Imperial College London

DrSarahJoseph

Faculty of MedicineDepartment of Infectious Disease

Clinical Immunologist
 
 
 
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s.joseph

 
 
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457Medical SchoolSt Mary's Campus

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Publications

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61 results found

Jentsch U, Lunga P, Lacey C, Weber J, Cairns J, Pinheiro G, Joseph S, Stevens W, McCormack Set al., 2012, The implementation and appraisal of a novel confirmatory HIV-1 testing algorithm in the microbicides development programme 301 trial (MDP301), PLOS One, Vol: 7, ISSN: 1932-6203

We describe the application of a novel HIV confirmatory testing algorithm to determine the primary efficacy endpoint in alarge Phase III microbicide trial. 9385 women were enrolled between 2005 and 2009. Of these women, 537 (6%) had at leastone positive HIV rapid test after enrolment. This triggered the use of the algorithm which made use of archived serum andBuffy Coat samples. The overall sample set was.95% complete. 419 (78%) of the rapid test positive samples wereconfirmed as primary endpoints using a combination of assays for the detection of HIV-specific antibodies (EIA’s andWestern Blot), and for components of the virus itself (PCR for the detection of nucleic acids and EIA for p24 antigen). 63(12%) cases were confirmed as being HIV-positive at screening or enrolment and 55 (10%) were confirmed as HIV negative.The testing algorithm confirmed the endpoint at the same visit as that of the first positive rapid test in 90% of cases and atthe time of the preceding visit in 10% of cases. Of the 63 cases which were subsequently confirmed to be HIV-1 positive ator before enrolment, 54 specimens contained no detectable HIV antibodies at screening or enrolment. However, 43 werepositive using an EIA which detects both HIV antigen and antibody and also had a positive p24 antigen or HIV PCR test,which was highly suggestive of acute infection. There were 6 unusual cases which had undetectable HIV-1 DNA or RNA. In 4of the 6 cases the presence of HIV-1-specific antibodies was confirmed by Western Blot. One of these cases with anindeterminate Western Blot was a previous vaccine trial participant. The algorithm served the objectives of the study welland can be recommended for use in determining HIV as an endpoint in clinical trials.

Journal article

Bauer A, Podola L, Haule A, Sudi L, Nilsson C, Mann P, Missanga M, Kaluwa B, Maboko L, Lueer C, Mwakatima M, Aboud S, Bakari M, Currier J, Robb M, Joseph S, McCormack S, Lyamuya E, Wahren B, Sandström E, Biberfeld G, Hoelscher M, Kroidl A, Geldmacher Cet al., 2012, Preferential targeting of conserved Gag regions after vaccination with a heterologous DNA prime Modified Vaccinia Ankara boost HIV vaccine regime, Retrovirology, Vol: 9

Journal article

Podola L, Bauer A, Haule A, Sudi L, Nilsson C, Godoy-Ramirez K, Mann P, Missanga M, Kaluwa B, Maboko L, Lueer C, Mwakatima M, Aboud S, Bakari M, Currier J, Robb M, McCormack S, Joseph S, Lyamuya E, Hoelscher M, Wahren B, Sandström E, Biberfeld G, Geldmacher C, Kroidl Aet al., 2012, Breadth, phenotype and functionality of Gag-specific T cell responses induced by a heterologous DNA/MVA prime-boost HIV-1 vaccine regimen, Retrovirology, Vol: 9

Journal article

Hendriksen AM, 2012, Diagnosing Severe Falciparum Malaria in Parasitaemic African Children: A Prospective Evaluation of Plasma PfHRP2 Measurement, PLOS Medicine, Vol: 9, ISSN: 1549-1277

Background: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidentalPlasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by maturesequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance ofplasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria.Methods and Findings: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, TheGambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years withsevere febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparingparenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadiumfalciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p,0.0001), and severe anaemia (p,0.0001).Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350–1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991–1,104) ng/mL in survivors (n = 3,445, p,0.0001), without differences in parasitaemia as assessed by microscopy. There was aU-shaped association between log10 plasma PfHRP2 and risk of death. Mortality increased 20% per log10 increase in PfHRP2above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05–1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortalityless than 50% with plasma PfHRP2#174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patientswas 0.61 (95%CI 0.44–0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile(OR 1.05; 95%CI 0.69–1.61; p = 0.82). A li

