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The rapid elimination of the intestinal phase of Trichinella spiralis in NIH mice is associated with progressive inflammation of the intestinal tract. The non-specific effects of this inflammation were studied in. mice concurrently infected with an unrelated parasite, Hymenolepis diminuta, which does not stimulate a visible inflammatory response but is also immunologically rejected by this strain of mice.It was demonstrated that the rejection phase of T. spiralis infection had a marked effect upon the growth and survival of H. diminuta,. The cestode either failed to establish or to grow; if the worms were already strobilate when inflammation developed then destrobilation occurred. There was no cross–immunity between the parasites, nor was the interaction a direct consequence of inter–specific competition.

SUMMARYTwo groups of H-2 congenic strains of mice were compared for their susceptibility to a primary infection with the nematode Trichuris muris. Mice of the BALB genetic background were markedly more resistant than mice of the BIO genetic background, as reflected by the rate of expulsion of T. muris from the large intestine. Within each of the two groups of H-2 congenic strains mice possessing the H-2k haplotype (BALB/k, B10.BR) were more susceptible to infection than mice expressing other haplotypes; B10 background strains expressing H-2b (B10) or H-2q (B10.G) alleles were the most resistant of the four congenic strains studied. Differential resistance was observed within three of the four BIO congenic strains and this is discussed in terms of rate of development of the protective immune response in relation to worm development. The results support the conclusion that both H-2-linked and non-H-2 genes play important roles in controlling the immune response which expels worms from the gut.

SummaryLethal irradiation (850 rads) of mice made resistant to Trichuris muris markedly depressed their ability to expel a challenge infection. Expulsion was restored within 7–10 days when MLNC from uninfected mice were transferred on the day of infection, but no significant restoration was evident after transfer of immune serum. Transfer of BM alone had no restorative effect within 10 days and no synergism was seen when both BM and MLNC were transferred. MLNC from uninfected donors did not restore challenge expulsion when transfer was delayed until day 7 and the mice were killed 3 days later, although MLNC from resistant donors were effective within this time. When irradiated mice were given BM and the challenge infection allowed to continue for 15 days expulsion was restored, as it was when challenge was delayed for 7 days after BM transfer in thymectomized mice. The results confirm that expulsion of T. muris involves both antibody-mediated and lymphoid cell-mediated phases and offer no evidence for the involvement of other cell types.

Mice infected with Trichuris muris during lactation were unable to expel the infection at the normal time, but expulsion occurred when lactation was terminated. Suppression of expulsion was uniform in mice suckling more than five young but variable with smaller litters. Mice exposed to a primary infection while lactating were shown to have serum antibodies capable of passively transferring immunity to recipient mice and showed near normal immunity to a secondary infection given after lactation had ceased.Acquired immunity to T. muris was also suppressed by lactation, but the worms which became established in lactating resistant mice were fewer and smaller than those in non-lactating, non-resistant controls.It is suggested that the suppressive effect of lactation in this hostparasite relationship is exerted on the second, lymphoid cell-mediated phase of worm expulsion.

Summary Adoptive transfer of immunity with immune mesenteric lymph node cells (IMLNC) was used to analyse the roles of immune and inflammatory events in determining the strain-characteristic time of expulsion of Trichinella spiralis from mice. Transfer of IMLNC within and between three rapidly responding strains (NIH, SWR, DBA1–all H-2q) resulted in accelerated worm expulsion, worm loss commencing before day 8 in each case. When NIH cells were transferred to slow-responder B10 congenic mice (B10G-H-2q) mice, immunity was evident at 8 days as a reduction in worm fecundity and only by 12 days as a reduction in worm numbers. A similar result was obtained when B10G cells were given to B10G recipients. In the reciprocal transfer, IMLNC from B10G transferred immunity to NIH as effectively and as rapidly as did NIH cells. Cells capable of transferring immunity were present in B10G mice as early as 4 days after infection, even though worm expulsion in this strain does not occur until after day 12. Thus following heterologous transfers of IMLNC, the time of worm expulsion was determined by the response of the recipient, and presumably by the ability to generate intestinal inflammatory changes. Earlier work has shown that the strain-characteristic time of worm expulsion is genetically determined, but not by H-2 linked genes. A corollary of the present work is that non-H-2 linked genes control the generation of intestinal inflammatory changes in T. spiralis infections. H-2 genes may control lymphocyte responsiveness to infection and the haplotype H-2q may determine a rapid response. Comparisons are made with the genetic control of resistance to Listeria monocytogenes and possible mechanisms are discussed.

SUMMARYA technique for the transplantation of Trichinella spiralis worms directly into the host intestine is described. Infections established by the direct transfer of adult worms were essentially normal both in terms of their survival and reproduction and in their stimulation of, and susceptibility to, host immune responses. Worms transplanted from NIH mouse donors at intervals after infection had an equal ability to survive in the recipient, even when taken from the donor shortly before or during the process of worm expulsion, showing that expulsion does not require worms to be irreversibly damaged. It was noted, however, that after 7 days in the donor the ability of the worm to reproduce in the recipient was temporarily impaired.

Infections with the nematode Nematospiroides dubius fail to elicit mucosal mast cell (MMC) responses in the intestines of host mice, and suppress MMC responses generated by heterologous infection. Larval N. dubius have the capacity to prime for mastocytosis, and to elicit this response in primed mice during a challenge, but only if adult worms are prevented from developing, either by anthelmintic treatment or by irradiation of the larvae themselves. The suppressive effect of the adult stage was confirmed in experiments where such worms were implanted directly into the intestines of mice primed by exposure to irradiated N. dubius larvae or concurrently infected with Trichinella spiralis. Data on the mechanisms underlying this suppressive effect were obtained from experiments involving the adoptive transfer of mastocytosis by mesenteric lymph node cells (MLNC) from T. spiralis infected mice. When MLNC were taken from mice infected concurrently with both T. spiralis and N. dubius no enhanced mastocytosis was seen in recipients after challenge with T. spiralis. Exposure of MLNC from T. spiralis infected donors to the presence of adult N. dubius after transfer did not reduce the adoptively transferred response. The response was also unaffected when MLNC from adult N. dubius infected mice were simultaneously transferred with MLNC from T. spiralis donors. It is concluded that the suppressive effect of adult N. dubius upon the expression of mucosal mastocytosis acts upon the generation of lymphocytes capable of promoting the development of MMC from precursor cells.

