus anubis), which are natural hosts for Schistosoma mansoni and also develop allergic-type immunity with infection. In one experiment, animals were exposed to a single infection (1,000 cercariae) or were exposed multiple times (100 cercariae per week for 10 weeks) and subsequently were cured with praziquantel prior to challenge with 1, 000 cercariae. Singly and multiply infected animals mounted 59 and 80% reductions in worm burden, respectively (P < 0.01). In a second experiment, animals were inoculated with S. mansoni ova and recombinant human interleukin 12 (IL-12). This produced a 37 to 39% reduction in adult worm burden after challenge (P < 0.05). Parasite-specific IgG, IgE, IgM, and peripheral blood cytokine production were evaluated. The only immune correlate of protection in both experiments was levels of soluble adult worm antigen (SWAP)-specific IgE in serum at the time of challenge infection and/or 6 weeks later. Baboons repeatedly infected with cercariae or immunized with ova and IL-12 developed two- to sixfold-greater levels of SWAP-specific IgE in serum than did controls, and this correlated with reductions in worm burden (r2, -0.40 to -0.64; P, <0. 01). Thus, in baboons and unlike mice, adult worm-specific IgE is uniquely associated with acquired immunity to S. mansoni infection. This similar association of parasite-specific IgE and protection among primates infected with schistosomiasis, along with similar pathology, anatomy, and genetic make-up, indicates that baboons provide an excellent permissive experimental model for better understanding the mechanisms of innate and acquired immunity to schistosomiasis in humans.

Animals↗
PubMed1999

Long-term suppression of adult bladder morbidity and severe hydronephrosis following selective population chemotherapy for Schistosoma haematobium.

Repeated selective population chemotherapy of school age children reduces infection and morbidity associated with Schistosoma haematobium infection. To examine the long-term effect of this treatment on susceptibility to re-infection and late disease, a cohort of Kenyans (n = 194) were re-examined for infection and urinary tract morbidity 7-13 years after they underwent annual ultrasonography and treatment for an average of 5 years beginning in 1984 as children. Controls were previously untreated age-matched individuals residing in the same or adjacent villages. The overall prevalence and intensity of infection were equivalent between the 2 groups. In contrast, the prevalence of bladder wall pathology was 11-fold lower in previously treated (1.5%) versus untreated subjects (17%). Severe hydronephrosis was completely reversed. These data demonstrate that treatment significantly reduced urinary tract morbidity despite re-infection, and suggest that the important risk factors for urinary tract morbidity in adulthood are cumulative intensity and duration of infection during early adolescence.

Adolescent↗
PubMed1998

B cell sensitization to helminthic infection develops in utero in humans.

Human neonates are generally deficient in their ability to generate humoral immunity. This deficiency is thought to reflect physiologic immaturity of T and B cell function and lack of previous exposure to exogenous Ags. To determine whether neonatal humoral immunity can be modified by maternal helminth infection during pregnancy, we assessed Ig production by cord blood lymphocytes from healthy newborns of mothers living in an area of Kenya where schistosomiasis, bancroftian filariasis, and geohelminth infections are endemic. Twelve of 40 and 17 of 39 cord blood lymphocyte preparations from healthy newborns in Coast Province, Kenya, spontaneously made polyclonal IgE (range, 0.15-21 ng/ml) and IgG (1.6-10.1 ng/ml) in vitro. In vitro IgE synthesis by cord blood lymphocytes (CBL) was, on the average, 10-fold less than that of PBMC of Kenyan mothers (1.1-98 ng/ml) and was undetectable for CBL from newborns delivered in the United States. Schistosome and filarial Ags stimulated a 3- to > 100-fold increase in the production of polyclonal IgE and parasite-specific IgG Abs by lymphocytes from 10 of 40 and 6 of 39 Kenyan newborns, respectively. CBL observed to have helminth Ag-driven B cell responses were more likely to be from newborns of schistosome- or filaria-infected mothers than from uninfected mothers (p < 0.05). These data indicate that the human fetus can be sensitized in utero to produce helminth-specific B cells and that neonatal B cells are intrinsically capable of IgE and IgG production.

Antibodies, Helminth↗
PubMed1998

Nucleic acid vaccine-induced immune responses require CD28 costimulation and are regulated by CTLA4.