Journal article

Manjurano A, Okell L, Lukindo T, Reyburn H, Olomi R, Roper C, Clark TG, Joseph S, Riley EM, Drakeley Cet al., 2011, Association of sub-microscopic malaria parasite carriage with transmission intensity in north-eastern Tanzania, MALARIA JOURNAL, Vol: 10, ISSN: 1475-2875

Journal article

Kagina BMN, Abel B, Scriba TJ, Hughes EJ, Keyser A, Soares A, Gamieldien H, Sidibana M, Hatherill M, Gelderbloem S, Mahomed H, Hawkridge A, Hussey G, Kaplan G, Hanekom WAet al., 2010, Specific T Cell Frequency and Cytokine Expression Profile Do Not Correlate with Protection against Tuberculosis after Bacillus Calmette-Guérin Vaccination of Newborns, American Journal of Respiratory and Critical Care Medicine, Vol: 182, Pages: 1073-1079, ISSN: 1073-449X

Journal article

Soares AP, Scriba TJ, Joseph S, Harbacheuski R, Murray RA, Gelderbloem SJ, Hawkridge A, Hussey GD, Maecker H, Kaplan G, Hanekom WAet al., 2008, Bacillus Calmette-Guérin Vaccination of Human Newborns Induces T Cells with Complex Cytokine and Phenotypic Profiles, The Journal of Immunology, Vol: 180, Pages: 3569-3577, ISSN: 0022-1767

<jats:title>Abstract</jats:title><jats:p>The immune response to vaccination with bacillus Calmette-Guérin (BCG), the only tuberculosis vaccine available, has not been fully characterized. We used multiparameter flow cytometry to examine specific T cell cytokine production and phenotypic profiles in blood from 10-wk-old infants routinely vaccinated with BCG at birth. Ex vivo stimulation of whole blood with BCG for 12 h induced expression of predominantly IFN-γ, IL-2, and TNF-α in CD4+ T cells in seven distinct cytokine combinations. IL-4 and IL-10 expression was detected in CD4+ T cells at low frequencies and only in cells that did not coexpress type 1 cytokines. Specific CD8+ T cells were less frequent than CD4+ T cells and produced mainly IFN-γ and/or IL-2 and less TNF-α, IL-4, and IL-10. Importantly, many mycobacteria-specific CD4+ and CD8+ T cells did not produce IFN-γ. The predominant phenotype of BCG-specific type 1 T cells was that of effector cells, i.e., CD45RA−CCR7−CD27+, which may reflect persistence of Mycobacterium bovis BCG in infants until 10 wk of age. Among five phenotypic patterns of CD4+ T cells, central memory cells were more likely to be IL-2+ and effector cells were more likely to be IFN-γ+. We concluded that neonatal vaccination with BCG induces T cells with a complex pattern of cytokine expression and phenotypes. Measuring IFN-γ production alone underestimates the magnitude and complexity of the host cytokine response to BCG vaccination and may not be an optimal readout in studies of BCG and novel tuberculosis vaccination.</jats:p>

Journal article

Hanekom W, Soares A, Scriba T, Hussey G, Kaplan Get al., 2007, Cytokine and phenotypic profiles of specific T cells induced by newborn BCG vaccination (47.1), The Journal of Immunology, Vol: 178, Pages: S66-S66, ISSN: 0022-1767

