Antisera were produced by immunizing rabbits with either a trichloroacetic acid-soluble fraction, or a high molecular weight (Mr) fraction of Schistosoma mansoni SEA (a salinesoluble fraction of homogenized egg). Both of these sera reacted monospecifically in immunoelectrophoresis against unfractionated SEA, recognizing a cathodally migrating antigen. This antigen had been identified previously as being responded to by S. mansoni-infected mouse sera, and has been designated K3 (Kappa 3). The rabbit antisera were used to partially characterize antigen K3 as having Mr in the range > 750 – 70 K, and being resistant to boiling, resistant to the action of proteases, but sensitive to periodate. It partially binds to Concanavalin A. In addition to SEA, the antigen was present in homogenized cercariae and schistosomula, but not adult worms, and it was also present in detergent extracts of intact cercariae and schistosomula. Using an antibody-dependent cell adherence assay, anti-K3 serum was found to react with the surface of live cercariae and with the surface of schistosomula recovered from the skin of mice infected up to 48 h previously. Anti-K3 serum also reacted with the surface of S. bovis, S. haematobium and to a lesser extent S. japonicum schistosomula.

Single percutaneous immunizations of Fischer rats with 1000 ultra-violet attenuated Schistosoma japonicum cercariae induced 52–88% resistance to challenge 4 weeks later. Increasing this to 3 immunizations induced 90% resistance to challenge, and this level of protection remained undiminished for up to 40 weeks after vaccination. Rats vaccinated with gamma-irradiated S. mansoni cercariae were resistant to challenge with S. mansoni but not S. japonicum. Similarly rats vaccinated with u.v.-attenuated S. japonicum cercariae were not resistant to heterologous challenge. Thus irradiated vaccines are species-specific in both permissive and non-permissive hosts.

Using foot-pad infection of female C57BL/6, DBA/2J and NMRI-IVIC mice as an animal model for American cutaneous leishmaniasis (ACL), we evaluated the inhibitory effect of Formycin B (FoB) on the infection produced by 7 different Leishmania isolates. When treatment was initiated some days, or even some weeks, after infection a significant leishmanistatic effect was detected on mice infected with all Leishmania isolates, which reached 30–55 weeks for some isolates. The optimal dose schedule was 1·25 mg/kg body weight/day, injected intraperitoneally for 20 consecutive days. Significant differences in the sensitivity of various Leishmania spp. to FoB were found, either in vivo, or in vitro where a high [3H]FoB incorporation rate was found only for certain Leishmania isolates. The low toxicity of this drug and the sensitivity of the 7 Leishmania isolates tested suggest that FoB could be useful in the treatment of ACL.

The term severe falciparum malaria implies an infection with manifestations and complications which are potentially fatal in man, the natural host for this parasite. Much that has been written on the pathophysiology of animal malarias is of doubtful relevance to the understanding of the mechanism of Plasmodium falciparum infection in man. The clinical picture of severe P. falciparum infection differs in several respects from severe animal malarias, even those of non-human primates. Cerebral dysfunction is the most common severe manifestation of falciparum malaria in man. Coma develops suddenly after a generalized convulsion or gradually towards the end of the first week of illness. There are signs of a symmetrical upper motor neurone lesion and brain-stem dysfunction, but only about 5% of survivors show persisting neurological deficit after 2 or 3 days of unconsciousness. The mortality of cerebral malaria depends on how it is defined and on the predominant age group and other factors. In patients with proved acute P. falciparum infection with unrousable coma, in whom other causes of encephalopathy have been excluded, the mortality is between 15 and 50% despite treatment with antimalarial drugs (Warrell, Looareesuwan, Warrell, Kasemsarn, Intaraprasert, Bunnag & Harinasuta, 1982).