The results of experimental infections ofTrichuris murisin wild field mice (Apodemus sylvaticus) and laboratory-bred wild house mice (Mus musculus) showed that the parasite elicited an immune response similar to that previously described in strains of laboratory mice. Experiments in laboratory mice showed that the parasite was able to become sexually mature only when small single infections or repeated low-level infections were given. A survey of a population of 43 wild house mice naturally infected withT. murisshowed that the pattern of small worm burdens in the majority of mice was consistent with a situation of repeated low-level infection, except in the case of six female mice which harboured larger mature worm burdens. It is suggested that in these mice pregnancy and/or lactation may have suppressed the immune response, allowing the accumulation of a worm burden in excess of the threshold for worm expulsion.

Transfer of immunity against Trichuris muris in the mouse by serum and cells. Internationaljournal for Parasitology3: 717–722. A protective immunity against the nematode Trichuris muris was transferred with antiserum and cells taken from immunized mice. Immunity was transferred most reliably by cells, especially mesenteric lymph node cells, but most effectively by serum. The protective capacity of serum and cells taken from the same mice was not always related. Multiple immunization of the donors did not markedly increase protection in the recipients.

Infestation of the gastrointestinal tract by parasitic nematodes is invariably associated with mucosal mastocytosis1,2, which is a thymus-dependent phenomenon in parasitized rats3, and is adoptively transferable with a T cell-enriched population of thoracic duct lymphocytes4. When derived by in vitro culture, mucosal mast cells (MMC) arise from a bone marrow precursor after stimulation by T cell-derived factors5. In rats infected with the nematode Trichinella spiralis, mucosal mastocytosis is temporally associated with the immune expulsion of the adult worms6 whereas in the case of Nippostrongylus brasiliensis, mastocytosis is frequently observed to occur after worm expulsion has been completed7–9. Consequently, there has been doubt as to whether MMC are active and serve a functional role in the expulsion of rat intestinal nematodes. MMC contain and secrete a neutral proteinase, rat mast cell protease II (RMCPII)10–13; detection and assay of secreted RMCPII therefore provides a direct measurement of MMC activity. Here we describe the release of this enzyme into the blood of rats infected with N. brasiliensis or T. spiralis. Our results show that the systemic secretion of RMCP II coincides with the immune expulsion of these nematodes, demonstrating clearly for the first time that rat MMC are functionally active during the immune elimination of primary nematode infections.

Maximum increases in cell numbers in the mesenteric lymph node (MLN) of CBA/Ca mice were evident by day 20 post-infection with the parasitic nematode Trichuris muris , a time which correlates with the onset of worm expulsion. Mesenteric lymph node cells (MLNC) taken at this time (day 20) were most consistently effective at transferring immunity to naive animals (cells taken earlier or later were much less effective) and showed high levels of incorporation of radiolabelled thymidine ( 3 H-thymidine) indicating blastic activity. At least 4 × 10 7 unseparated MLNC were needed to transfer immunity, whereas 2 × 10 7 but not 1 × 10 7 T enriched cells transferred considerable protection. Nylon wool adherent (B enriched) populations had no effect. The immunity transferred by the MLNC was persistent even in the absence of antigenic stimulation, as evidenced by the accelerated expulsion of a delayed challenge (42 days after cell transfer). The results are discussed in terms of T cell mediated inflammatory responses in the small and large intestine.

The course of infection with Eimeria vermiformis was determined in BALB/b, BALB/c, and C57BL/10ScSn (B10) mice and in radiation chimeras prepared from the H-2-compatible BALB/b and B10 mice. The BALB strains, irrespective of H-2 haplotype, were resistant, the B10 mice were susceptible, and in the chimeras infection was characterized by the genotype of the donated bone-marrow cells and not by the phenotype of the recipient. Thus, the genetic control of relative resistance or susceptibility to infection with this parasite is expressed through bone-marrow-derived cells.

SummaryImmunity to the adult stage of Trichinella spiralis, assessed by an acceleration of worm expulsion, was transferred to recipient mice with mesenteric lymph node cells (MLNC) or serum taken from infected donors. Immunity was transferred most effectively by MLNC taken from donors infected for 8 days, i.e. donors actively responding to infection. Transfer of both MLNC and serum brought about a marked acceleration of worm expulsion in all cases, even where MLNC or serum given separately failed to transfer a significant degree of immunity.

The immune response of mice to the nematode Trichinella spiral's was markedly altered when the infection was superimposed upon an existing infection with Nematospiroides dubius. The expulsion of a primary infection of T. spiralis was delayed in such mice, and the worms persisted for at least 4 weeks longer than they did in control mice. The degree to which expulsion was suppressed was related to the number of N. dubius present. It would appear that both adult and larval stages of N. dubius can exert a suppressive effect, since the expulsion of T. spiralis was affected within days of a super-imposed (i.e., larval) N. dubius infection. When adult N. dubius were removed from mice 4 days before infection with T. spiralis, the mice expelled the latter parasite within the normal time, indicating that recovery from the suppressive effects of concurrent infection occurred rapidly. Concurrent infection with N. dubius appeared to affect both the afferent and efferent arms of the immune response to T. spiralis, since sensitization by, and memory of, prior infection were impaired and the expression of acquired immunity was inferior to that of controls.

