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Function-related antigens on the neutrophil (PMN) surface were identified using two newly developed PMN-specific mouse monoclonal antibodies. These IgG antibodies, designated Ab 1-14 and Ab 1-15, were selected for detailed study after initial testing revealed their significant inhibition of PMN superoxide generation in response to N-formyl-Met-Leu-Phe (FMLP) (64% for 1-14 and 64% for 1-15; P less than .05). In further experiments, Ab 1-14 augmented PMN adhesion (by 111%; P less than .01) and degranulation (by 52%; P less than .05) in response to FMLP, while Ab 1-15 inhibited these responses by 42% and 29%, respectively (P less than .05). Ab 1-14 reduced PMN chemotaxis in response to FMLP by 37% (P less than .02), and unlike Ab 1-15, Ab 1-14 significantly reduced unstimulated PMN binding of complement-coated sheep red blood cells. Ab 1-14 and Ab 1-15 significantly reduced PMN superoxide production in response to phorbol myristate acetate (PMA) (14% and 23%, respectively; P less than .05). Whereas 1-14 was found to increase PMA-induced cell degranulation significantly (175%), Ab 1-15 did not alter degranulation response to PMA. Immunoprecipitation showed that Ab 1-14 and Ab 1-15 recognized respective surface antigens of 94,000 mol wt and 130,000 to 180,000 mol wt. Our findings suggest that the surface molecules identified by these two monoclonal antibodies play a significant role in neutrophil activation by both FMLP and PMA.

The dynamics of biosynthesis and accumulation of collagenous proteins and glycosaminoglycans (GAGs) in liver granulomas induced by eggs of Schistosoma mansoni were studied in mice following eradication of adult worms by chemotherapy. The relatively synchronous granulomas around parasite eggs were isolated from the livers at ensuing 2-week intervals; the number of recoverable granulomas per liver gradually decreased and was 7% of initial values at 20 weeks. Hepatic or granuloma-associated extracellular matrix components increased for 4 weeks after treatment despite cessation of ova deposition. At 12 weeks after chemotherapy the rate of GAG biosynthesis per total liver granuloma fraction, measured by 3H-glucosamine incorporation, decreased dramatically; this was followed by a decrease in the amount of GAGs present. The rate of collagen biosynthesis per total liver granuloma fraction, measured by 3H-proline incorporation, began to decline at 14 weeks and a decrease in the amount of collagen present was noted at 16 weeks. Our results demonstrated that liver granulomas induced by S. mansoni eggs synthesize collagens and GAGs for about 4-6 weeks following parasitological cure. The subsequent resolution of granulomas proceeds first by a reduction in GAG biosynthesis followed 4-8 weeks later by decreased collagen biosynthesis, followed by accelerated resolution of both collagen and GAGs.

Several studies of schistosomiasis haematobia in Africa have revealed a correlation between intensity of infection as measured by urine egg counts and severity of disease as determined by intravenous pyelography. The present study consisted of a survey of 390 school children in the coastal area of Kenya involving a single egg count, and intravenous pyelograms in a stratified random sample of 69 children; the results showed a greater prevalence of urinary tract disease in those with higher intensities of infection. This survey was then followed by a more detailed study in which nine consecutive daily egg counts were done on 121 children; 17 of these children, subdivided into three groups with different intensities in infection, were given intravenous pyelograms. The results were similar in the 11 children with minimal and moderate counts (averaging, respectively, less than 1 egg and 167 eggs/10 ml urine daily), with approximately 30% having bladder or renal abnormalities. In comparison, all of the six children with heavy counts (averaging 1,288 eggs/10 ml urine daily) had bladder lesions and five of them had renal lesions.