Mucus is a sticky visco-elastic material which coats all mucosal surfaces. Florey, in 1955, noted the following three functions for gastrointestinal mucus: protection of the underlying mucosa from chemical and physical injury, lubrication of the mucosal surface to facilitate passage of luminal contents, and removal of parasites by binding and entrapment. In the 31 years since Florey's review, detailed analyses of the composition of mucus and of the biochemistry of mucin glycoproteins, as well as measurements of the physical properties of mucus from different organs and sites have yielded information at the molecular level which provide additional support for his views on its function (Allen, 1981; Forstner, Wesley & Forstner, 1982).

Three IgM monoclonal antibodies, M22G11P, M7B7 and M22B3G, which reacted with the surface of Schistosoma mansoni schistosomula in an indirect fluorescent antibody assay, were found to recognize a polysaccharide-containing egg antigen previously designated K3. The monoclonal antibodies and a monospecific rabbit anti-K3 serum also recognized a crossreacting antigen in a crude cercarial antigen preparation. In an eosinophil-mediated schistosomulum killing assay, all three monoclonal antibodies significantly inhibited the level of killing produced by human infection serum. An IgG3 monoclonal antibody, M22C1C, which also recognized the egg antigen K3, did not inhibit eosinophil-mediated killing. However, when lower concentrations of human serum were used in the assay, this monoclonal antibody significantly enhanced the level of killing, despite having no capacity to induce eosinophil-mediated damage in the absence of human infection serum. On the basis of these and other results we suggest the possibility that antibodies to S. mansoni egg antigens which cross-react with the surface of the early post-penetration schistosomulum may influence the effective expression of antibody-dependent, eosinophil-mediated effector mechanisms in human infections.

Laboratory studies on a group of 20 patients from the Rio Negro Valley, Colombia selected for detailed study showed that 14 gave antibody reactions on immunoassay consistent with Trypanosoma cruzi or T. rangeli infections. Four were diagnosed as having T. rangeli infection, 4 had mixed infections and 6 were infected with T. cruzi alone. Immunoprecipitation analysis showed that sera from T. crwzi-infected patients recognized a similar range of trypomastigote-derived polypeptides as sera from patients in Brazil, and all of the Colombian sera reacted with the 160 kiloDalton (kDa) polypeptide associated with active infection. Although sera from patients with T. rangeli infection alone gave a positive immunofluorescence or ELISA reaction with T. rangeli, they failed to bind to parasite polypeptides by either immunoprecipitation or Western blotting. Intriguingly, sera from patients with mixed infections consistently gave a stronger, but qualitatively similar, binding reaction in immunoprecipitation and Western blotting compared to sera from patients infected with T. cruzi alone.

Fischer rats infected with Fasciola hepatica showed significant resistance to Schistosoma mansoni challenge, and vice versa, whereas immunization with 20 Krad-irradiated S. mansoni cercariae failed to protect against F. hepatica challenge, but did protect against homologous challenge. When groups of rats received intraperitoneal implants of newly excysted juvenile flukes, 20- to 22-day-old juveniles, or 8- to 10-week-old flukes, none was significantly protected against S. mansoni challenge, whereas juvenile implants did protect against homologous F. hepatica challenge. In passive transfer experiments in rats, serum from F. hepatica-infected rats or rabbits protected recipients against homologous, but not heterologous challenge, and serum from rats vaccinated with 20 Krad-irradiated S. mansoni cercariae protected recipients against homologous, but not heterologous challenge. These experiments provide evidence that the mechanisms involved in homologous and heterologous resistance are different, the latter lacking immunological specificity. Microsphere injections in F. hepatica-infected rats demonstrated ‘shunting’ from the portal system to the systemic circulation. If migrating schistosomula are also ‘shunted’ in Fasciola-infected rats, this, rather than immunologically specific effector mechanisms, might explain their failure to establish in the portal system.