<jats:title>Abstract</jats:title> <jats:p>Bacillus Calmette-Guerin (BCG), the only currently available TB vaccine, is the most widely administered vaccine in the world. However, the immune response to BCG has not been fully characterized. This knowledge is critical for studies of protective immunity induced by vaccination and for developing novel, improved TB vaccines.</jats:p> <jats:p>We aimed to describe phenotypic and cytokine profiles of specific T cell subsets in blood of 10-week old infants following their routine vaccination with BCG at birth.</jats:p> <jats:p>Whole blood of 30 infants was incubated with BCG for 12 hrs; Brefeldin A was added for the last 5 hrs. Red cells were lysed and white cells fixed and cryopreserved. Thawed cells were permeabilized, stained and analysed by multiparameter flow cytometry.</jats:p> <jats:p>We observed predominant expression of presumably protective Type 1 cytokines: distinct Type 1 CD4+ and CD8+ T-cell subsets were identified, based on IL-2, TNF and IFN-gamma expression. TNF expression was virtually absent from CD8+ T cells. IL-4 could not be detected; IL-10 expression was low, but only in cells that did not express Type 1 cytokines. The distinct phenotypes of IL-2, TNF and IFN-gamma expressing cells will be described: the most common phenotypes were CD45RA-CCR7+/−CD27+.</jats:p> <jats:p>We conclude that newborn BCG vaccination induces predominantly Type 1 cytokine responses in CD4+ and CD8+ T cells. Significant numbers of specific T-cells did not produce IFN-gamma, suggesting that assays relying on detection of this cytokine alone do not measure the entire mycobacteria-induced response. Type 1 cytokine expressing CD4+ and CD8+ T cells have predominantly effector and central memory phenotypes. We will now apply this knowledge to a large ongoing study of BCG-induced immune correlates o

Journal article

Fitzsimmons CM, McBeath R, Joseph S, Jones FM, Walter K, Hoffmann KF, Kariuki HC, Mwatha JK, Kimani G, Kabatereine NB, Vennervald BJ, Ouma JH, Dunne DWet al., 2007, Factors Affecting Human IgE and IgG Responses to Allergen-Like &lt;i&gt;Schistosoma mansoni &lt;/i&gt;Antigens: Molecular Structure and Patterns of in vivo Exposure, International Archives of Allergy and Immunology, Vol: 142, Pages: 40-50, ISSN: 1018-2438

<jats:p>&lt;i&gt;Background:&lt;/i&gt; The human IgE response is associated with allergy and with host defence against parasitic worms. A response to Sm22.6, the dominant IgE antigen in adult &lt;i&gt;Schistosoma mansoni&lt;/i&gt; worms, correlates with resistance to re-infection after treatment. Sm22.6 is one of a family of EF-hand containing parasite proteins with sequence similarity to dynein light chain (DLC) and with major non-parasite allergens. Here we compare human IgE and IgG responses to other family members, Sm20.8 and Sm21.7, as well as to SmDLC1, relating these to antigen structure and expression in parasite life stages. &lt;i&gt;Methods:&lt;/i&gt; Recombinant antigens were used in ELISA to measure antibody isotype responses in 177 cases from an endemic area, before and 7 weeks after treatment. Parasite antigen expression was assessed by RT-PCR and Western blotting. &lt;i&gt;Results:&lt;/i&gt; Levels of antibodies to Sm22.6 and Sm20.8 (but not to Sm21.7 or SmDLC1) showed posttreatment increases in all but young children. Many produced IgE to Sm22.6 and Sm20.8 (2 EF-hands), few to Sm21.7 (1 EF-hand) or SmDLC1 (no EF-hands). Sm21.7 was expressed in cercariae, adults and eggs, Sm22.6 and Sm20.8 were concentrated in the adult. &lt;i&gt;Conclusions:&lt;/i&gt; These studies suggest that IgE antigens Sm22.6 and Sm20.8 are only released to boost antibodies when adult worms die, whilst Sm21.7 and SmDLC1 are released constantly from eggs dying in host tissue. IgE responses to these allergen-like molecules may be influenced by patterns of exposure and the number of EF-hand motifs.</jats:p>

Journal article

Walter K, Fulford AJC, McBeath R, Joseph S, Jones FM, Kariuki HC, Mwatha JK, Kimani G, Kabatereine NB, Vennervald BJ, Ouma JH, Dunne DWet al., 2006, Increased Human IgE Induced by Killing <i>Schistosoma mansoni</i> In Vivo Is Associated with Pretreatment Th2 Cytokine Responsiveness to Worm Antigens, The Journal of Immunology, Vol: 177, Pages: 5490-5498, ISSN: 0022-1767