Immunization with plasmids expressing specific genes (DNA or nucleic acid vaccination (NAV)) elicits robust humoral and cell-mediated immune responses. The mechanisms involved in T cell activation by NAV are incompletely characterized. We have examined the costimulatory requirements of NAV. CD28-deficient mice did not mount Ab or CTL responses following i.m. immunization with eukaryotic expression plasmids encoding the bacterial gene beta-galactosidase (beta gal). Because these mice retained their ability to up-regulate the CTLA4 receptor (a negative regulator of T cell activation), we examined CTLA4's role in the response of wild-type BALB/c mice to NAV. Intact anti-CTLA4 mAb but not Fab fragments suppressed the primary humoral response to pCIA/beta gal without affecting recall responses, indicating CTLA4 activation inhibited Ab production but not T cell priming. Blockade of the ligands for CD28 and CTLA4, CD80 (B7-1) and CD86 (B7-2), revealed distinct and nonoverlapping function. Blockade of CD80 at initial immunization completely abrogated primary and secondary Ab responses, whereas blockade of CD86 suppressed primary but not secondary responses. Simultaneous blockade of CD80 + CD86 was less effective at suppressing Ab responses than either alone. Enhancement of costimulation via coinjection of B7-expressing plasmids augmented CTL responses but not Ab responses, and without evidence of Th1 to Th2 skewing. These findings suggest complex and distinct roles for CD28, CTLA4, CD80, and CD86 in T cell costimulation following nucleic acid vaccination.

Abatacept↗
PubMed1998

Effect of mild hypothermia during cardiopulmonary bypass on erythrocytic hemoglobin oxygen delivery.

OBJECTIVES: To observe and define the degree of change in hemoglobin oxygen affinity induced by hypothermic extracorporeal circulation (ECC). DESIGN: A prospective, nonrandomized, observational study. SETTING: A single university medical center. PARTICIPANTS: Seventeen patients presenting for elective cardiac surgery. INTERVENTIONS: Systemic hypothermia during ECC. MEASUREMENTS AND MAIN RESULTS: During and after ECC, simultaneous arterial and mixed-venous whole-blood samples were obtained and immediately analyzed for gas tensions and hemoglobin saturation. Samples were obtained during the following times on ECC: initially after cardiopulmonary bypass onset during normothermia (37 degrees C), after cooling to 32 degrees C, and after rewarming to 37 degrees C. A fourth sample was obtained 10 to 20 minutes after discontinuation of cardiopulmonary bypass. Extracorporeal pump flow and thermodilution-determined cardiac output were also recorded for calculation of oxygen delivery and consumption. Mixed-venous results were used to calculate in vivo the blood gas tension at which hemoglobin was 50% saturated with oxygen (P50). There were no differences in P50 for the 17 patients by analysis of variance (ANOVA) for repeated measures with paired t-test with Bonferroni correction. Furthermore, no change in P50 was observed during the course of cooling and rewarming in any individual patient's samples. Oxygen delivery decreased after hypothermia and rewarming from mild hypothermia; oxygen consumption was decreased after rewarming and markedly increased after discontinuation from ECC. CONCLUSION: Mild hypothermia to 32 degrees C during ECC does not result in in vivo alterations in oxyhemoglobin dissociation and thus does not induce changes in oxygen delivery to peripheral tissues. However, oxygen usage appears to be markedly increased after cardiopulmonary bypass.

Adult↗
PubMed1998

Increased interleukin-4 and interleukin-5 production in response to Schistosoma haematobium adult worm antigens correlates with lack of reinfection after treatment.

Acquired immunity to human schistosomiasis correlates with increased serum levels of schistosome antigen-specific IgE. Since interleukin (IL)-4 stimulates IgE production, the hypothesis that Th2-associated cell-mediated immunity participates in protection to reinfection was studied in a cohort of adolescent boys 12-18 months after chemotherapeutic cure in Upper Egypt. Initial Schistosoma haematobium prevalence was 51% and posttreatment incidence was 44%. Water contact was similar between putatively resistant and susceptible patients. Resistant persons had a 3.5- to 14-fold greater frequency of schistosome adult worm antigen (SWAP)-specific lymphocytes secreting IL-5 or IL-4 (by ELISPOT) and IL-5 or IL-4 production in peripheral blood lymphocyte culture supernatants (P < .05 to < .001, n = 48) versus susceptible subjects (n = 38). In contrast, SWAP-induced interferon-gamma and IL-10 production and lymphocyte proliferation were similar between the 2 groups. Schistosome egg antigen and streptolysin O each stimulated similar cytokine production in susceptible and resistant persons. Thus, enhanced SWAP-driven IL-4 and IL-5 production correlates with immunity to reinfection in adolescents exposed to urinary schistosomiasis.

