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Kenyan subjects with visceral leishmaniasis were examined for evidence of increased production of soluble interleukin-4 receptor (sIL-4R). Soluble IL-4R regulates the bioactivity of IL-4, a cytokine important in mediating progressive forms of leishmaniasis. Persons with visceral leishmaniasis sustained 8- to 10-fold more circulating sIL-4R compared with Papua New Guinea residents with documented filariasis or uninfected Kenyan and North American subjects. Soluble IL-2R concentrations were elevated nonspecifically in both visceral leishmaniasis and filariasis patients. These findings are significant given that IL-4 induces sIL-4R in mice, and treatment with recombinant sIL-4R cures progressive murine leishmaniasis dependent on IL-4 bioactivity. Further studies are indicated to determine whether the immunologic detection of IL-4 produced in human visceral leishmaniasis is obscured because of sequestration by soluble receptor and whether the production of sIL-4R is relevant to the pathogenesis of visceral leishmaniasis.

A test for the lymphokine eosinophil stimulation promoter (ESP) has been adapted to the study of Trichinella spiralis infections in mice and has been used as an aid in the diagnosis of trichinosis in a patient. With use of soluble antigen extracted from T. spiralis larvae and peritoneal exudate cells rich in eosinophils obtained from mice with trichinosis of four weeks' duration, a dose-response curve was constructed and analyzed. The soluble larval antigens greatly enhanced the migration of eosinophils from the mice with trichinosis but had no effect on the eosinophils from mice with schistosomiasis, nor did soluble schistosome egg antigens have any effect on the cells from mice with trichinosis. On two occasions peripheral white blood cells from a patient with presumed T. spiralis infection gave strongly positive results in ESP tests on stimulation with soluble larval antigen, but the cells did not respond significantly to soluble schistosome egg antigen; the result in the ESP test was positive before the patient's serum produced a weakly positive agglutination response.

Intravenous administration of a lyphilized preparation of bacille Calmette-Guérin (BCG-Tice) into mice significantly protected these animals from infection with Schistosoma mansoni. The protective effect depended on the dose of BCG and required the administration of at least 2 X 10(7) viable organisms. The route of administration of BCG was also crucial, as only intravenous inoculation produced significant protection. The BCG-induced resistance was found to last for eight weeks. Significant inflammation of the lungs was observed in mice receiving either viable or heat-killed BCG; however, protection followed only the administration of viable bacilli. Expression of BCG-induced protection was dependent on the presence of significant numbers of viable organisms and may have been associated with pulmonary inflammation at the time of passage of the schistosomula through the lungs.

Schistosomiasis is characterized clinically by an increase in eosinophil counts in bone marrow and peripheral blood. This eosinophil response is also manifest pathologically by cell accumulation around the invading schistosomula and the parasite ova retained in host tissues. The parasites undergo a series of antigenic and maturational changes within the host that result in two distinct peaks of eosinophilia. Furthermore, products of parasite interaction with complement, antibodies, and sensitized T lymphocytes have been shown to enhance eosinophil migration and chemotaxis. Eosinophils, which constitute a prominent cellular component in the host response to the schistosomes, may be activated biochemically. Both in vivo and in vitro studies have delineated a protective role for the eosinophils against schistosomula and eggs. The ability of these cells to destroy multicellular parasites has been shown to be due to highly reactive oxygen reduction products or to release of cationic or major basic proteins from the granules.

The influence of genetic factors on the manifestations of disease associated with infection with Schistosoma mansoni (portal hypertension, liver granulomas, hepatosplenomegaly) and their modulation were studied in inbred strains of mice. Three groups were identified according to the degree of portal hypertension: high (portal venous pressure, 19.1 cm H2O: DBA/1J), intermediate (8.9-13.4 cm H2O; BALB/cJ, DBA/2J, CBA/CaJ, C3H/HeJ, and BUB/BnJ), and low responders (6.1 cm H2O; C57BL/6J). Granuloma size, organomegaly, and portal venous pressure were strain dependent and not H-2 dependent and were determined by more than one gene. Studies of schistosomiasis in the F1 generation of high and low responders indicated that more than one gene is involved. Modulation of portal venous pressure between eight and 20 weeks of infection occurred in C57BL/6J but not in BALB/cJ mice and was transferable with immune lymphoid cells. These data indicate that disease associated with infection with S. mansoni and its modulation in mice are influenced by the genetic (non-H-2) background of the host and dependent in part on cell-mediated immunity.

An in vitro assay for the new lymphokine eosinophil stimulation promoter has been adapted for use with human material. Peripheral eosinophils from patients with schistosomiasis mansoni were specifically induced to migrate on incubation with egg antigen. Furthermore, the peripheral lymphocytes of these patients on incubation with the egg antigen secreted the lymphokine eosinophil stimulation promoter, which enhanced the migration of purified eosinophils from patients with or without schistosomiasis. The test can be easily performed with human target cells and may be helpful for diagnostic or investigative purposes.

