Parasitology Today, vol. IO, no. IO, I 994 377

Huma(n Immunity to Schistosomes: Concomitant Immunity?

R.J. Terry

It is over 15 years since I last worked with schistosome infections but, as Ron Smithers and I were the first to use the term ‘concomitant irnmuni~ in respect of these parasites, I have been asked to write briefly about the phenomenon as it may relate to the two papers that follow (Butterworth and Gryseels, this issue).

The term ‘concomitant immunity’ was first used in 1908 in relation to possible immunity to tumoursi. Years later (in 1967) the phenomenon was investi- gated in tumour-bearing hamstersz. Hamsters bearing a specific tumour were sometimes resistant to a second graft of the same tumour, even though the original tumour continued to grow seemingly unimpeded. Thus a tumour graft could survive whilst other grafts from the same source were being destroyed: survival of some cells was concomitant with the immune de- struction of others cells of the same cell line. Smithers noticed that this situation was similar to our own findings with experimental schistosome infections in rhesus monkeys. They too demonstrated a form of concomitant immunity. Monkeys, carrying an initial infection of adult Schistusoma mansoni were able to destroy a cercarial challenge infection, but at the same time were unable to rid themselves of the original established schistosomesa.

We carried the investigation further by surgically im- planting adult schistosomes from mice into the portal s x

stems of uninfected monkeys and later challenged em with large numbers of cercariae. The monkeys

were almost totally resistant to the cercarial challenge, although they had no p:revious experience of migrat- ing juveniles, but they failed to reject the implanted adults.

We had then the curious situation of the adult worms being exempt from the immune responses which they themselves had provokedd. It seemed to us that this example of concomitant immunity provided some ad- vantages both to host and to parasites, although the parasites came off best. It may be that schistosomes derived from early infections will, in conjunction with host immunity, restrict the levels of reinfection which might otherwise lead to the death of both host and parasites. I recall Prof. George Nelson describing the situation as: . . . ‘the early worm getting the bird.

How adult schistosomes are protected from the im- mune responses that they invoke in their hosts has been the subject of much research and not a little controversy. A great deal of experimental work has shown ‘host- like’ molecules, generally referred to as ‘host antigens’,

Roland Terry is at Fairview, Rockcliffe, Dalbeattie, UK DG5 4QF.

0 1994, Elsener Science Ltd

present at the surface of all but the earliest stages of the parasite in the vertebrate host. In some instances, there is good evidence that these antigens are in fact syn- thesized by the parasite but crossreact with antigens of the host. A prime example is a schistosome synthesized molecule that strongly resembles mouse cl,-macro- globulin5. In contrast, a number of molecules present on the adult parasite surface are derived from the host. For example, schistosomulae cultured in medium con- taining human blood will adsorb blood group sub- stances such as A, B and Lewis, presumably in the form of glycolipids6. Other examples of the attachment of ‘host antigens’ relate to major histocompatibility com- plex (MHC) antigens and immunoglobulins. The para- sites do not possess genes which could encode these molecules, thus ruling out ‘antigenic mimicry’. The host antigens must somehow become bound to the external surface of the parasite but the mechanisms involved remain obscure. The immunoglobulins are seemingly attached by their Fc region to receptors on the parasite surface7.

We can summarize the experiments on the de- velopment of concomitant immunity to schistosome in rhesus monkeys along the following lines. Follow- ing cercarial invasion, the resulting schistosomulae, in ways not understood, stimulate the immune system to produce a range of antibody (and cell-mediated?) immune responses against the surface and secreted(?) antigens of the parasite. Concomitantly, the schisto- somulae appear to acquire a ‘surface coat’ of host molecules, probably glycolipids with blood-group specificity in humans. This coat acts, at least to a degree, as an immunological disguise, enabling the parasites to mate and the females to produce eggs in large numbers. Authentic parasite antigens, perhaps by synthesis and release, may continue to stimulate an immune response which is effective against fresh invading schistosomula but not so against the estab- lished, disguised parasites.

Thus, to summarize, the original demonstration of concomitant immunity in schistosomiasis was by Smithers and Terry in 1969 (Ref. 4), and was based on work carried out on S. mansoni infections in rhesus monkeys. We showed that a primary infection of adult parasites could stimulate an immunity which was ef- fective against incoming juveniles from secondary in- fection. This immunity, however, failed to damage the adult worms which had largely provoked the response, perhaps because their acquisition of ‘host antigens’ made them no longer a legitimate target.

It was an attractive hypothesis. How far it is relevant to human schistosomiasis and how far it can explain

378 Parasitology Jodoy, vol. IO, no. IO, I994

the patterns of infections in the field is for others to determine.

