Low dose oral alpha-interferon therapy for patients seropositive for human immunodeficiency virus type-1 (HIV-1)

Thirty eight symptomatic and two asymptomatic patients seropositive for human immunodeficiency virus type-1 (HIV-1) were treated with a natural human interferon alpha (HuIFN alpha). Patients were given 2 IU/kg HuIFN alpha orally once daily in powdered maltose held in the mouth to promote mucosal absorption. This oral immunomodulating HuIFN alpha therapy resulted in an increase in CD4+ lymphocytes, an increase in weight, and a dramatic alleviation of clinical symptoms related to HIV-1 infection.     

Naturally acquired CD8+ cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein.

In rodent malaria model systems, protective immunity induced by immunization with irradiated sporozoites is eliminated by in vivo depletion of CD8+ T cells, and adoptive transfer of CTL clones against the circumsporozoite protein protects against malaria. We recently demonstrated that volunteers immunized with irradiated Plasmodium falciparum sporozoites produce CTL against peptide 368-390 of the P. falciparum circumsporozoite protein. To determine whether natural exposure to malaria induced similar CTL, we studied 11 adult, male, life-long residents of a highly malarious area of Kenya, who were selected because their lymphocytes had been shown to proliferate after stimulation with peptides 361-380, 371-390, or 368-390 and because nine had been resistant to malaria in previous studies. In four of the 11 individuals there was peptide-specific, genetically restricted, CTL activity. In all four individuals, this activity was unaffected by depletion of CD4+ T cells. In three volunteers the activity was eliminated or reduced by depletion of CD8+ T cells; in the fourth volunteer the CD8+ T cell depletion was uninterpretable. This first demonstration of CD8+ T cell, genetically restricted, Ag-specific CTL against a malaria protein among individuals exposed to endemic malaria provides a foundation for studying the relationship between circulating CTL and resistance to malaria infection.     

Untargeted metabolomics reveals differences between commercial and non-commercial Camellia sinensis cultivars used in black tea production

Journal of Plant Biochemistry and Biotechnology - Tea (Camellia sinensis) has enthralled both consumers and researchers, due to its taste, aroma and its medicinal attributes. Tea consumers concern...     

Human cord blood CD4+CD25hi regulatory T cells suppress prenatally acquired T cell responses to Plasmodium falciparum antigens

In malaria endemic regions, a fetus is often exposed in utero to Plasmodium falciparum blood-stage Ags. In some newborns, this can result in the induction of immune suppression. We have previously shown these modulated immune responses to persist postnatally, with a subsequent increase in a child's susceptibility to infection. To test the hypothesis that this immune suppression is partially mediated by malaria-specific regulatory T cells (T(regs)) in utero, cord blood mononuclear cells (CBMC) were obtained from 44 Kenyan newborns of women with and without malaria at delivery. CD4(+)CD25(lo) T cells and CD4(+)CD25(hi) FOXP3(+) cells (T(regs)) were enriched from CBMC. T(reg) frequency and HLA-DR expression on T(regs) were significantly greater for Kenyan as compared with North American CBMC (p < 0.01). CBMC/CD4(+) T cells cultured with P. falciparum blood-stage Ags induced production of IFN-γ, IL-13, IL-10, and/or IL-5 in 50% of samples. Partial depletion of CD25(hi) cells augmented the Ag-driven IFN-γ production in 69% of subjects with malaria-specific responses and revealed additional Ag-reactive lymphocytes in previously unresponsive individuals (n = 3). Addition of T(regs) to CD4(+)CD25(lo) cells suppressed spontaneous and malaria Ag-driven production of IFN-γ in a dose-dependent fashion, until production was completely inhibited in most subjects. In contrast, T(regs) only partially suppressed malaria-induced Th2 cytokines. IL-10 or TGF-β did not mediate this suppression. Thus, prenatal exposure to malaria blood-stage Ags induces T(regs) that primarily suppress Th1-type recall responses to P. falciparum blood-stage Ags. Persistence of these T(regs) postnatally could modify a child's susceptibility to malaria infection and disease.     

Immunity in human schistosomiasis mansoni: cross-reactive IgM and IgG2 anti-carbohydrate antibodies block the expression of immunity

We have previously reported that the slow development of immunity to reinfection after treatment of Schistosoma mansoni infections is partly attributable to the continued presence of 'blocking' antibodies in young, susceptible children. A further analysis of this phenomenon supports the hypothesis that such blocking antibodies can be of the IgG2 as well as the IgM isotype, and that they react with carbohydrate epitopes expressed both on egg polysaccharides and on schistosomulum surface antigens, of particular importance being those antigens that are shed from the schistosomulum surface during the early stages of maturation in vitro. Evidence is also presented that, in those patients lacking high levels of IgG2 blocking antibodies, resistance to reinfection after treatment is associated with the presence of other IgG isotypes against the same shed antigens.     