Adolescent↗
PubMed1997

B7-2 requirement for helminth-induced granuloma formation and CD4 type 2 T helper cell cytokine expression.

B7 ligands on APCs engage CD28/CTLA4 counter-receptors on T cells critical for T lymphocyte activation and functional differentiation of T helper subsets. To examine whether the ligands B7-1 (CD80) and B7-2 (CD86) affect gene expression of Th2 cytokines and development of Th2-mediated pathologic tissue reactions, mice were treated with anti-B7-1 or anti-B7-2 at the time of sensitization to footpad inoculation of Schistosoma mansoni eggs or induction of pulmonary granuloma by i.v. injected eggs. Anti-B7-2 treatment inhibited pulmonary granuloma formation by 74% and decreased levels of lung IL-5 and IL-13 transcripts compared with those in animals given control Ig by 20- and 5-fold, respectively, while anti-B7-1 administration has no effect. Anti-B7-2 treatment blocked CD4 cell gene expression of IL-4, IL-5, and IL-13, but had no effect on IFN-gamma or IL-10 in animals inoculated with S. mansoni ova, larvae from the filarial helminth Brugia malayi, or CFA. Anti-B7-1 administration had no effect on CD4 cell transcript levels of IL-4 and IL-5, but inhibited IFN-gamma in mice inoculated with ova. Similar effects of anti-B7-2 on CD4 cell cytokine expression were observed in IL-4 knockout mice, indicating the existence of an alternative pathway for induction and/or expression of these cytokine genes. These findings suggest a possible role for anti-B7-2 in the therapy of infectious and atopic diseases in which immunopathologic reactions are mediated by selected Th2 cytokines.

Animals↗
PubMed1997

In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults.

Neonates exposed to parasite antigens (Ags) in utero may develop altered fetal immunity that could affect subsequent responses to infection. We hypothesized that cord blood lymphocytes (CBL) from offspring of mothers residing in an area highly endemic for schistosomiasis, filariasis, and tuberculosis in Kenya would either fail to respond or generate a predominantly Th2-associated cytokine response to helminth and mycobacterial antigens (PPD) in vitro compared to maternal PBMC. Kenyan CBL generated helminth Ag-specific IL-5 (range 29-194 pg/ml), IL-10 (121-2,115 pg/ml), and/or IFN-gamma (78 pg/ml-10.6 ng/ml) in 26, 46, and 57% of neonates, respectively (n = 40). PPD induced IFN-gamma in 30% of Kenyan CBL (range 79-1,896 pg/ml), but little or no IL-4 or IL-5. No Ag-specific IL-4, IL-5, or IFN-gamma release was detected by CBL obtained in the United States (n = 11). Ag-driven cytokine production was primarily CD4-dependent. Cytokine responses to helminth and mycobacterial Ags by maternal PBMC mirrored that observed in neonates. CBL from helminth infected and/or PPD-sensitized mothers produced more Ag-specific cytokines compared to CBL from uninfected mothers (P < 0.05). These data demonstrate that the human fetus develops similar patterns of cytokine production observed in adults and indicates that prenatal exposure may not lead to tolerance or altered fetal immunity. .

Antigens, Bacterial↗
PubMed1997

Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with Schistosoma mansoni.

Although IgE has been considered to play an essential role in host defense against parasitic helminth infections such as Schistosoma mansoni, in vivo evidence of a protective function of IgE in infected mice is lacking. In the present study, mice with a null mutation of the C epsilon gene, and thus incapable of making IgE (IgE deficient), were infected by S. mansoni cercariae percutaneously. In two independent experiments, IgE-deficient mice were significantly more susceptible to primary infection, developing worm burdens twofold greater than those of wild-type mice (p < 0.001). In contrast, resistance to challenge infection following three immunizations with irradiated cercariae was similar in the two groups. The percentage of reduction in worm burdens in immunized IgE-deficient animals compared with unimmunized mice was 50%; immunized wild-type mice had a reduction of 55% compared with the baseline parasite count. Levels of parasite-specific IgG1 were more than twofold lower in IgE-deficient mice after primary infection (p = 0.005), whereas no significant difference was observed in the IgG1 response of animals previously immunized with irradiated cercariae. IgE-deficient animals also developed significantly smaller granulomas (by 37-40%) around schistosome eggs deposited in their livers compared with wild-type animals (p < 0.001). The spleens of IgE-deficient mice contained significantly more Ag-specific IL-4-secreting cells following primary infection. These data show that IgE participates in parasite elimination in primary infection with S. mansoni and in the generation of humoral immunity and cytokine responses to the parasite.