Alterations in the hepatic portal vasculature of NMRI mice infected with Schistosoma mansoni were assessed using a microsphere injection technique. The accumulation of eggs in the livers of infected mice and the development of portal hypertension were closely related to the worm pair burden during the first 15 weeks of infection. Individual variation between mice harbouring identical patent worm pair burdens was partially explained by the reduced fecundity of females from sexually biased infections. As eggs accumulated in the liver and portal hypertension increased, the number of injected microspheres escaping from the hepatic portal system rose in rank order of diameter from 9 μm through 15 μm and 25 μm to 50 μm. There was a strong correlation between the numbers of parasite eggs in the lungs and injected microspheres recovered from the lungs. The pattern of detection of microspheres in the lungs indicated a progressive increase in diameter of intra-hepatic porta-systemic connexions, followed by development of large-bore extra-hepatic collateral vessels. An accurate temporal profile of the pathological state of the host and the extent of collateral vessel formation was obtained. Injection of 141Ce-labelled microspheres demonstrated that the arterial supply to all organs of the body was affected by alterations in the micro-vasculature of the liver and lungs.

The inflammatory responses to lymphatic filariae and to Onchocerca volvulus are reviewed with particular attention to (1) evolutionary biology; (2) inflammatory host spectrum; (3) non-specific components; (4) immunoregulation; (5) immune evasion versus immunomodulation; (6) chronic tissue damage and scarring and (7) disease models. Basic principles of pathogenesis are emphasized, comparisons drawn with schistosome infection, and critical items of missing information are highlighted.

Embryonic stages of various Onchocerca species have been used to stimulate resistance in CBA mice to challenge injections with the microfilariae of Onchocerca lienalis. Comparable levels of resistance to challenge (29–37% reductions) were conferred by living, freeze-killed, or sonicated organisms administered with Freunds‘ Complete Adjuvant (FCA). Antigens extracted in saline, or with the detergent sodium deoxycholate, were also protective. Adjuvants enhanced the protective effect, particularly FCA (78% reduction), Freunds‘ Incomplete Adjuvant (74% reduction), aluminium hydroxide (70% reduction) and Bordetella pertussis (70% reduction). Detergent extracts prepared from intact embryos with n-octyl glucoside also stimulated significant levels of protection against microfilarial challenge when given with FCA (37–45% reductions). Levels of resistance induced by immunizations with intact organisms were greatest following subcutaneous (s.c.) injection over the neck or by intramuscular inoculation. Soluble extracts were also particially effective given by s.c. inguinal or intraperitoneal injection. A time-interval of greater than 3 weeks between the completion of immunization and challenge was required for the expression of immunity. Cross-protection against challenge with O. lienalis microfilariae was also afforded to mice by immunization with intact embryos or detergent extracts of Onchocerca gutturosa (45 and 34% reductions), Onchocerca gibsoni (66 and 47% reductions) or Onchocerca volvulus (58 and 41% reductions). It is concluded that the embryonic stages of both human and animal parasites provide a source of cross-protective antigens of value in studies on resistance to Onchocerca microfilariae in experimental hosts.

A total of 129 children were treated for Schistosoma mansoni infections, and followed for intensity of reinfection at 3-monthly intervals over a 21-month period. Blood samples were taken before treatment and at 5 weeks and 6, 12 and 18 months after treatment. This paper presents a statistical analysis of the relationship between various immune responses and subsequent reinfection. Responses analysed were: blood eosinophil levels; IgE antibodies against schistosomulum antigens; IgG antibodies mediating eosinophil-dependent killing of schistosomula; antibodies inhibiting the binding to schistosomulum antigens of two rat monoclonal antibodies that also recognize egg antigens; the levels of anti-adult worm and of anti-egg (total, IgM and IgG) antibodies; and IgM anti-schistosomulum antibodies. Results for each assay were well correlated for each of the five separate blood samples. None of the assays were predictive of resistance to reinfection, but susceptibility to reinfection was strongly correlated with results in the preceding blood samples for total anti-egg antibodies and the inhibition of binding of one of the two monoclonal antibodies. Further analysis also revealed a correlation between reinfection intensities and both IgM anti-schistosomulum antibodies and IgM and IgG anti-egg antibodies. These results are consistent with the hypothesis that early infections elicit the development, in response to egg antigens, of antibodies that block immune mechanisms directed against schistosomula. Blocking antibodies may be IgM, but might also be of an ineffective IgG isotype. The existence of such antibodies in young children would explain the slow development of immunity in the face of a range of detectable, potentially protective immune responses.