Niridazole, an anti-parasitic drug, suppresses manifestations of delayed hypersensitivity and retards allograft rejection in laboratory animals. We investigated the immunosuppressive effects of the standard antihelminthic regimen of niridazole (25 mg/kg/day for seven days) in five patients with schistosomiasis. Although 15-minute skin reactions to schistosomal antigens remained unchanged, niridazole reduced or ablated positive 48-hour skin reactions to tuberculin (PPD), mumps and schistosome antigens in all patients tested six and 15 days after therapy began. Complete recovery of delayed dermal hypersensitivity was observed by 114 days. PPD-induced lymphocyte transformation was severely depressed in three and partially depressed in two of the five patients. Suppression was observed at either six or 15 days (or both) after beginning of treatment, and complete recovery at 114 days. It is concluded that therapeutic doses of niridazole suppress delayed hypersensitivity and antigen-induced lymphocyte transformation in man.

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.

In schistosomiasis mansoni, the pathogenesis of hepatosplenic disease has been shown to be due primarily to immune mechanisms. The present study was designed to examine the relationship between the development of schistosomal hepatosplenomegaly in Egyptian school children and the HLA antigens. Two groups of schistosome-infected children with similar fecal egg counts were examined: one group (23 children) had no clinically demonstrable hepatosplenomegaly whereas all the children (28) in the second group suffered from liver enlargement. Furthermore, 13 of the 28 individuals in the latter group had splenomegaly as well. Our results show that hepatosplenomegaly was related to the presence of two HLA antigens: HLA AI and B5. The average relative risk of developing hepatomegaly is 29 for HLA AI and 18.9 for 55.6. Furthermore, the severity of hepatomegaly was correlated with the presence of these two HLA antigens. These findings represent a step toward elucidating the factors controlling the pathogenic mechanisms in human schistosomiasis mansoni.

Mutation diabetes in the mouse occurs in the C57BL/Ks strain. All homozygous animals (db/db) develop obesity, elevated blood sugar levels and increased or normal blood insulin concentration. The defects in cellular immunity in db/db mice and their littermate controls were examined both in vivo and in vitro. Significant suppression of delayed footpad swelling and first and second set skin allograft rejection time were observed. In addition, DNA synthesis in spleen cells after nonspecific mitogen stimulation was markedly inhibited. Diabetic animals with a mean blood sugar of 512 +/- 101 mg/100 ml did not respond to exogenous insulin therapy by lowering their blood sugar levels or reversing the defect in DNA synthesis. Adding insulin to spleen cell culture in vitro had no demonstrable effect on their response to mitogens. Thus, mutation diabetic mice with their known defect in the peripheral utilization of insulin have markedly suppressed cell-mediated immune mechanisms.

Freeze-thaw (FT)-disrupted schistosomula or their membrane extract induced significant resistance in mice to Schistosoma mansoni infection (34 and 25%, respectively) without the use of adjuvant. Antigens identified in schistosome extracts by sera from immunized animals were then evaluated for protective potential. Immunization with schistosomal antigens of 97 and 68-70 kD resulted in significant protection that was equivalent to that obtained by FT schistosomula. Since the 97-kD antigen was suggested to be parasite paramyosin, we used a biochemical technique to purify this muscle protein. Purified schistosome paramyosin ran as a single band on 10% SDS-PAGE and was recognized both by sera from mice immunized with FT schistosomula and a polyclonal antiserum raised against the 97-kD parasite protein. Preincubation of schistosome paramyosin with sera from mice immunized with FT schistosomula resulted in the removal of reactivity with the 97-kD protein in crude worm extracts. Paramyosin was identified by Western blotting to be in the tegument of schistosomula. The purified schistosome paramyosin resulted in significant protection in three separate experiments (24, 46, and 53%) without the use of adjuvant. Addition of BCG to paramyosin resulted in enhanced protection.