<jats:title>Abstract</jats:title> <jats:p>In schistosomiasis endemic areas, children are very susceptible to postchemotherapy reinfection, whereas adults are relatively resistant. Different studies have reported that schistosome-specific IL-4 and IL-5 responses, or posttreatment worm-IgE levels, correlate with subsequent low reinfection. Chemotherapy kills i.v. worms providing an in vivo Ag challenge. We measured anti-worm (soluble worm Ag (SWA) and recombinant tegumental Ag (rSm22.6)) and anti-egg (soluble egg Ag) Ab levels in 177 Ugandans (aged 7–50) in a high Schistosoma mansoni transmission area, both before and 7 wk posttreatment, and analyzed these data in relation to whole blood in vitro cytokine responses at the same time points. Soluble egg Ag-Ig levels were unaffected by treatment but worm-IgG1 and -IgG4 increased, whereas worm-IgE increased in many but not all individuals. An increase in worm-IgE was mainly seen in &amp;gt;15-year-olds and, unlike in children, was inversely correlated to pretreatment infection intensities, suggesting this response was associated both with resistance to pretreatment infection, as well as posttreatment reinfection. The increases in SWA-IgE and rSm22.6-IgE positively correlated with pretreatment Th2 cytokines, but not IFN-γ, induced by SWA. These relationships remained significant after allowing for the confounding effects of pretreatment infection intensity, age, and pretreatment IgE levels, indicating a link between SWA-specific Th2 cytokine responsiveness and subsequent increases in worm-IgE. An exceptionally strong relationship between IL-5 and posttreatment worm-IgE levels in &amp;lt;15-year-olds suggested that the failure of younger children to respond to in vivo Ag stimulation with increased levels of IgE, is related to their lack of pretreatment SWA Th2 cytokine responsiveness.</jats:p>

Journal article

Booth M, Shaw MA, Carpenter D, Joseph S, Kabatereine NB, Kariuki HC, Mwatha JK, Jones FM, Vennervald BJ, Ouma JH, Dunne DWet al., 2006, Carriage of <i>DRB1*13</i> Is Associated with Increased Posttreatment IgE Levels against <i>Schistosoma mansoni</i> Antigens and Lower Long-Term Reinfection Levels, The Journal of Immunology, Vol: 176, Pages: 7112-7118, ISSN: 0022-1767

<jats:title>Abstract</jats:title> <jats:p>Praziquantel treatment for Schistosoma mansoni infection enhances Th2 responsiveness against parasite Ags, but also increases the variance in Ab isotype levels. This effect may arise partly from genetic heterogeneity. In this study, associations between HLA polymorphisms at three loci (HLA-DQB1, HLA-DQA1, and HLA-DRB1) and posttreatment Ig responses to S. mansoni Ags were assessed in 199 individuals aged 7–50 years from Uganda. Blood samples were assayed for IgG1, IgG4, and IgE levels against soluble worm Ag (SWA), soluble egg Ag, tegument Ag, and a recombinant tegumental Ag (rSm 22.6) 7 wk after treatment. Multivariate ANOVA analysis initially revealed associations between carriage of DRB1*13 and increased levels of IgG1, IgG4, and IgE against SWA, tegument Ag, and rSM22.6. Subsequent analysis of covariance, which controlled for correlations between isotype levels and also included pretreatment IL-4, IL-5, and IL-13 responsiveness against SWA as covariates, revealed an independent association only between DRB1*13 and a factor score summarizing IgE levels to worm-derived Ags, which was strongest in adults. A post hoc age- and sex-stratified analysis revealed lower reinfection intensities at 1 year, 22 mo, and 6 years after the first round of treatment among carriers of DRB1*13. These results indicate that genetic background has a prominent influence on the posttreatment Th2 immune response to S. mansoni Ags, as well as a downstream association with long-term reinfection levels.</jats:p>

Journal article

Reimert CM, Fitzsimmons CM, Joseph S, Mwatha JK, Jones FM, Kimani G, Hoffmann KF, Booth M, Kabatereine NB, Dunne DW, Vennervald BJet al., 2006, Eosinophil Activity in<i>Schistosoma mansoni</i>Infections In Vivo and In Vitro in Relation to Plasma Cytokine Profile Pre- and Posttreatment with Praziquantel, Clinical and Vaccine Immunology, Vol: 13, Pages: 584-593, ISSN: 1556-6811