Animals↗
PubMed1997

Schistosoma mansoni: development and modulation of the granuloma after or multiple exposures in the baboon (Papio cynocephalus anubis).

The ability of the host to modulate the granulomatous response around ova trapped in tissues determines the severity of disease to schistosome infections. Multiple factors may affect this modulation such as age, prior sensitization, history of treatment, and exposure. The present study examines the effect of different patterns of exposure on the sequential development and modulation of granuloma in juvenile Kenyan baboons (Papio cynocephalus anubis) after receiving either a single infection (SI) of 1500 Schistosoma mansoni cercariae or multiple infections (MI) of 150 cercariae, once a week for 10 weeks. Prior to sacrifice at 17 weeks postinfection (p.i.), liver biopsies were obtained at Weeks 0, 6, 9, and 13. SI animals experienced more prolonged dysentery and greater weight loss compared to MI animals. Peak hepatic granuloma size (mean 355 +/- 65.5 microns diameter), the maximum percentage of eosinophils in the granuloma (61%), and severity of disease occurred at 6 weeks in SI animals. Peak granuloma size and pathology did not appear until Week 9 in the MI animals (mean 317.7 +/- 67.3 microns diameter). Granuloma size, tissue eosinophilia, and gross pathology diminished by Week 13 p.i. and were virtually absent in both groups by Week 17. The decrease in granuloma size, pathology, and clinical illness resolved more rapidly in the MI baboons. Singly infected baboons were more susceptible to infection (83 +/- 12% of cercariae developed into adult worms) compared to MI baboons (67 +/- 7%, P < 0.01). Eggs recovered from tissues at necropsy were primarily confined to the large intestine (85% of total egg recovered), followed by liver (10%) and small intestine (5%). Significantly more eggs were recovered from MI compared to SI animals, indicating a higher fecundity of female worms in the MI baboons. These date demonstrate that granulomatous responses develop more slowly and modulate more rapidly with repeated infection compared to a single heavy infection and suggest the type of exposure may affect the pathologic response to infection.

Animals↗
PubMed1997

T-cell immunity to peptide epitopes of liver-stage antigen 1 in an area of Papua New Guinea in which malaria is holoendemic.

Liver-stage antigen 1 (LSA1) is one of several pre-erythrocytic antigens considered for inclusion in a multiantigen, multistage subunit vaccine against falciparum malaria. We examined T-cell proliferation and cytokine responses to peptides corresponding to amino acids 84 to 107, 1813 to 1835, and 1888 to 1909 of LSA1 in asymptomatic adults living in an area of Papua New Guinea where malaria is holoendemic. Whereas T cells from North Americans never exposed to malaria did not respond to any of the peptides, those from 52 of 55 adults from the area where malaria is endemic had vigorous proliferation responses to one or more of the LSA1 peptides (mean stimulation indices of 6.8 to 7.2). Gamma interferon (IFN-gamma) production driven by LSA1 peptides ranged from 34 to more than 3,500 pg/2 x 10(6) cells, was derived primarily from CD8+ cells, and was dissociated from T-cell proliferation. The frequencies of IFN-gamma response to the amino acid 1819 to 1835 and 1888 to 1909 peptides were significantly greater than that to the amino acid 84 to 107 peptide (87 and 88% versus 33% of subjects; P < 0.0001). In contrast to proliferation and IFN-gamma, interleukin 4 (IL-4) and/or IL-5 responses to LSA1 peptides were detected in only 18% of the subjects. These data show that T-cell immunity to epitopes in the N- and C-terminal regions of LSA1 are common in persons living in this area of Papua New Guinea where malaria is endemic. The dominance of type 1 CD8 cell IFN-gamma responses is consistent with a role for this T-cell population in immunity to liver-stage Plasmodium falciparum in humans.

