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

Abstract

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 Schistosoma mansoni-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 beta 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 (n = 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 (>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.

Figures

FIG. 1.

Pretreatment intensity of infection and changes in plasma IL-5 concentration. The intensity of infection before treatment, defined as number of S. mansoni eggs per gram of feces, is plotted against the plasma IL-5 concentration in blood taken before treatment and at 1 day posttreatment (n = 64).

FIG. 2.

Cytokine production in whole-blood cultures. Blood taken before treatment (day 0) or at 1 or 21 days after treatment was diluted with 5 volumes of medium only (control) or medium containing SEA or SWA to give final antigen concentrations of 10 μg/ml. After 96 h of culture supernatants were harvested for analysis. The broad lines indicate median values (n = 51). The boxes represent the 25th to 75th percentile ranges, and the error bars show the ranges of data excluding outlying values and extremes. For antigen specificity, for a given stimulus, results significantly different (Wilcoxon signed rank test) from the equivalent “medium only” result are indicated by +++ (P < 0.001), ++ (P = 0.001 to 0.01), and + (0.01 to 0.05). For change in response following treatment, for a given time point results significantly different from the equivalent pretreatment result are indicated by *** (P < 0.001), ** (P = 0.001 to 0.01), and * (P = 0.01 to 0.05).

FIG. 3.

Increase in plasma IL-5 level on day 1 posttreatment and the accompanying in vitro decrease in SWA-induced cytokines. Subjects were divided into four equal groups based on the increase in their plasma IL-5 levels between pretreatment and 1 day posttreatment (n = 16 per group). The IL-5 (A), IL-13 (B), and IL-10 (C) responses to SWA of the four groups in cultures established before treatment (open boxes) and at 1 day posttreatment (hatched boxes) are shown as box plots as defined in the legend to Fig. 2. Groups where there was a significant difference (Wilcoxon signed rank test) between pretreatment and 1 day posttreatment are indicated by ** (P = 0.001 to 0.01) and * (P = 0.01 to 0.05).

FIG. 4.

Increase in plasma IL-5 level and the accompanying decrease in eosinophil counts. Subjects were divided into four equal groups (n = 16 per group) based on the increase in their plasma IL-5 levels between pretreatment and 1 day posttreatment. Group 1 increase, 0 pg/ml; group 2, 2.5 to 24 pg/ml; group 3, 25 to 100 pg/ml; group 4, >100 pg/ml. The mean eosinophil counts ± 95% confidence limits at pretreatment and 1 day posttreatment are shown for the four groups. Groups where there was a significant difference (paired t test) between pretreatment and 1 day posttreatment are indicated by *** (P = 0.001 to 0.01) and * (P = 0.01 to 0.05).

FIG. 5.

Antibody responses before and after treatment and the influence of the peak in plasma IL-5 level. Shown are scatter graphs of the pretreatment versus 21-day-posttreatment levels of IgG1, IgG4, and IgE directed against SWA and SEA. Each circle represents an individual volunteer (n = 51), and those in group 4 (first day posttreatment increase in plasma IL-5, >100 pg/ml) are indicated as filled circles. Levels were determined by isotype-specific ELISA, and the values represent means of triplicate optical density measurements.