Fine specificity of neonatal lymphocytes to an abundant malaria blood-stage antigen: epitope mapping of Plasmodium falciparum MSP1(33)

Cord blood T cells have been reported to respond to a variety of exogenous Ags, including environmental allergens and various viruses and parasites, as demonstrated by enhanced proliferation and cytokine secretion. This finding is evidence that Ags in the maternal environment transplacentally prime and result in fetal development of memory T cells. Some studies suggest these neonatal T cell responses may arise by nonspecific activation of T cells that express TCRs with low binding affinity, thus lacking fine lymphocyte specificity. To address this question, we examined malaria Ag stimulation of human cord and adult blood mononuclear cells in samples from residents of a malaria endemic area in Kenya. We constructed overlapping 18-mer peptides derived from sequences contained in dimorphic alleles of the C-terminal 33-kDa fragment of Plasmodium falciparum merozoite protein 1. This study identified a dominant T cell epitope for one MSP1(33) allele (MAD20) and two T cell epitopes for the second allele (K1); these epitopes were nonoverlapping and allele specific. In a given donor, peptide-specific proliferation and IFN-gamma secretion were highly concordant. However, IL-10 and IL-13 secretion were not correlated. Importantly, the fine specificity of lymphocyte proliferation and cytokine secretion in cord and adult blood mononuclear cells was similar. Cord blood cells obtained from malaria-infected pregnant women were 4-fold more likely to acquire a peptide-specific immune response. We conclude that the fetal malaria response functions in a fully adaptive manner and that this response may serve to help protect the infant from severe malaria during infancy.     

Social and Economic Characteristics of Street Youth by Gender and Level of Street Involvement in Eldoret,Kenya

Background

Street-connected youth are a neglected and vulnerable population, particularly in resource-constrained settings. The development of interventions and supports for this population requires insight into how they live. This study describes the social and economic characteristics of a convenience sample of street youth (SY) in Eldoret, Kenya.

Methods

Participants were eligible if they were aged 12–21, living in Eldoret, spending days only (part-time), or nights and days on the street (full-time) and able and willing to consent or assent. Data were collected using a standardized interview conducted in English or Kiswahili. Binary dependent variables were having been arrested and/or jailed, and first priority for spending money (food vs. other). Nominal categorical dependent variables included major source of support, and major reason for being street-involved. Multivariable analysis used logistic regression models to examine the association of gender and level of street-involvement with social and economic factors of interest adjusting for age and length of time on the street. Data were analyzed using SAS 9.3.

Results

Of the 200 SY enrolled, 41% were female, mean age of 16.3 years; 71% were on the street full-time, and 29% part-time. Compared with part-time SY, full-time SY were more likely to have been arrested (Adjusted Odds Ratio [AOR]: 2.33, 95% Confidence Interval [95%CI]:1.01–5.35), name food as their first spending priority (AOR: 2.57, 95%CI:1.03–6.45), have left home due to violence (AOR: 5.54, 95%CI: 1.67–18.34), and more likely to report friends on the street as a major source of support (AOR: 3.59, 95% CI: 1.01–12.82). Compared with females, males were more likely to have ever been arrested (AOR: 2.66, 95%CI:1.14–6.18), and to have ever been jailed (AOR: 3.22, 95%CI:1.47–7.02).

Conclusions

These results suggest a high degree of heterogeneity and vulnerability among SY in this setting. There is an urgent need for interventions taking into consideration these characteristics.     

Quantifying Age-Related Rates of Social Contact Using Diaries in a Rural Coastal Population of Kenya

Background

Improved understanding and quantification of social contact patterns that govern the transmission dynamics of respiratory viral infections has utility in the design of preventative and control measures such as vaccination and social distancing. The objective of this study was to quantify an age-specific matrix of contact rates for a predominantly rural low-income population that would support transmission dynamic modeling of respiratory viruses.