A comparison has been made of the responses of random-bred CFLP and inbred NIH mice to infection with Trichuris muris. Random-bred mice showed greater variation in worm burdens and less uniformity in worm expulsion. Irradiation prior to infection reduced variation, but did not increase the mean level of infection above that shown by the most susceptible unirradiated mice. In NIH mice, however, irradiation raised the level of infection in all mice. The factors responsible for variation between CFLP mice and for the level of infection in NIH mice came into play after the fifth day of infection and were inactivated by cortisone acetate. It is suggested that these factors are immunologically mediated and under direct genetic control. Uniformity of infection and expulsion in NIH mice is therefore seen as a consequence of genetic uniformity; variability in CFLP mice as a consequence of genetic variation.The time of worm expulsion was found to differ markedly between inbred strains of mice. Hybrid progeny showed the expulsion time characteristic of the parental strain with the most rapid expulsion; greater resistance was therefore inherited as a dominant characteristic. The genetic control of immunity to T. muris is discussed in the context of the antibody- and cell-mediated components of the expulsion process.

SummaryImmunity to Hymenolepis nana was adoptively transferred to recipient mice of 4 strains using mesenteric lymph node cells (MLNC), spleen cells (SC), and/or serum taken from infected donor mice. Donor cells capable of transferring immunity appeared in the mesenteric lymph nodes and spleen at an early stage (5 days) after infection. Immunity was most effectively transferred with MLNC and immune serum did not enhance this effect. It is suggested that effective immunity to H. nana involves both antibody and T cell-mediated inflammatory events.

Immune serum accelerated the expulsion of Trichuris muris when transferred into normal mice on days 0 and 3 after infection, but had no effect when the recipient mice had been immunosuppressed by sublethal irradiation or by cortisone treatment. Delaying serum transfer until days 7 and 8 in normal mice failed to accelerate expulsion, although immune mesenteric lymph node cells (MLNC) accelerated expulsion whether transferred early or late in infection.Expulsion from NIH mice, normally complete by 12 days, was prevented by sublethal irradiation given as late as 9 days after infection, but could be restored by subsequent transfer of immune MLNC or, to a lesser degree, non-immune MLNC. Immune MLNC were unable to restore worm expulsion in mice irradiated before infection.These results are interpreted as showing that the immune expulsion of T. muris from mice during a primary infection requires the sequential activities of antibody-mediated and lymphoid cell-mediated components.

The development of a reliable model for the adoptive transfer of immunity to coccidiosis (infection with Eimeria vermiformis in NIH mice) is described. More than 10(8) of a mixture of spleen and mesenteric lymph node (MLN) cells, given either intravenously or intraperitoneally, were required to transfer a significant degree of protection. Dividing cells, present in the donors at 10 or 14 days after priming, but not at 5 or 19 days, were shown to be the effectors. When examined separately, MLN cells were found to be superior to spleen cells, and the injection of as few as 5 x 10(7) was capable of substantially reducing the oocyst output from a challenge inoculum. The recipients of cells from primed mice had earlier, and sometimes higher, titres of specific antibodies in the serum but, overall, there was no correlation between these titres and protection. Further characterization of the cells responsible for adoptively transferring immunity to this infection should now be possible.

Immune responses to infections with par~zsitic worms show well defined genetic control. In man, domestic animai~ and experimental rodents, the level and na:ture of these responses may differ markedly between individuals or be- tween breeds and strains, and be reflected in the overall outcome of the infection in terms of resis- tance, susceptibility and pathology. A basic tenet of evolutionary biology is that populations embrace a substantial degree of genetic diversity upon which natural selection can act to maximize the fitness of particular populations within particular en- vironments. An important element of such diversity is seen in the differing abilities of individuals to cope with infectious diseases, an element which par~,sitologists have rec- ognized much later th~xl their colleagues in virology, bacteriology and plant pathology. (Genetic diversity wiflfin parasite popula- tions probably has equal significance in the context of the evolulJLon and stability of host-parasite relationslfips but will not be considered here.) Although the existence of host variation in respo~Lse to helminth infec- tions has been recorded empirically for some time, the systematic exploration and exploitation of this phenomenon is com- paratively recent. It is now widely recog- nized that a substantial part of this variation has its origins in differential immune re- sponsiveness to infection and is genetically determined. Progress in understanding the genetic control of variation has gone hand- in-hand with analysis of the immunological mechanisms involved; indeed the two pro- vide reciprocally fruit_tiff fields of research 1. Inevitably attention has concentrated largely upon the genetic control of resis- tance elicited by infection or by vaccination, but immunosuppressive and im- munopathological phenomena have also been examined. Much of the work has been carried out in experimental systems using laboratory rodents and particularly the mouse, for which a wide variety of defmed strains is available (Table 1). Important studies have also been made in domestic ani- mals and in man. The extent of the variation of responses to infection that can occur can be illustrated by reference to the nematode Trichinella spiralis in the mouse, an experimental system which has been studied in greater detail than any other (Table 2). Variation exists in almost every parameter that has been moni- tored, but it is important to note that, as far as the infection itself is concerned, variation is essentially quantitative, not qualitative. All strains of mice so far tested (excluding mutant strains) terminate the intestinal phase of infection by means of an immune response, although some take considerably longer than others to do so and may, in con- sequence, acquire heavier burdens of larvae in the muscles. Qualitative variation has been recorded in other systems, for example individuals of certain mouse strains appear completely incapable of controlling infec- tion with Trichuris muris 3.