<jats:title>ABSTRACT</jats:title><jats:p>Eosinophil activity in vivo and in vitro was studied in relation to infection intensities and plasma cytokine profiles of 51<jats:italic>Schistosoma mansoni</jats:italic>-infected Ugandan fishermen before treatment and 24 h and 3 weeks posttreatment. Blood eosinophil numbers significantly declined 24 h posttreatment, but significant eosinophilia had developed by 3 weeks posttreatment. Cellular eosinophil cationic protein (ECP) content increased significantly during the transient eosinopenia but was significantly reduced 3 weeks later. No similar reduction in cellular eosinophil protein X (EPX) content was seen. Before treatment,<jats:italic>S. mansoni</jats:italic>infection intensity was positively correlated with 24-h boosts in plasma interleukin-5 (IL-5) and IL-6 levels, which were in turn negatively correlated with the posttreatment fall in eosinophil numbers. Significant correlations were observed between pretreatment infection intensities and plasma IL-10 and eotaxin levels. Treatment induced significant fluctuations in plasma IL-5, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), and eotaxin levels. Optimal relative release of ECP and EPX in vitro was detected in<jats:italic>S. mansoni</jats:italic>soluble egg antigen-stimulated cultures during transient eosinopenia. Our data suggest that blood eosinophils are activated during<jats:italic>S. mansoni</jats:italic>infection and that treatment induces a burst in released antigens, causing increased production of IL-5, IL-6, IL-10, and eotaxin; a drop in TNF-α levels; and a transient sequestration of eosinophils, which leaves fewer degranulated eosinophils in the circulation 24 h posttreatment, followed by the development of eosinophilia 3 weeks later. During these events, it appears that preferential release of ECP occurs in vivo. Moreover, it is possible that infection intensity-dependent level

Journal article

Dunne DW, Vennervald BJ, Booth M, Joseph S, Fitzsimmons CM, Cahen P, Sturrock RF, Ouma JH, Mwatha JK, Kimani G, Kariuki HC, Kazibwe F, Tukahebwa E, Kabatereine NBet al., 2006, Applied and basic research on the epidemiology, morbidity, and immunology of schistosomiasis in fishing communities on Lake Albert, Uganda, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 100, Pages: 216-223, ISSN: 0035-9203

Journal article

Soares A, Joseph S, Maecker H, Kaplan G, Hanekom Wet al., 2006, Su.84. Cytokine Profile of Specific T-Cells Induced By Newborn Bcg Vaccination, Clinical Immunology, Vol: 119, Pages: S188-S189, ISSN: 1521-6616

Journal article

Brown M, Mawa PA, Joseph S, Bukusuba J, Watera C, Whitworth JAG, Dunne DW, Elliott AMet al., 2005, Treatment of<i>Schistosoma mansoni</i>Infection Increases Helminth‐Specific Type 2 Cytokine Responses and HIV‐1 Loads in Coinfected Ugandan Adults, The Journal of Infectious Diseases, Vol: 191, Pages: 1648-1657, ISSN: 0022-1899

Journal article

Kabatereine NB, Kemijumbi J, Ouma JH, Kariuki HC, Richter J, Kadzo H, Madsen H, Butterworth AE, Ørnbjerg N, Vennervald BJet al., 2004, Epidemiology and morbidity of Schistosoma mansoni infection in a fishing community along Lake Albert in Uganda, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 98, Pages: 711-718, ISSN: 0035-9203

Journal article

Joseph S, Jones FM, Walter K, Fulford AJ, Kimani G, Mwatha JK, Kamau T, Kariuki HC, Kazibwe F, Tukahebwa E, Kabatereine NB, Ouma JH, Vennervald BJ, Dunne DWet al., 2004, Increases in Human T Helper 2 Cytokine Responses to<i>Schistosoma mansoni</i>Worm and Worm‐Tegument Antigens Are Induced by Treatment with Praziquantel, The Journal of Infectious Diseases, Vol: 190, Pages: 835-842, ISSN: 0022-1899

Journal article

Joseph S, Jones FM, Laidlaw ME, Mohamed G, Mawa PA, Namujju PB, Kizza M, Watera C, Whitworth JAG, Dunne DW, Elliott AMet al., 2004, Impairment of the<i>Schistosoma mansoni–</i>Specific Immune Responses Elicited by Treatment with Praziquantel in Ugandans with HIV‐1 Coinfection, The Journal of Infectious Diseases, Vol: 190, Pages: 613-618, ISSN: 0022-1899