Methods and Findings

From the population register of the Kilifi Health and Demographic Surveillance System, coastal Kenya, 150 individuals per age group (<1, 1–5, 6–15, 16–19, 20–49, 50 and above, in years) were selected by stratified random sampling and requested to complete a day long paper diary of physical contacts (e.g. touch or embrace). The sample was stratified by residence (rural-to-semiurban), month (August 2011 to January 2012, spanning seasonal changes in socio-cultural activities), and day of week. Usable diary responses were obtained from 568 individuals (∼50% of expected). The mean number of contacts per person per day was 17.7 (95% CI 16.7–18.7). Infants reported the lowest contact rates (mean 13.9, 95% CI 12.1–15.7), while primary school students (6–15 years) reported the highest (mean 20.1, 95% CI 18.0–22.2). Rates of contact were higher within groups of similar age (assortative), particularly within the primary school students and adults (20–49 years). Adults and older participants (>50 years) exhibited the highest inter-generational contacts. Rural contact rates were higher than semiurban (18.8 vs 15.6, p = 0.002), with rural primary school students having twice as many assortative contacts as their semiurban peers.

Conclusions and Significance

This is the first age-specific contact matrix to be defined for tropical Sub-Saharan Africa and has utility in age-structured models to assess the potential impact of interventions for directly transmitted respiratory infections.     

Nutritional Status of Orphaned and Separated Children and Adolescents Living in Community and Institutional Environments in Uasin Gishu County,Kenya

Objective

To describe the nutritional status of orphaned and separated children and adolescents (OSCA) living in households in the community (HH), on the street, and those in institutional environments in western Kenya.

Methods

The study enrolled OSCA from 300 randomly selected households (HH), 19 Charitable Children’s Institutions (CCIs), and 100 street-involved children. Measures of malnutrition were standardized with Z-scores using World Health Organization criteria; Z-scores ≤-2 standard deviations (sd) were moderate-severe malnutrition. Data were analyzed using multivariable logistic regression adjusting for child age, sex, HIV status, whether the child had been hospitalized in the previous year, time living with current guardian, and intra-household clustering for adequacy of diet and moderate-severe malnutrition.

Results

Included are data from 2862 participants (1337 in CCI’s, 1425 in HH’s, and 100 street youth). The population was 46% female with median age at enrolment of 11.1 years. Only 4.4% of households and institutions reported household food security; 93% of children in HH reported an adequate diet vs. 95% in CCI’s and 99% among street youth. After adjustment, OSCA in HH were less likely to have an adequate diet compared to those in CCI’s (AOR 0.4, 95% CI 0.2–1.0). After adjustment, there were no differences between the categories of children on weight-for-age, weight-for-height, or BMI-for-age. Children living in HH (AOR 2.6, 95% CI: 2.0–3.4) and street youth (AOR: 5.9, 95% CI: 3.6–9.5) were more likely than children in CCI’s to be low height-for-age.

Conclusion

OSCA in HH are less likely to have an adequate diet compared to children in CCI’s. They and street children are more likely to be moderately-severely low height-for-age compared to children in CCI’s, suggesting chronic malnutrition among them.     

HLA-DR-promiscuous T cell epitopes from Plasmodium falciparum pre-erythrocytic-stage antigens restricted by multiple HLA class II alleles

Previously, we identified and established the antigenicity of 17 CD8+ T cell epitopes from five P. falciparum Ags that are restricted by multiple common HLA class I alleles. Here, we report the identification of 11 peptides from the same Ags, cicumsporozoite protein, sporozoite surface protein 2, exported protein-1, and liver-stage Ag-1, that bind between at least five and up to 11 different HLA-DR molecules representative of the most common HLA-DR Ags worldwide. These peptides recall lymphoproliferative and cytokine responses in immune individuals experimentally immunized with radiation-attenuated Plasmodium falciparum sporozoites (irradiated sporozoites) or semi-immune individuals naturally exposed to malaria in Irian Jaya or Kenya. We establish that all peptides are recognized by individuals of each of the three populations, and that the frequency and magnitude of helper T lymphocyte responses to each peptide is influenced by the intensity of exposure to P. falciparum sporozoites. Mean frequencies of lymphoproliferative responses are 53.2% (irradiated sporozoites) vs 22.4% (Kenyan) vs 5.8% (Javanese), and mean frequencies of IFN-gamma responses are 66.3% (irradiated sporozoites) vs 27.3% (Kenyan) vs 8. 7% (Javanese). The identification of HLA class II degenerate T cell epitopes from P. falciparum validates our predictive strategy in a biologically relevant system and supports the potential for developing a broadly efficacious epitope-based vaccine against malaria focused on a limited number of peptide specificities.