Slow-responder C57BL/10 (B10) mice responded poorly to immunization with muscle larval antigen of Trichinella spiralis showing no accelerated loss of worms from a subsequent challenge infection. In contrast, rapid-responder NIH mice and (B10 X NIH) F1 mice developed high levels of immunity after immunization. Lymphocyte proliferation studies showed that immunized B10 mice did respond to in vitro restimulation with antigen, though less well than NIH mice. Failure of B10 mice to respond to immunization did not therefore reflect a failure to recognize larval antigen, a view confirmed by the fact that immunization was achieved using abbreviated enteral infections and, to a smaller extent, by parenterally administered muscle larvae.

Attempts were made to correct the low responder phenotype of microfilaraemic Acanthocheilonema viteae ( Dipetalonema viteae ) infected BALB/c mice through the transfer of immune spleen cells and immune serum from amicrofilaraemic B10 background mice. The transfer of immune cells and serum prior to infection failed to influence development of microfllaraemia in BALB/c recipients. Attempts to alter the course of an established microfilaraemia in BALB/c mice through the transfer of 3 × 10 7 immune spleen cells were unsuccessful but transfer of 3 × 10 8 cells reduced microfilaraemia temporarily. Treating microfilaraemic BALB/c mice with immune serum brought about a rapid reduction in microfllaraemia. This effect was only temporary and numbers of circulating microfllariae returned to control levels within a short time. Repeated serum transfers reduced the microfilaraemia only during the period of treatment. Similar results were obtained when immune serum was given to microfilaraemic, immunodeficient CBA/N mice.

Irradiation prevented the accelerated expulsion of Trichinella spiralis from mice immunized by transfer of immune mesenteric lymph node cells (IMLNC) or by prior infection. Nevertheless, worms in irradiated immune mice were smaller and less fecund than those in controls. In adoptively immunized and irradiated mice expulsion could not be achieved by increasing the numbers of IMLNC transferred, although the effect upon worm length was more severe. Thus IMLNC express a direct, anti-worm immunity which is independent of their role in worm expulsion. IMLNC cause expulsion in irradiated mice only when adequate levels of bone marrow-derived cells are available. The results are discussed in terms of a possible antibody-mediated basis for direct anti-worm immunity.

Trichinella spiralis is a highly successful parasite in that it can establish, develop, and reproduce in a wide range of vertebrate hosts. This low host specificity implies that the organism has the ability to adapt to a variety of environmental conditions and hence is relatively unaffected by many of those aspects of natural immunity that impose a more rigid specificity on other species. However, in common with all metazoan parasites, T. spiralis presents the host with a complex antigenic stimulus and thus evokes a powerful immune response. The complexity of the stimulus arises not only from the diversity of antigens present at any one time, but also from the fact that antigens may show stage specificity, changing qualitatively and quantitatively throughout development, and may be released in different tissues of the body. Many components of the immunological response probably have little or no effect on either host or parasite, though they may prove useful in diagnosis; some are deleterious to the parasite and provide protective resistance against infection, yet others are actually or potentially harmful to the host, either from their involvement in immunopathological reactions or through their modulation of unrelated immune responses. This chapter will concentrate on those responses that confer resistance on the host; immune responses in the contexts of diagnosis and pathology are dealt

In mice concurrently infected with Nematospiroides dubius and Trichinella spiralis, survival of the latter was prolonged and spontaneous cure delayed. Mesenteric lymph node (MLN) cells taken from such mice failed to transfer a significant degree of immunity to T. spiralis after injection into recipients, whereas cells from mice infected with T. spiralis alone did so successfully. Conversely, when recipients of T. spiralis-immune cells were concurrently infected with larval or adult N. dubius, immunity was expressed as a reduction in size and fecundity of female T. spiralis, but there was no accelerated worm expulsion. Infection with N. dubius prevented the normal cellular responses to T. spiralis, i.e., there was no increase in total MLN cell recovery, instead a marked decrease occurred, and there was no increase in blast cell activity over the level in mice infected with N. dubius alone. In addition N. dubius delayed the onset of the changes which allow increased blast cell localization in the intestines of T. spiralis-infected mice.

The helminths—that is, the parasitic worms belonging to the Platyhelminthes and Nematoda—collectively constitute one of the major causes of morbidity and mortality in man and his domestic animals. The prevalence of infection is, to a great extent, determined by climatic conditions and by standards of hygiene and sanitation; together, these influence the availability of vectors (where required), the survival of infective stages, and the ease of transmission. The impact of infections upon the health of the population is, in turn, determined by nutritional levels and by the presence of intercurrent infections. For all these reasons helminth infections are commonest and most serious in tropical and subtropical regions of the world, although some are widespread also in temperate regions and may be a source of major economic loss in domestic stock.

SummaryThe intestinal changes brought about by rejection of Trichinella spiralis from mice were studied in relation to their effects on a concurrent infection with Hymenolepis microstoma, a cestode not normally rejected from mice. The rejection phase of T. spiralis was associated with a marked stunting of growth of H. microstoma given just before, during, or just after rejection of the nematode. The survival of H. microstoma was affected only when rejection of T. spiralis coincided with the intestinal phase of the cestode: if T. spiralis rejection was timed to occur after the scolex of the cestode had entered the bile duct there was no loss of H. microstoma. It is suggested that the adverse effects on growth and establishment of H. microstoma were due to the non-specific inflammatory component of the host's response to infection with T. spiralis.

Intestinal parasites are common in man and animals and can cause severe disease. Knowledge of immunity to such infections is limited and comes largely from studies using laboratory host-parasite systems. Understanding how immunity can operate, and why it often does not, is not only of intrinsic interest but necessary for the development of immunological methods of control.