Recent progress in parasite immunobiology has led to the identification of several plasmodial antigens representing the target of the protective antibody response of the infected host. As a consequence, some of these antigens have been envisaged as potential malaria vaccines in man. However, in spite of these achievements, the fine mechanisms which lead to the development of a state of partial protective immunity or to the triggering of immunopathology during malaria infection are not yet fully understood. Thus, it may be appropriate to evaluate the relative importance of individual host immune responsiveness to parasite epitopes involved in the induction of immunity, or of some immunologically mediated adverse reactions such as glomerulonephritis, anaemia, thrombocytopenia, and cerebral syndrome.

Two isolates of Schistosoma mansoni from Puerto Rico and Egypt were examined to determine if there were differences in surface antigens of the schistosomulum and to assess the ability of the two isolates to induce protection against one another in vivo. Immune mouse and human patient antisera recognized the same antigens on the schistosomulum surface of both isolates. However, mice immunized with schistosomula-released products from the Egyptian isolate recognized an additional antigen of Mr 13K on the Egyptian schistosomulum surface which was not present in the Puerto Rican isolate. In quantitative radioimmunoassay, sera from mice vaccinated with irradiated Egyptian cercariae bound more strongly to Egyptian schistosomula than to Puerto Rican parasites. Both isolates cross-protected against each other, but mice were less immune to challenge with Egyptian cercariae after being immunized with Puerto Rican irradiated cercariae. There was no difference in immunity to challenge when Egyptian irradiated cercariae were used to immunize. Although this evidence suggested some heterogeneity within the Egyptian isolate, cloned cercariae of the Egyptian isolate did not vary in their ability to cross-protect against each other. Furthermore, antisera from mice immunized with clones of Egyptian cercariae recognized the same schistosomulum surface antigens. The results reported here indicate that although there were small differences between the two isolates the major surface antigens are conserved.

The development of resistance in mice to reinfection with Schistosoma mansoni was recorded during an early chronic infection, and compared with hepatic portal pathological and vascular changes. The latter were assessed using a microsphere injection technique. The degree of acquired resistance was directly dependent on the patent worm burden and the time post-infection. Strong correlations were noted between the development of resistance and the appearance of parasite eggs in the lungs and spleens of infected hosts. Weaker associations were present between resistance and other aspects of the disease pathology, such as portal hypertension and organ weights. The appearance of injected microspheres in the lungs and spleens correlated well with the appearance of eggs in those organs and with the development of resistance. The levels of resistance had risen and microspheres were detected in the lungs, before the development of major extra-hepatic, porta-systemic collateral vessels. It is concluded that intra-hepatic vascular alterations may be a causal factor in the development of resistance, preventing the sequestration of migrating schistosomula in the liver. It is estimated that as much as 70–75% of the recorded resistance can be attributed to this immunologically non-specific mechanism.

All serum transfers from donor rats or rabbits given single or multiple vaccinations of ultraviolet (u.v.)-attenuated Schistosoma japonicum cercariae conferred significant resistance against challenge to mice. Donors given 5 vaccinations, however, produced the most effective sera; rat sera giving up to 88% protection and rabbit sera up to 80%. This protective effect was species-specific and titratable. Sera from vaccinated rabbits and rats were were most effective when transferred to mice 2 h before challenge, but became progressively less effective when transferred with increasing time after challenge. These sera had no efficacy when given 6 days after challenge. Thus, sera from vaccinated rabbits and rats were effective against the early stage of migration, but did not necessarily have to act in the skin as all serum transfers were as effective against intraperitoneal as percutaneous challenge. By contrast, serum from multiply vaccinated mice had little or no protective effect when transferred to mice before challenge, but conferred 62% resistance when transferred 5 days after challenge. Further, there was an additive protective effect when vaccinated rat and mouse sera were given in combination at their optimum transfer times (days 0 and +5, respectively). Thus, there appears to be a stage-specific immune response induced by vaccination depending upon whether the vaccinated hosts are truly permissive or not. Vaccinated rats and rabbits respond to the early phase of migration and vaccinated mice make protective responses against the lung phase of migration.