Journal article

Fitzsimmons CM, Joseph S, Jones FM, Reimert CM, Hoffmann KF, Kazibwe F, Kimani G, Mwatha JK, Ouma JH, Tukahebwa EM, Kariuki HC, Vennervald BJ, Kabatereine NB, Dunne DWet al., 2004, Chemotherapy for Schistosomiasis in Ugandan Fishermen: Treatment Can Cause a Rapid Increase in Interleukin-5 Levels in Plasma but Decreased Levels of Eosinophilia and Worm-Specific Immunoglobulin E, Infection and Immunity, Vol: 72, Pages: 4023-4030, ISSN: 0019-9567

<jats:title>ABSTRACT</jats:title><jats:p>Chemotherapy for blood-dwelling schistosomes kills the worms and exposes parasite antigen to the circulation. In many people from areas of endemicity, this treatment increases parasite-specific immunoglobulin E (IgE) and other Th2 responses in the months following therapy, responses that have been associated with subsequent resistance to reinfection. Here we investigate much earlier changes in immune reactions after praziquantel therapy in<jats:italic>Schistosoma mansoni</jats:italic>-infected fishermen working in an area of high transmission in Uganda. The subjects gave blood before treatment and at 1 and 21 days posttreatment. Blood cultures were incubated with schistosome soluble worm antigen (SWA) or soluble egg antigen (SEA). Interleukin-4 (IL-4), IL-5, IL-10, IL-13, gamma interferon, and transforming growth factor β levels were measured in the cultures and in plasma. A marked transient increase in plasma IL-5 levels was observed in 75% of the subjects (<jats:italic>n</jats:italic>= 48) by 1 day posttreatment. This response was dependent on pretreatment intensity of infection and was accompanied by a transient decrease in eosinophil numbers. One day posttreatment, blood cultures from the 16 subjects with the greatest increase in plasma IL-5 level (&gt;100 pg/ml) displayed reduced IL-5, IL-13, and IL-10 responses to SWA, and in contrast to the rest of the cohort, these high-IL-5 subjects displayed reduced levels of SWA-specific IgE in plasma 21 days posttreatment. Twenty months after treatment, the intensity of reinfection was positively correlated with the increase in plasma IL-5 level seen 1 day posttreatment. These studies describe the heterogeneity in early immune reactions to treatment, identifying subgroups who have different patterns of reaction and who may have different capacities to mount the responses that have been associated with resistance to reinfection.<

Journal article

Joseph S, Jones FM, Kimani G, Mwatha JK, Kamau T, Kazibwe F, Kemijumbi J, Kabatereine NB, Booth M, Kariuki HC, Ouma JH, Vennervald BJ, Dunne DWet al., 2004, Cytokine Production in Whole Blood Cultures from a Fishing Community in an Area of High Endemicity for<i>Schistosoma mansoni</i>in Uganda: the Differential Effect of Parasite Worm and Egg Antigens, Infection and Immunity, Vol: 72, Pages: 728-734, ISSN: 0019-9567

<jats:title>ABSTRACT</jats:title><jats:p>The human host is continuously exposed to the egg and the adult worm developmental stages of<jats:italic>Schistosoma mansoni</jats:italic>during chronic infections with the parasite. To assess the cytokine responses induced by these different costimulating stages and how they are influenced by host age and infection intensity, whole blood samples from a cross-sectional cohort of 226 members of a Ugandan fishing community who had been resident in an area with high transmission of<jats:italic>S. mansoni</jats:italic>for the previous 10 years or from birth were stimulated with<jats:italic>S. mansoni</jats:italic>egg antigen (SEA) or worm antigen (SWA). SWA-specific gamma interferon (IFN-γ) production increased with age, and the levels of SWA- and SEA-specific interleukin 3 (IL-3) were weakly correlated with schistosome infection intensity. The production of most cytokines was little affected by age or infection intensity but was either SEA or SWA specific. One hundred thirty-two members of the cohort coproduced IL-5 and IL-13 specifically in response to SWA, whereas only 15 produced these cytokines, and at much lower levels, in response to SEA. IL-10, IL-4, and IFN-γ were also produced in response to SWA, whereas the response to SEA consisted almost exclusively of IL-10. Our results suggest that, in contrast to what has been described for the murine model of<jats:italic>S. mansoni</jats:italic>and during acute human infections, chronic intense exposure to and infection with<jats:italic>S. mansoni</jats:italic>in this cohort resulted in very low levels of response to SEA in vitro in the presence of a vigorous and mixed Th1-Th2 response to SWA.</jats:p>