Summary Genetically based differences in the antibody responses to the large intestinal nematode Trichuris muris were studied in two groups of H–2 congenic strains of mice that differed in their relative resistance to infection with this parasite. The primary antibody response to parasite excretory/secretory (E/S) antigen was predominantly an IgG response with the strains forming two distinct groups, defined by their genetic background. The more susceptible B10 genetic background mice had strikingly higher antibody levels than mice of the BALB genetic background. Superimposed upon these background effects were clearly defined influences attributable to H–2–linked genes, strains which differed genetically only at H–2 loci exhibiting differences in the kinetics of the antibody response. Only B10.G and B10.BR mice showed any great increase in IgM levels post–infection. No IgA specific to E/S antigen was detected in the peripheral circulation of any strain at any time post–infection. Antibody responses to a 40–43 kD antigen revealed clear H–2–linked gene effects, with mice sharing the H–2k haplotype (B10.BR, BALB/K) exhibiting considerably higher total antibody levels than strains expressing other haplotypes; mice of the H–2d haplotype (BALB/c, B10.D2/n) responded very weakly to this antigen. A Western blot analysis of antigen recognition by antibody revealed similarities between the mouse strains in their total antibody responses to T. muris E/S antigen. However, immunoprecipitation studies showed that in general the more susceptible B10 congenic strains had wider spectra of antigen recognition than the BALB congenics. Strains sharing the same H–2 haplotype had dissimilar antigen recognition profiles, but strains sharing the H–2b haplotype (B10, BALB/B) recognized a low mol. wt antigen (20–23 kD) not recognized by any other strain, suggesting an exclusively H–2b restriction in the recognition of this antigen. These results support the conclusion that both H–2–linked and background genes play important roles in controlling the humoral immune response to T. muris infection.

SummaryDipetalonema viteae (Filarioidea) infections were established in inbred strains of mice by the s. c. implantation of adult female worms and the resulting microfilaraemia and adult worm survival monitored. BALB/c mice were the most susceptible strain examined, showing a high level microfilaraemia of approximately 6 month's duration. C57B1 10. CBA/Ca and C3H/He mice were all equally resistant to infection, showing a low level of microfilaraemia of approximately 1 month's duration. The response of NIH mice was intermediate. Relatively little strain difference was seen in adult worm survival although worms lived slightly longer in C57B1/10 mice than in BALB/c mice. The adult females became depleted of microfilariae over a period of approximately 1 month before becoming encapsulated in host tissue. Challenge infections given to mice previously implanted with worms resulted in lower level, shorter lasting microfilaraemias than those seen in the initial primary infections. All strains showed immunity when challenged. High responsiveness (resistance) was inherited as a dominant trait in F1 hybrids produced by crossing high and low responder strains. Genes linked with the major histocompatability complex (H-2) were found to have no effect on the response phenotype as demonstrated by the similar responses of H-2 congenic mice on the BALB/c or C57B1/10 backgrounds. The response phenotype of radiation chimaeras was determined by the phenotype of the donor from which bone marrow (BM) cells were taken for reconstitution. Susceptible BALB c mice reconstituted with resistant B10D2/n BM behaved identically to the donor strain, indicating that the genetic variation which exists between mouse strains in their responses to D. viteae is expressed through a population of BM derived cells and is not simply a consequence of host structure or physiology.

Alizadeh H. and Wakelin D. 1982. Comparison of rapid expulsion of Trichinella spiralis in mice and rats. International Journal for Parasitology 12 : 65–73. Primary infections of Tricliinella spiralis in both NIH mice and Wistar rats resulted in increased levels of mucosal mast cells and goblet cells. In mice the numbers of both cell types rose sharply before worm expulsion (days 8–10), remained at an increased level for a short time and declined quickly, reaching control levels on day 14 for goblet cells and between days 28 and 35 for mast cells. In contrast, in rats, the numbers of goblet cells and mast cells increased during worm expulsion and remained above control levels for a prolonged period. Challenge infections given shortly after expulsion of a primary infection (day 14) were expelled rapidly, worm loss being virtually complete with 24 h. In mice this response to challenge was short-lived and persisted only until day 16 after primary infection. After this time, challenge worms were expelled more slowly after infection. In rats the rapid expulsion response was expressed for at least 7 weeks after primary infection. Mice and rats showed differences in the conditions of infection necessary to prime for rapid expulsion, mice requiring larger and longer duration primary infections, but the expression of the response appeared to be similar in both species. In mice it was shown that rapid expulsion of T. spiralis was a response evoked specifically by prior infection with this species; infections with other intestinal nematodes had no effect. Similarly, the effect upon challenge infection was also specific to T. spiralis . The rapidity with which challenge infections are expelled suggests that either the specific inflammatory changes generated during primary infection result in an environment that is unsuitable for establishment of subsequent infections or that challenge infections provide a stimulus that can provoke an almost instantaneous response in the primed intestine. The relationship of the observed cellular changes to such mechanisms is discussed.

SUMMARYIt is proposed that, for many species of parasites, evasion of the host immune response may be achieved passively through enhanced survival within host individuals that have a genetically determined low responsiveness to infection. Evasion by this means may contribute significantly to continued transmission of infection in man and domestic animals and influence the severity of pathology. Low responsiveness plays an important role in determining over-dispersion of parasites within host populations, and the common occurrence of this form of distribution is seen as supporting evidence for the proposition, although few of the examples available provide conclusive proof. The extensive individual and strain variation in response to parasitic infection in laboratory strains of mice is tak as a homologue of the natural situation and allows analysis of the mechanisms underlying low responsiveness. Two examples are considered in detail. In Leishmania infections both non-H-2 and H-2-linked genes influence resistance, but the primary expression of genetically determined low response is at the level of the macrophage. Genetic influences upon acquired immunity regulate macrophage–T-cell interactions. In Trichinella spiralis H-2-linked and non-H-2 genes influence development of the intestinal responses necessary for expulsion of the adult worm, the former through the response of helper T-cells to worm antigen and the amplification of this response through other T-cells, the latter through an effect upon the response of myeloid stem cells to T-cell signals. Modification of genetically determined low responsiveness is discussed in terms of (a) improving host responsiveness through vaccination or non-specific immunostimulation and (b) altering host genotype through selective breeding or the introduction of resistance alleles into a population.