The inhibitory effect of niridazole on hydrogen production by metronidazole-resistant (CDC-85) and susceptible (Cl-NIH) Trichomonas vaginalis strains was investigated. The results show that niridazole is more effective than metronidazole in inhibiting hydrogen production by the resistant isolate. In CDC-85 aerobic inhibition requires a 4-fold increase in metronidazole concentration compared with that required anaerobically, but the corresponding factor for niridazole is only 1·5-fold. Reduction of the drug by a hydrogenosome-enriched preparation gave rise to a multiline electron spin resonance detectable signal, which is due to a nitrogen-centred radical.

The roles of different antibody isotypes in the transfer of protection with serum from rats vaccinated with irradiated cercariae were investigated by immunoadsorption of IgG, IgG2a and IgG2c, and by heating at 56°C to remove IgE. Only depletion of IgG2a reduced the levels of vaccine-induced immunity transferred, whereas immunity transferred by infection serum was reduced by both IgG2a and IgE depletion. It was also shown that exposure to irradiated parasites did not lead to either specific or non-specific induction of an IgE response. The successful passive-transfer experiments using serum from non-resistant 25 week-infected rats into recipient animals demonstrated that the waning of resistance observed in 25 week-infected rats was not due to a failure of the humoral response to protective antigens.

Immunity to Schistosoma mansoni was investigated in congenitally athymic (Nu/Nu) rats, irradiated rats and in mast cell-depleted rats. Nu/Nu rats failed to develop significant resistance following vaccination with irradiated cercariae, although Nu/Nu recipients of serum from vaccinated Fischer rats (VRS) manifested resistance comparable to heterozygous controls, suggesting that T-cells were required in the induction of resistance but were not involved in the efferent arm of antibody-dependent elimination. Radiosensitive cells (including eosinophils, basophils, neutrophils, lymphocytes and mast cells) were apparently not essential for the antibody-dependent elimination of lung or post-lung stages since irradiated (700–750 rad.) recipients of VRS manifested comparable degrees of resistance to unirradiated controls in spite of a greater than 85% reduction in total blood leucocyte counts after irradiation. Depletion of 99 % of tissue mast cells by treatment of rats with Compound 48/80 had no significant effect on the attrition of a challenge infection in rats rendered immune by vaccination with irradiated cercariae or by transfer of VRS. However, there was a significant increase in worm recovery in unimmunized and mast cell-depleted or irradiated rats, indicating that mast cells and perhaps other radio-isotope sensitive cells may be involved in innate resistance.

During the primary immune response to an infectious agent, specific memory cells are generated which enable the immune system to respond more rapidly and efficiently to re-exposure to the same agent. Under normal circumstances, this acquired resistance leads to the effective elimination of the agent, and recovery. However, under certain circumstances these secondary infections, rather than aiding recovery, actually produce tissue damage and often contribute to the disease process. This stage has been termed hypersensitivity and such hypersensitivity reactions play an important role in the immunopathology of several diseases. Coombs & Gell (1963) have classified hypersensitivity into four types of reaction. Types I, II and III involve antibody-mediated processes whereas type IV is mediated solely by lymphocytes. Many parasitic infections have characteristics which would appear to predispose the host to the development of hypersensitivity states and consequent immunopathology. These include (1) the chronicity of the infections, (2) the release of parasite antigens in large amounts and their persistence in the circulation and host tissues, (3) the sharing of antigens between parasite and host and (4) the ability of the parasite to damage host tissues and alter their antigenicity. However, direct evidence that these mechanisms lead to the development of immunopathology in parasitic infections is limited. In this article, these four types of hypersensitivity will be briefly discussed in the context of the immunopathology following parasite infection. There then follows a more extensive consideration of type III hypersensitivity with particular emphasis on the mechanisms underlying the development of immune-complex mediated disease.