Journal article

Booth M, Mwatha JK, Joseph S, Jones FM, Kadzo H, Ireri E, Kazibwe F, Kemijumbi J, Kariuki C, Kimani G, Ouma JH, Kabatereine NB, Vennervald BJ, Dunne DWet al., 2004, Periportal Fibrosis in Human <i>Schistosoma mansoni</i> Infection Is Associated with Low IL-10, Low IFN-γ, High TNF-α, or Low RANTES, Depending on Age and Gender, The Journal of Immunology, Vol: 172, Pages: 1295-1303, ISSN: 0022-1767

<jats:title>Abstract</jats:title> <jats:p>Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6–50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-α, IFN-γ, IL-1β, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (&amp;lt;47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-γ factor scores (&amp;gt;83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-γ and relatively high (&amp;gt;60th percentile) TNF-α factor scores. Adult males at lowest risk of fibrosis had moderate TNF-α factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-α factor scores (&amp;gt;82nd percentile), or intermediate TNF-α combined with low RANTES factor scores (&amp;lt;58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.</jats:p>

Journal article

Elliott AM, Kyosiimire J, Quigley MA, Nakiyingi J, Watera C, Brown M, Joseph S, French N, Gilks CF, Whitworth JAGet al., 2003, Eosinophilia and progression to active tuberculosis in HIV-1-infected Ugandans, TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, Vol: 97, Pages: 477-480, ISSN: 0035-9203

Journal article

Naus CWA, Jones FM, Satti MZ, Joseph S, Riley EM, Kimani G, Mwatha JK, Kariuki CH, Ouma JH, Kabatereine NB, Vennervald BJ, Dunne DWet al., 2003, Serological Responses among Individuals in Areas Where Both Schistosomiasis and Malaria Are Endemic: Cross‐Reactivity between<i>Schistosoma mansoni</i>and<i>Plasmodium falciparum</i>, The Journal of Infectious Diseases, Vol: 187, Pages: 1272-1282, ISSN: 0022-1899

Journal article

Elliott AM, Mawa PA, Joseph S, Namujju PB, Kizza M, Nakiyingi JS, Watera C, Dunne DW, Whitworth JAGet al., 2003, Associations between helminth infection and CD4+ T cell count, viral load and cytokine responses in HIV-1-infected Ugandan adults, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 97, Pages: 103-108, ISSN: 0035-9203

Journal article

King A, Allan DSJ, Bowen M, Powis SJ, Joseph S, Verma S, Hiby SE, McMichael AJ, Wai Loke Y, Braud VMet al., 2000, HLA-E is expressed on trophoblast and interacts with CD94 / NKG2 receptors on decidual NK cells, European Journal of Immunology, Vol: 30, Pages: 1623-1631, ISSN: 0014-2980

Journal article

BRUNET LR, JOSEPH S, DUNNE DW, FRIED Bet al., 2000, Immune responses during the acute stages of infection with the intestinal trematode <i>Echinostoma caproni</i>, Parasitology, Vol: 120, Pages: 565-571, ISSN: 0031-1820

<jats:p>This study investigated the nature of the immune response of C57BL/6 mice infected with the trematode <jats:italic>Echinostoma caproni</jats:italic>. To determine the preferential development of either a Th1 or Th2 cytokine pattern during early stages of infection, cytokine production by spleen and mesenteric lymph node (MLN) cells during the first 3 weeks of infection was followed. Whereas spleen cells failed to respond to antigen stimulation, MLN cells produced IFN-γ and to a lesser extent IL-4. IL-5 levels were elevated throughout the period studied. The humoral response was consistent with a Th1 cytokine pattern as antigen-specific IgG2a antibodies were preferentially developed. We investigated whether IFN-γ is critical for establishment of <jats:italic>E. caproni</jats:italic> infection. Worm burden in infected mice treated with a single injection of anti-IFN-γ mAb was significantly reduced compared to that of animals treated with a control antibody.</jats:p>

Journal article

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