The development of immunity to Nematospiroides dubius was studied in three strains of inbred mice (BALB/c, C3H and NIH). Although a primary infection in NIH mice persisted for two months without evidence of a reduction in worm numbers, female mice of this strain readily developed resistance to reinfection. The degree of resistance was enhanced when an immunizing infection of 600 larvae was administered as 6 separate doses of 100 larvae given between days 0 and 11, and the worms removed by anthelmintic treatment given on days 15, 21, 28 and 35. Immunity in mice immunized in this way was manifest both as a reduction in worm recoveries on days 9–14 after challenge and also as an expulsion of established worms from the intestine. BALB/c mice were initially less resistant, but expelled most of the worms which became established; C3H mice showed no evidence of expulsion. The finding that inbred NIH and BALB/c mice acquire resistance to N. dubius offers possibilities for the systematic analysis of lymphoid cell activity in initiating and expressing immunity to this parasite.

Neutralization of endogenous gamma interferon by treatment with a rat monoclonal antibody caused enhancement of infection with the protozoon Eimeria vermiformis in naive BALB/c mice. The effect was dose dependent and was apparent when a monoclonal antibody was given at 2 h before infection or up to 7 days postinfection, but it decreased with increasing time postinfection between days 4 and 7. The titers of parasite-specific antibodies in the serum were not significantly affected by the injection of monoclonal antibodies. Treatment during priming did not prevent the development of resistance to challenge, and treatment at the time of challenge did not abrogate established immunity. The results indicate that gamma interferon is involved in the control of primary infection with E. vermiformis in BALB/c mice but not in the expression of immunity to challenge.

The consequences of prior and concurrent infection with two species of nematodes were studied in rats. Primary infection with Strongyloides ratti adversely affected the development of a secondary Trichinella spiralis infection. Both immediate and delayed challenge with T. spiralis , following the expulsion of the previous S. ratti infection, reduced the percentage of worm recovery of the former as well as their fecundities and lengths. It is suggested that nonspecific inflammation produced by one species, during the peak period of worm expulsion, was not responsible for the accelerated rate of expulsion of the other; instead a direct, specific cross-immunity was probably operative affecting the survival of the challenge species. The response elicited by previous experience of the intestinal phase was reciprocal, but there was evidence of an enhancing effect by the muscle larval stages of T. spiralis on S. ratti . Rats concurrently infected with both species expelled S. ratti more rapidly than T. spiralis . Possible mechanisms underlying the interaction between the two species are suggested and discussed.

The consequences of previous and concurrent infection with two related species of cestodes,Hymenolepis nanaandH. diminuta, were studied in CD1 mice. AH. diminutainfection strongly affected the establishment and the survival of a secondaryH. nanaegg or cyst infection administered 30 days later. An infection of 20H. nanaeggs strongly protected against a 5-cystH. diminutachallenge, whereas an infection of 10H. nanacysts was ineffective; 20H. nanaeggs also protected against a challenge with 5 cysts ofH. diminutaadministered 5 days later. No effects were observed in either parasite during a concurrent infection established by administration of cysts. AnH. nanaegg-infection was unable to affect the establishment of a secondaryH. nanacyst-infection given 1 month later; however a significant decrease in growth was found. Similar results were found when a primaryH. nanaegg-infection was followed 5 days later by the homologous cyst-infection. But an infection with 5H. nanacysts was unable to protect against a homologous challenge of 5 cysts or 20 eggs. The reciprocal cross immunity between the heterologous parasites and the failure of protection of homologous challenges are discussed in relation to light infections.

Infections with gastrointestinal (GI) nematodes are among the most prevalent infections of man. Not only are they common and widespread in populations throughout the world, but they are frequently chronic and occur repeatedly throughout the lifetime of an individual. It is now well established that such parasites can be highly immunogenic and that their environment, the gastrointestinal tract, is well equipped to mount potent immune and inflammatory responses. The abundance and long-term survival of GI nematodes therefore present a paradox. This review takes the standpoint that man as a species has the capacity to produce effective and protective responses against GI infections, but that this capacity is subject to a number of powerful constraints, arising from parasite evasion, depression of response capacity and deficiency in response capacity. These constraints are discussed in the light of evidence drawn from experimental studies with animal models.

When mice were irradiated immediately before infection withTrichinella spiralisthere was a profound and long-lasting interference with their ability to expel adult worms from the intestine. Irradiation given after the fifth day of infection was progressively less effective in this respect. The ability to expel worms was not restored when mesenteric lymph node cells (MLNC) were transferred (a) on the day of infection in mice irradiated one day previously, or (b) on day 7 of an infection in mice irradiated on day 6, even though the MLNC transferred immunity to intact recipients. Transfer of bone marrow (BM) alone was also without effect. However, worm explusion was restored if, following irradiation and injection of BM, 10 days were allowed for BM differentiation before transfer of MLNC. This restoration was effective even after lethal levels of irradiation and was clearly dependent upon a donor-derived BM component cooperating with, or responding to, the activity of the transferred MLNC. The possibility that the BM component is non-lymphoid in nature is discussed.

