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.
SUMMARYAntigenic polymorphism and HLA restriction may limit the immunogenicity of a subunit vaccine against liver-stage Plasmodium falciparum. We examined 59 clinical isolates and five laboratory clones of P. falciparum for polymorphism in the N-and C-terminal regions of LSA-1, evaluated binding of the corresponding peptides to selected HLA class I alleles, and measured IFN-g responses in residents of a malaria-endemic area of Papua New Guinea where HLA-A*1101, -24, -B13, and -B40 are the most common class I alleles. LSA-1 polymorphism was limited to a single non-synonymous mutation encoding serine (S), proline (P), or threonine (T) at amino acid 85. Nine-mer 84±92 peptides with S, T, or P at the primary anchor position bound differentially to HLA-A11, -A2, and -B7. IFN-g ELISPOT responses increased with age in malaria-exposed subjects: 14±16% and 30±36% of 2±5-and 6±54-yearolds, respectively, had $ 10 IFN-g-secreting cells/10 6 peripheral blood mononuclear cells when stimulated with at least one peptide variant (P , 0´05). IFN-g responses to all three peptides were also greater for older than younger individuals. No children , 3 years old had lymphocytes that responded to all three 84±92 peptides, whereas 45% of adults (mean age 48 years) had aggregated IFN-g responses. These data support the notion that age-related cumulative exposure to P. falciparum increases the frequency of IFN-g responses to polymorphic epitopes of liver-stage antigens such as LSA-1.
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-␥) production driven by LSA1 peptides ranged from 34 to more than 3,500 pg/2 ؋ 10 6 cells, was derived primarily from CD8 ؉ cells, and was dissociated from T-cell proliferation. The frequencies of IFN-␥ 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-␥, 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-␥ responses is consistent with a role for this T-cell population in immunity to liver-stage Plasmodium falciparum in humans.
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