Eosinophilopoietin (EPP) was previously characterized by the ability to stimulate eosinophil production in vivo, but these studies could not ascertain whether EPP had a direct effect on the bone marrow or acted indirectly by causing release of eosinophilopoietic activity by other tissues. The present studies demonstrate that EPP stimulates eosinophil growth in liquid culture of mouse bone marrow in vitro. The timing of stimulation by EPP in vivo and in vitro were parallel, with maximal eosinophil growth after 48 hr. Moreover, EPP appears similar to, and possible identical with, the eosinophil growth-stimulating substance (EO-GSF) released by antigenic stimulation of immune nonadherent spleen cells. Both EPP and EO-GSF are of low molecular weight, both produce stimulation of eosinophil growth with identical kinetics, and both produced similar dose-response curves in the liquid culture system.

Resistance to Schistosoma mansoni infection in the mouse has been induced either specifically by a primary infection with this parasite or nonspecifically by a variety of immunostimulants such as BCG. In the present study we developed an in vitro system to examine the effector mechanism of nonspecifically induced resistance. Activated macrophage monolayers obtained from BCG- or Corynebacterium parvum treated mice killed a respective mean 32 +/- 6% and 48 +/- 5% of schistosomula after 24 hr incubation. The killing of the parasites was verified by their inability to mature to adult worms upon injection into normal mice. The activated macrophage-mediated killing was related to cell:parasite ratio, and was partially lost if the macrophage monolayers were kept in cultures for 24 hr before incubation with the organism. Supernatants of macrophages cultured in the presence of schistosomula killed a mean of 51 +/- 3% of the organisms whereas those from cells cultured alone resulted in a mean killing of 25 +/- 3%. Furthermore, toxic supernatants could be generated equally well on incubation with S. mansoni schistosomula or Trichinella spiralis larvae. Our data show that activated macrophage monolayers through soluble mediators destroy a significant proportion of the multicellular parasite S. mansoni schistosomula in vitro.

The present study was designed to examine the possible association of HLA antigens and schistosomal hepatosplenomegaly and colonic polyposis in a large number of patients and controls. The results show that hepatosplenomegaly was significantly associated with the presence of two HLA antigens: HLA-A1 and B5; and colonic polyposis to HLA-B5 and B8. Furthermore, asymptomatic infection was significantly seen more in subjects with CW2. These results point to possible gentic factors controlling the pathogenesis of disease and susceptibility to infection in human schistosomiasis.

1. Mice were infected with fertile bisexual Schistosoma mansoni and compared with similar animals infected with unisexual worms or sterile bisexual worms. 2. A significant increase in splenic weight occurred in all infected animals. 3. Administration of well-tolerated doses of 6-mercaptopurine abolished the increase in relative splenic weight in animals infected with ordinary S. mansoni. 4. In splenectomized uninfected mice leucocytosis but no other haematological changes developed. 5. In splenectomized mice lower values for packed cell volume were observed 8 weeks after, but not 12 weeks after, infection with S. mansoni. 6. Slight prolongation of the life-span of erythrocytes occurred in splenectomized infected mice. 7. It is concluded that anaemia in schistosomiasis depends to a significant extent on immunity developed to adult schistosomal worms and can develop in the absense of schistosomal ova. 8. The anaemia resulting from such an immune response may be suppressed by administration of 6-mercaptopurine. 9. Such anaemia occurs even in splenectomized mice; thus hypersplenism is not necessary for its development although splenectomy slightly prolongs the erythrocyte life-span.

Antieosinophil serum (AES), obtained by immunizing rabbits with a highly purified suspension of mouse eosinophils, contains high titers of specific agglutinating and cytotoxic antibodies to eosinophils. Absorption with macrophages, lymphocytes, and neutrophils does not affect the antieosinophilic activity while it is markedly lowered by absorption with eosinophils. One dose of AES (0.1 ml) injected into mice with schistosomiasis mansoni caused a mean decrease in circulating eosinophils of 90% within 1 h which was maintained for 5 days, followed by gradual recovery. No other changes in the total or differential white cell counts were noted. In normal mice AES markedly depressed exudation of eosinophils in the peritoneal cavity after repeated saline stimulation. Some of the immunological and clinical implications of a monospecific AES are discussed.