The role of zinc (Zn) in the immunological expulsion of the nematode Nippostrongylus brasiliensis (Nb) from the small intestine of the rat was investigated. Three groups of 28 rats each were fed a basal diet providing either 3 mg Zn/kg for the zinc-deficient group (-Zn) or 40 mg Zn/kg for ad libitum-fed and pair-fed controls. After 6 wk each group was divided into two equal subgroups and infected with either 1000 or 4000 infective Nb larvae/rat. The -Zn rats showed significant reductions (P less than 0.001) in food intake, weight gain and food conversion efficiency when compared to the rats fed ad libitum but not when compared to the pair-fed controls. Plasma zinc concentration in the -Zn rats (0.50 microgram/ml) was significantly lower than in both ad libitum-fed (1.33 micrograms/ml) and pair-fed (1.45 micrograms/ml) controls (P less than 0.001). The recovery of worms from the rats 3, 7 and 12 d postinfection was similar for the corresponding day and dose of infection in all groups. Expulsion was almost complete in all groups by 12 d post-infection. There were no significant differences in size and fecundity of worms recovered from the different groups of rats on 7 d postinfection. However, over the whole period of infection, the -Zn rats excreted significantly more parasite eggs than did controls (P less than 0.001). These results indicate that although zinc deficiency affected growth performance of the rats, it did not affect the establishment or expulsion of Nb. Impairment of the immune response of the zinc-deficient rat was manifested only by a significant increase in the number of parasite eggs excreted in feces.

Summary Surface antigens of muscle larvae of Trichinella spiralis were stripped from the cuticle of live worms by the cationic detergent cetyltrimethylammonium bromide (CTAB). Such antigen preparations were shown to contain surface antigens of approximate molecular weights 100000, 90000, 69000, 55000, 46000 and 35000. Immunoprecipitation experiments confirmed that the surface of muscle larvae share antigenic epitopes with antigens contained within and secreted by the stichosome. CTAB antigen preparations were shown to be protective in NIH mice against a challenge infection as assessed by reduction in intestinal worm burden, worm fecundity, worm length and muscle larvae burden. The role of surface antigens in protective immunity to T. spiralis is discussed.

Transplantation experiments were conducted to assess the reversibility or irreversibility of the damage sustained by Strongyloides ratti during infections in the rat host. Worms of different ages from primary and secondary infections were recovered from their original hosts and transplanted surgically into naive rats. The size and fecundity of normal (Days 6–11 postinfection) worms were maintained after transfer. Damaged worms from primary infection (Days 22–26) showed complete recovery of size and fecundity within 10 days of transfer; damaged worms from a secondary infection (Days 6–7) also showed functional recovery but to a lesser extent. The ultrastructural changes observed mainly in the intestine of damaged worms from primary infections, prior to their transfer, were, however, only partially ameliorated following transplantation into new naive hosts; there was no complete return to structural normality. On the other hand, second infection worms did show almost complete ultrastructural recovery. The course of a transplanted infection established with either damaged or normal worms was similar to infections established percutaneously. Increase in the size of transplanted infections from 100 to 250 worms per recipient did not alter the dynamics of the host/parasite relationship. There was no evidence of adaptation in S. ratti and damaged worms, when transplanted into naive rats, were as successful as normal worms in protecting the host against a subcutaneous larval infection. The implications of this work on the present understanding of the phenomenon of autoinfection in experimental rodent strongyloidiasis are discussed.

SUMMARYThe immunogenicity of the secretory exo-antigen (EXA) originating in the stichosome of Trichuris muris has been investigated. High levels of immunity to challenge were produced using EXA (100 μg) by subcutaneous administration. Vaccination with a range of doses of EXA in Freunds' Incomplete Adjuvant (FIA) showed a dose response; 1 μg of EXA reduced the worm burden by 50% and doses of 10 μg or more reduced the worm burden by 80–90% at Day 9 post-infection. Worms recovered from vaccinated mice were significantly smaller than those from controls. A precipitin line identifiable with EXA was shown to immunize mice against T. muris challenge by vaccination. The protective antigen contained in EXA has been partially isolated using gel filtration, ion exchange filtration and isoelectric focusing and has been shown to be a protein of 30000 molecular weight having a pi of 6·8–7·3.

In young (6- to 8-week-old) NTH strain inbred mice expulsion of a primary infection of Trichinella spiralis began on day 8 and was virtually complete by day 11·5. In older mice expulsion occurred 1 or 2 days earlier. Experience of a primary infection elicited strong immunity to challenge, whether the challenge was given immediately after worm expulsion (day 14) or delayed (day 42). Challenge infections were expelled rapidly, the majority of worms being lost during the first day. Immunity to challenge was elicited by low-level primary infections and was effective against large challenge infections. These results are discussed in relation to conventionally accepted parameters of immunity to T. spiralis in mice which, it is considered, are applicable only to mice with a genetically-determined low-level of responsiveness to the parasite.

SUMMARYA comparison was made of the development, survival and reproduction of 5 isolates of Trichinella spiralis in inbred mice. Low responder C57BL/10 mice allowed worms of all isolates to survive longer and reproduce more successfully than did high responder NIH mice, suggesting that host immunity exerted a dominant influence upon infectivity. One isolate (Is-5 (W) — an arctic isolate) had a markedly lower infectivity than all other isolates, and was selected for more detailed study, together with isolate Is-1 (S) (a temperate isolate) which showed high infectivity. The lower infectivity of Is-5 (W) reflected a more rapid onset of immunity in mice infected with this parasite, immunity reducing the reproductive potential of female worms and causing an early expulsion from the intestine. No evidence of a dose-dependent suppression of immunity was found to explain the higher infectivity of Is-1 (S). Is-5 (W) provided a very rapid mucosal mastocytosis in infected mice, whereas Is-1 (S) caused no measurable response. In contrast, Is-1 (S) elicited higher levels of circulating parasite-specific antibodies than did Is-5 (W). These results are discussed in relation to the interplay of parasite immunogenicity and host immune responsiveness in determining infectivity, and point to the importance of identifying those immunodominant parasite molecules which control the balance of the host—parasite relationship.