Adult↗
PubMed1996

Cytokine control of parasite-specific anergy in human urinary schistosomiasis. IL-10 modulates lymphocyte reactivity.

Humans chronically infected with schistosomiasis usually have impaired parasite Ag-specific lymphocyte proliferation and IFN-gamma production that may facilitate persistence of the parasite while producing little clinical disease. The mechanisms that contribute to the immunologic hyporesponsiveness in these patients remain undefined. IL-10 has been shown to exert an inhibitory effect on cell-mediated immunity. To determine whether endogenous IL-10 has a role in regulating parasite-specific anergy in schistosomiasis, neutralizing anti-IL-10 added to PBMC from Schistosoma haematobium patients' enhanced adult worm (SWAP)- or egg Ag (SEA)-driven lymphocyte proliferation and/or IFN-gamma production by 2- to >100-fold in 32 of 38 subjects. In contrast, anti-IL-10 failed to significantly augment the mycobacterial Ag, purified protein derivative (PPD)-driven lymphocyte proliferation, or IFN-gamma production in 9 or 10 of 14 individuals, respectively. SWAP or SEA triggered IL-10 release from PBMC of both patients and healthy individuals; however, CD4+ cells were a significant source of IL-10 only in infected subjects. PPD relative to SWAP induced fivefold less IL-10 release by CD4+ cells (p < 0.01). A possible mechanism whereby IL-10 suppressed Ag-specific T cell responses was demonstrated by the ability of SWAP and not PPD to suppress B7 expression on PBMC. Anti-IL-10 completely inhibited the parasite Ag-induced down-regulation of B7 expression. These studies indicate that IL-10 contributes to parasite Ag-induced T cell hyporesponsiveness observed in patients with chronic schistosomiasis hematobia.

Adolescent↗
PubMed1996

CD28-deficient mice generate an impaired Th2 response to Schistosoma mansoni infection.

Engagement of CD28 on T cells provides a co-stimulatory signal necessary for T cell activation and differentiation. Recent findings suggest that priming of T helper (Th)2 cells is more dependent on CD28 activation that Th1 cells. The present study examines whether mice that lack expression of CD28 as a result of gene targeting are capable of generating a Th2 response characteristic during infection with the intravascular trematode parasite Schistosoma mansoni. Mutant and control mice were either inoculated in the footpad with S. mansoni eggs (a potent inducer of a Th2 response) or infected percutaneously with the parasite. Draining lymph nodes (after footpad injection) or spleen cells (after natural infection) were harvested at 12 days and 8 weeks, respectively, and examined for cytokine responses to egg antigens. CD28-deficient mice (-/-) generated diminished egg antigen-driven interleukin (IL)-4 and IL-5 production (by 5- to 17-fold, respectively) compared to CD28-expressing (+/+) littermates. In contrast, lymphocyte proliferation and interferon (IFN)-gamma production to egg antigens were equivalent for mutant and control mice. Infected CD28-/- mice also had reduced immunoglobulin secretion. Serum levels of parasite antigen-specific IgG1 and polyclonal IgE were significantly diminished in CD28-/- compared to CD28+/+ mice. Lack of CD28 expression had no effect on granuloma formation around eggs trapped in the liver, but increased susceptibility of mice to primary schistosomiasis infection. These studies indicate that CD28 activation contributes to T cell priming required for generation of a Th2 response to an intravascular dwelling helminth parasite.

Abatacept↗
PubMed1996

Schistosoma mansoni: protective immunity in IL-4-deficient mice.