The present investigations of the recently discovered lymphokine eosinophil stimulation promoter have (1) shown that the assay system is highly sensitive and reproducible via the establishment of dose-response curves and their statistical analysis, (2) demonstrated that the direct assay is specific with use of eosinophilrich peritoneal exudate cells obtained from mice with either schistosomiasis or trichinosis, (3) demonstrated that the indirect test with splenic lymphocytes is specific with use of both the above method and radioisotope-labeled antigens, and (4) provided information on the roles of eosinophils and mononuclear cells via purification, reconstitution, and the use of antiserum to eosinophils.

The effect of streptozotocin-induced diabetes mellitus on both the host and the parasite was studied in mice infected with Schistosoma mansoni. Neither the drug nor the marked rise in concentration of blood glucose had any effect on penetration of the skin by the cercariae, their subsequent maturation into adult worms, or their output of eggs. During the acute stages of the infection (at eight weeks), the diabetic animals showed marked suppression of the host granulomatous reaction to schistosome eggs trapped in the liver, accompanied by an alleviation of hepatosplenic disease. During the chronic stages of infection (at 16 weeks), there was a pronounced megalocytosis of the hepatocytes only in the infected animals with streptozotocin-induced diabetes; these animals also had an exacerbation of hepatosplenic disease.

Infection with Toxoplasma gondii has been shown to suppress markedly the in vitro splenic lymphocyte response to nonspecific mitogens and the in vivo antibody response to sheep red blood cells. The effect of toxoplasmosis on an in vivo cell-mediated response, granuloma formation around Schistosoma mansoni eggs, was examined in the present study. The granulomas were markedly suppressed from two to 20 weeks after infection with T. gondii. In subsequent experiments the effect of toxoplasmosis-induced immunosuppression on the development of hepatosplenic schistosomiasis was evaluated. Mice with the combined infections had markedly smaller hepatic granulomas and lower mean portal pressures than those infected with S. mansoni alone. Although the prevalence of esophageal varices in the mice with schistosomiasis alone was 60%, there was no visible collateral circulation in the animals with both infections.

Resistance to schistosomiasis in mice can be acquired either specifically, by primary infection with Schistosoma mansoni, or nonspecifically, by treatment with a variety of unrelated agents such as bacille Calmette-Guérin. Several immunoadjuvants related to mycobacteria were examined for their ability to induce resistance to schistosomiasis. Natural cord factor (6,6'-trehalose dimycolate), a 100-carbon synthetic cord factor analogue, and dipalmitate trehalose induced significant protection. Trehalose dibehenate and muramyl dipeptide did not induce consistent protection. Since protection acquired by primary schistosomal infection or by any of these potentiating agents is partial, their possible additive effect was evaluated. The resistance of mice with schistosomiasis that were injected with trehalose dipalmitate and challenged with schistosomal cercariae was increased, as assayed by recovery of schistosomula from the lungs and of adult worms from the portal system. Thus, these synthetic adjuvants not only induce partial protection against schistosomiasis, but also significantly enhance acquired immunity in mice with primary infections.

Lymphocyte reactivity and its control was assessed in human hepatosplenic schistosomiasis, a disease in which host hypersensitivity may contribute to long-term morbidity. Antigen- and mitogen-induced incorporation of [3H]thymidine was evaluated in peripheral blood and splenic mononuclear cells of 15 patients at the time of splenectomy. The response to phytohemagglutinin (PHA) was depressed in the peripheral blood of 42% and in the spleen cells of 70% of these patients. Significant stimulation was noted, however, upon culture of blood with soluble schistosome egg antigen (SEA) in 80% and of spleen cells in 100% of the patients whose respective responses to PHA were depressed. The contribution of adherent cells to the overall response of mononuclear cells was evaluated by depletion techniques. A significant and specific decrease in the response of the resulting thymus-derived (T) lymphocyte-enriched splenic mononuclear cells to SEA was noted. These studies suggest preferential preservation of the response of circulating and splenic lymphocytes to SEA despite impairment of PHA reactivity in human hepatosplenic schistosomiasis, which may be causally related to the advanced disease of this group of patients. Moreover, activity of helper adherent cells was consistently restricted to the splenic T-lymphocyte response induced by the specific antigen SEA.

Vaccination with SmW68, a Schistosoma mansoni surface antigen, significantly protects mice against challenge infection. To investigate the vaccine potential of SmW68 in clinical schistosomiasis, human antibody response to SmW68 was studied as a function of intensity of infection in a chronically infected Egyptian population. In 85 serum samples obtained randomly from families in El Gazairy (population 1,310), antibody to SmW68 (determined by ELISA) was found to increase significantly with age, reaching a plateau at 15-19 y, 1-5 y after peak prevalence and intensity of infection. Among infected individuals (n = 54), antibody response showed a significant inverse correlation (r = -.28, P less than .04) with intensity of infection. In isotype analysis, a higher IgM but not IgG response was significantly associated with low parasite burden. These studies demonstrate that significant antibody response to SmW68 could occur in chronically infected humans. Whether parasite burdens suppress circulating levels of antibody to SmW68 or whether enhanced antibody response to SmW68 represents acquired protective humoral immunity remains to be determined.