Lammas D.A. , Mitchell L.A. and Wakelin D. 1988. Genetic control of eosinophilia in parasitic infections: responses of mouse strains to treatment with cyclophosphamide and parasite antigen. International Journal for Parasitology 18 :1077–1085. Strain-dependent variation in the capacity of inbred and congenic mice to mount an eosinophilia in response to inoculation with the antigens of Mesocestoides corti, Trichinella spiralis or with Limulus haemocyanin (LCH), following pretreatment with cyclophosphamide (CY), is described. SWR, NIH, BALB/c, C3H and SJL mice were eosinophil high responder strains whereas C57 BL/10 and CBA mice were eosinophil low responder strains. Congenic strains with the B10 background (B10.S, B10.G and B10.BR) were all low eosinophil responders, although B10.G mice showed a level of response consistently above the other B10 congenic strains. Some of the gene(s) for high responsiveness appeared to be dominant, because F(In1)hybrids between high and low eosinophil response parental strains were intermediate to high responders. The strain-dependent pattern of eosinophil responsiveness to LHC or to M. corti and T. spiralis antigens, following CY pretreatment, was similar to that obtained previously following infection with either M. corti or T. spiralis , suggesting that heterogeneity in capacity to produce eosinophils operates independently of the nature of the eliciting stimulus.

The effects of three immunosuppressive treatments--whole body irradiation and injections of cortisone acetate or cyclophosphamide, on the course of primary infections with Eimeria vermiformis were investigated in 'resistant' BALB/c and 'susceptible' C57BL/6 mice. Immunosuppression (and the nude athymic mutation in BALB/c mice) resulted in increased reproduction of the parasite in both strains of mice, indicating some immunological control of primary infections. The effect was, however, very much more marked in the BALB/c mice, resulting in an alteration in the relative susceptibilities of the two strains. The findings are discussed and it is suggested that the basis for the differences observed in the course of infection in normal BALB/c and C57BL/6 mice lies in their immune responses to this parasite.

SUMMARYParasitic infections in man and domestic animals exhibit two striking characteristics (a) their prevalence is high, but infections are unequally distributed among individuals within populations and (b) immunity is often slow to develop and appears, at best, only partially effective. Recent immunological and epidemiological studies suggest that effective immunity can develop, but that high prevalence within populations reflects the operation, not only of socio-economic and climatic factors, or husbandry practices, but also of powerful environmentally induced constraints upon the development of resistance. Immunogenetic studies suggest the operation of additional constraints which reflect individual genetic characteristics, and which influence the ability to develop and express effective immunity. A full understanding of all constraints is necessary before levels of population and individual resistance to infection can be increased; the need for such understanding has become more pressing with the prospect that anti-parasite vaccines may become available. Two aspects of environmentally induced constraints are considered, those arising from nutritional inadequacies and those resulting from exposure to infection in early life. Both are discussed primarily in terms of helminth parasites. Genetically determined constraints are discussed with reference to MHC-restricted recognition of malarial peptide vaccines and in terms of Class II molecule-directed control of T-cell function inLeishmaniainfections. Genetic influences are also considered from the standpoint of inflammatory cell function, in immunity against intestinal nematodes and in vaccine-induced immunity againstSchistosoma. Finally, parasite-induced constraints, particularly those which down-regulate protective responses are discussed briefly.

Mice infected with as few as ten eggs of the nematode Trichuris muris are highly resistant to a challenge infection given 5 weeks later. The rate of elimination of challenge larvae is similar in mice immunized by infection with ten or with 300 eggs. Stimulation of immunity to challenge by the low-level infections is dependent upon the persistence of the immunizing worm population and removal of the population at day 14 considerably reduces the level of immunity. Worms developing from a low-level immunizing infection are not eliminated by a ‘self-cure’ response, as is the case with larger infections, and become sexually mature. Adult worms from such an infection are, however, eliminated by the response to a superimposed challenge infection. Repeated infection of mice with small numbers of eggs stimulates an immune response and the worm population is eliminated before patency.

Immune responses to immunization and infection with Trichinella spiralis and T. britovi were studied in NIH high-responder mice. Overall it was shown that T. britovi was the more immunogenic, immunization and challenge with this species giving greater host-protective immunity. This greater immunogenicity was reflected in higher proliferative responses when mesenteric node lymphocytes (MLNC) from immunized mice were restimulated with T. britovi antigens in vitro and in higher levels of T helper 2 (Th2) lymphocyte-dependent specific IgG1 antibody responses against this species. MLNC from mice immunized against T. britovi released more IL-5 when restimulated in vitro, again suggesting a greater T helper 2 subset response, but after infection the highest levels of IL-5 were recorded from MLNC taken from T. spiralis challenged mice. These data are discussed in relation to current understanding of immunological differences between species and isolates of the genus Trichinella.

Trypanosoma cruzi -infected mice show disturbance in the peripheral immune system such as polyclonal lymphocyte activation, autoantibody production, and immunosuppression of T lymphocytes. Previous observations in our laboratory showed that some stocks of T. cruzi can be contaminated with mouse hepatitis virus type 3 (MHV-3). Literature has shown that MHV-3 infection induces immunologic disorders characterized by thymic involution with marked cell depletion. However, the effects of interactions between MHV-3 and the parasite on the immune system are not well understood. In the present study specific-pathogen-free CBA mice were inoculated with MHV-3, alone or associated with different stocks of T. cruzi . Concurrent murine virus infection resulted in increased pathogenicity of T. cruzi infection shown by profound thymic atrophy; loss of cortical thymocytes; depletion of Thy1.2 + , CD4 + , and CD8 + cells; enhancement of in situ labeling of nuclear DNA fragmentation; and eventually, death of the animals. Such lines of evidence show that the mechanism underlying this thymic atrophy is associated with apoptosis. These results also suggest that MHV-3 can account for the increased immunosuppression observed during experimental infection with the parasite.