Finally, it is fair to say that the immunological con- trol of schistosomiasis has ‘long had a bright future’, and it may be that candidate vaccines will be tested over the next ten years or so. It would be wrong, however, to neglect the search for other reliable and safe control measures effective against the parasite and its vector.

References 1 Bashford, E.F. et aI. (1908) Third Scientific Report on the Investi-

gations of the Imperial Cancer Research Fund, 262-283 2 Gershon, R.K. et al. (1967) Nature 213,674-676 3 Smithers, S.R. and Terry, R.J. (1967) Trans. R. Sot. Trap. Med.

Hyg. 61,517-533 4 Smithers, S.R. and Terry, R.J. (1969) Ann. New York Acud. Sci.

160,826-840 5 Damian, R.T. et al. (1973) J. Purusitol. 59,64-73 6 Goldring, O.L. et aI. (1976) Clin. Exp. Immunol. 26,181-187 7 Kemp, W.M. et al. (1977)J. Immunol. 124,806-811

Human Immunity to Schistosomes: Some Questions

A.E. Butter-worth

Evidence is accumulating from epidemiological studies for the development with age of a resistance to infec- tion, or to reinfection after treatment, with Schistosoma mansoni1,2 or S. huemutobium3~4. In particular, the convex shape of age-prevalence or age-intensity curves, both in untreated communities and in communities under- going reinfection following chemotherapy, can be explained only in part by an observed reduction in ex- posure to infection among older individuals. Although statistical analysis and interpretation of exposure data present considerable difficulties, it has been argued that there are additional age-dependent factors that limit infectionb-6. Such factors could include both specific acquired immunity and other age-dependent physio- logical processes: the questions addressed here are whether or not, to what extent, and how protective immune responses are involved. One approach to this problem is to examine the relationship between the ex- pression of an age-related resistance to infection and the presence of potentially protective immune responses.

Resistance or susceptibility, and different antibody isotypes

Early studies in Kenyan schoolchildren failed to reveal an association between resistance, reflected by low levels of reinfection after treatment of S. munsoni infections, and a variety of immune responses includ- ing, for example, the levels of serum antibodies me- diating eosinophil-dependent killing of schistosomulal~7. Instead, positive correlations were observed between intensities of reinfection and the presence of antibodies of the IgM and IgG2 isotypes that recognized carbo- hydrate epitopes present both in egg and schistosom- ulum antigens 7,s. The levels of such antibodies pre- dicted susceptibility to reinfection, rather than simply reflecting pretreatment intensities of infection, and it was suggested that they served to block the binding and action of antibodies of other, protective isotypes, and hence to prevent the expression of immunity in young children. Such blocking antibodies had previ- ously been described in a rat model of immunityg, and

Anthony Buttetworth is at the Department of Pathology, Tennis Court Road, Cambridge, UK CB2 I QP.

their possible role in maintaining susceptibility has been supported by other studies on both S. haemutobiumlo and S. munsonW1, which have also recorded a blocking effect of IgG4.

The demonstration of a role for blocking antibodies in maintaining the susceptibility to infection of young children suggested the involvement of protective im- mune responses in older individuals, but did not reveal the nature of such responses. Further progress came with the observation by Hagan and colleagues in The Gambia10 of a negufive association between intensities of reinfection with S. huemutobium and the levels of IgE antibodies against adult worm antigens, indicating the involvement of such antibodies in protection. Similar re- sults were obtained for S. munsoni in studies in Brazil12 and subsequently in Kenya’s, and are consistent with previous experimental demonstrations of a protec- tive effect of IgE, both in a rat model of schistosome immunity14 and as a mediator of human eosinophil- dependent killing of schistosomula in vitro*5. Recent, detailed analysis of results from the Brazilian study” has further shown that the expression of resistance is dependent on the balance between protective IgE and blocking IgG4 antibodies to larval antigens, whereas the blocking effect of IgG2 antibodies acts independently. In addition to IgE, evidence is also accumulating for a correlation with resistance of IgA antibodies14 es- pecially against a candidate vaccine antigen of S. mun- soni (glutathione-S-transferase, Sm28GST) that elicits high levels of protection in animal experiment@. The conclusion at this stage, therefore, is that a key feature of the expression of human immunity is not so much the presence or absence of an antibody response but rather the balance between different antibody isotypes. In particular, these various findings have provided the first evidence for an association in humans between IgE antibodies and any protective effect that could be of selective advantage.

Antigens recognized by protective antibodies Several candidate vaccine antigens of S. munsoni have

been identified from studies in experimental animal models, including S~I-L!~GST~~, triose phosphate isomer- ase (TPI)ls, paramyosinl9, Sm23 (Ref. 20) and W-5 (Ref. 21), some of which have been produced as recombinant

0 1994. Elsev~er Scence Ltd