Vaccination of mice with radiation-attenuated Schistosoma mansoni larvae (cercariae) either once or multiple times produces similar levels of resistance to subsequent infection, but by different immunological mechanisms. In singly immunized mice, protection is CD4+ cell mediated and IFN-gamma dependent. Resistance in multiply immunized mice is humorally mediated (especially the IgG1 isotype), suggesting a key role of Th2-associated cytokine responses. Since IL-4 has been shown to regulate Th2 development, animals in which the IL-4 gene has been knocked out by homologous recombination (IL-4 -/-) or wild-type mice (IL-4 +/+) were immunized three times with attenuated cercariae and challenged with normal cercariae. In three separate experiments the percentage of reduction of adult worms in immunized compared to unimmunized IL-4 +/+ animals (68 to 82%) was equivalent to IL-4 -/- (52 to 66%), although protection tended to be lower in each experiment. Serum levels of adult worm (SWAP)-specific IgG2a and IgG2b were 10- and 2-fold higher in IL-4 -/- mice while IgA levels were equivalent between the two groups. Serum levels of SWAP-specific IgG1 were slightly lower in IL-4 -/- mice (P = 0.07) compared to wild-type animals and inversely correlated with worm burdens (r = -0.65, P = 0.02), suggesting that the slightly diminished IgG1 accounts for the tendency toward lower worm burdens in IL-4 -/- animals. No relationships between worm numbers and the other isotypes were observed. SWAP-induced IL-5 production by splenocytes from IL-4 -/- animals were 6-fold lower, although present, compared to IL-4 +/+ mice while Ag-induced IFN-gamma production was increased by over 4-fold. These results demonstrate that IL-4 is not essential for development of protective immunity in mice multiply vaccinated with irradiated cercariae and that compensatory or alternative pathways exist to generate a Th2-associated response. The limitations of mice with targeted gene deletions in delineating the role of specific cytokines in regulating the immune response to complex infections like schistosomiasis are emphasized.

Animals↗
PubMed1996

Seroprevalence and specificity of human responses to the Plasmodium falciparum rhoptry protein Rhop-3 determined by using a C-terminal recombinant protein.

Rhoptry proteins participate in invasion of erythrocytes by malaria parasites. Antibodies to some of these proteins can inhibit invasion and partially protect monkeys from disease. To examine human serological responses to the 110-kDa component (Rhop-3) of the high-molecular-weight rhoptry protein complex, two cDNA clones corresponding to Rhop-3 were identified by immunologic screening. A recombinant protein representing the C-terminal one-third of the Rhop-3 was used to assess the seroprevalence to this protein in geographically isolated populations with different patterns of malaria transmission. The immunoglobulin G (IgG) positivity rate for the recombinant Rhop-3 in an enzyme-linked immunosorbent assay was 30% in an area of Papua New Guinea where malaria is holoendemic. In Kenya, the prevalence rates were 43 and 36%, respectively, in an area of hyperendemicity and an area of seasonal transmission. By contrast, rates of IgG seroprevalence to an extract of Gambian strain of Plasmodium falciparum were 48, 90, and 97% respectively, in these populations. In these areas, the pattern of antibody recognition of Rhop-3 is more similar (1.7-fold maximum difference) than the parasite extract (5-fold difference). The difference in seroresponses may represent antigenic polymorphism in different parasite strains, while their similarity for the Rhop-3 fragment may represent conservation of this protein. Recombinant- and parasite extract-specific IgG was not found in individuals infected only with Plasmodium vivax. Cross-reactivity was seen in the IgM assay. In Mombasa (Kenya), maternal and cord Rhop-3-specific IgG activities were similar. Fetal antigen-specific IgM reactivity was generally undetectable for all antigens.

Animals↗
PubMed1995

IL-12 regulation of parasite antigen-driven IgE production in human helminth infections.

Recombinant IL-12 inhibits IgE synthesis by IL-4-stimulated lymphocytes from healthy persons and influences the development of Th subset selection involved in Ig isotype selection. Whether endogenous IL-12 production modulates IgE synthesis in patients with elevated serum IgE is unknown. To examine this question we studied the effects of neutralizing anti-IL-12 or recombinant IL-12 on parasite Ag-driven polyclonal IgE production and corresponding IFN-gamma and IL-4 synthesis by PBMC from helminth-infected individuals. The addition of neutralizing anti-IL-12 Ab significantly inhibited parasite Ag-driven IgE production in 11 of 12 individuals (p < 0.001). Recombinant IL-12 (1-10 U/ml) suppressed Ag-driven IgE production in a dose-dependent fashion up to 94% relative to untreated cultures. The effect of endogenous IL-12 on IgE production occurred, in part, by suppressing Ag-induced IL-4 and augmenting IFN-gamma production. IL-12 did not suppress IgE synthesis by purified B cells. An IFN-gamma-independent effect of IL-12 on Ag-driven IgE production was suggested by the ability of human rIL-12 to suppress IgE synthesis in the presence of neutralizing anti-IFN-gamma. This study demonstrates that IL-12 modulates helminth Ag-driven IgE production, in part, by regulating the relative quantities of IFN-gamma and IL-4 generated by Ag-specific lymphocytes.

Adult↗