Suppression of muscosal mastocytosis by infection with the intestinal nematode Nematospiroides dubius

Mice exposed to primary infections with the parasite intestinal nematode Nematospiroides dubius failed to show the mucosal mast cell (MMC) response which is characteristic of infections with other species of intestinal nematode and which was readily induced in these mice by infections with Nippostrongylus brasiliensis or Trichinella spiralis. The failure to generate a mucosal mastocytosis was independent of host strain or sex. When infections with N. dubius were established before, or concurrently with, T. spiralis or N. brasiliensis, the MMC response elicited by these species was delayed and/or depressed as was expulsion of the worms themselves. Infection with N. dubius given when a MMC response was already established, by exposure to T. spiralis, had no effect on MMC numbers. The possibility that the effects of N. dubius upon MMC responses reflect a lack of mastocytopoietic potential, rather than an active interference, was excluded by showing that SJL mice, which expel primary infections with N. dubius and express strong immunity to reinfection, developed marked mastocytosis during secondary infections. The depression of MMC responses by N. dubius is discussed in relation to the known immunosuppressive properties of this parasite and in relation to the T cell mediated control of MMC development.     

Host genetics and resistance to acute Trypanosoma cruzi infection in mice. I. Antibody isotype profiles

Some strains of inbred mice survive acute infection with Trypanosoma cruzi while others die within a few weeks after infection. Mice which express B10 background genes and either the H-2q or H-2^d haplotypes are resistant and survive. However, mice which share the B10 genetic background but express H-2^k alleles die, usually within 4 weeks following infection. These data confirm that at least 1 gene in the major histocompatibility complex can determine whether an animal lives or dies during the acute phase. Expression of the H-2^q haplotype on the B10 genetic background or in DBA/l mice is associated with resistance, but H-2^q mice expressing the C3H background are susceptible. Therefore, at least I gene in the genetic background also influences resistance. Our data suggest that genes associated with resistance must be present in both the MHC and the genetic background or the animal will die. The isotypes and specificities of parasite reactive antibodies found in the serum of different inbred mouse strains were assessed during acute infection. Levels of IgM were higher in sera from mice which express the resistant B10 background than in sera from mice expressing the susceptible C3H background. Conversely, mice which share the C3H background genes produced high levels of anti-parasite IgG2a when compared to B10 congenic strains. Antigen specificity, however, may be influenced by both background and MHC genes, as congenic strains expressing different MHC haplotypes recognized different constellations of T. cruzi antigens. These data suggest a correlation between genes which influence antibody specificity or isotype and the genes which determine the ability of various inbred mouse strains to survive acute infection with T. cruzi.     

Expulsion of Nematospiroides dubius from the intestine of mice treated with immune serum

This paper describes experiments which demonstrated that the survival of Nematospiroides dubius was severely impaired in mice treated with immune serum. CFLP donor mice were given a series of infections ranging from 25 to 200 infective larvae, at weekly intervals for 6 weeks. The mice were treated with anthelmintic on day 21 and/or day 28 to prevent the accumulation of lethal numbers of parasites in the intestine, and were bled between day 42 and day 49. Female NIH recipient mice were given a total of 2.0-2.5 ml of immune serum i/p., in several separate smaller doses at various times in relation to the day of infection. Between the administration of immune serum begun during the first 4 days of infection and the animals being killed within the next 3 weeks, the mice harboured fewer worms than control animals, the worms were stunted and their fecundity was greatly reduced. Furthermore, these worms were subsequently lost from the intestines of treated mice, during and after the fourth week of infecton. These effects on N. dubius were not observed when mice were given normal serum nor when immune serum was administered after day 6 of the infection. The delayed rejection of adult worms from mice treated with immune serum is of particular significance and suggests that immune serum contained factors which facilitated the expression of a second component in worm expulsion not nornally effective in a primary infection. The possible immunologcal mechanisms underlying these findings are discussed and related to the immunosuppression which N. dubius is known to induce in the host.     

Mechanisms of protective immunity against 5. mansoni infection in mice vaccinated with irradiated cercariae. VI. Influence of the major histocompatibility complex

Summary Inbred mouse strains develop different levels of resistance to challenge infection with Schistosoma mansoni in response to vaccination with irradiated cercariae. The role of the major histocompatibility complex (MHC) in determining this genetic polymorphism in acquired resistance was investigated. Previous studies suggested that inbred mice bearing either the b or d MHC haplotypes develop a higher level of vaccine induced resistance than do mice with other MHC haplotypes. An analysis of an Fi cross between an H-2^b strain (C57BL/6) and an H-2^k strain (C3H/HeJ) indicated that the ability to develop high levels of immunity is inherited in a dominant fashion. In order to confirm that the development of high resistance is an MHC associated trait, B10, C3H, BALB and B6 congenic mice bearing different H-2 haplotypes were compared. On either the BIO, B6, or BALB background, substitution of b or d with k or a MHC alleles resulted in a decreased level of vaccine induced immunity. The observed decreases were more pronounced in BALB and B6 than in B10 congenics suggesting an influence of background (non-MHC linked) genes on protective immunity. Similarly, C3H. SW (H-2^b) mice developed a significantly higher level of acquired resistance than C3H/HeSn (H-2^k) mice. Cross and backcross experiments between H-2^b and H-2^k B6 congenic mice confirmed the dominant inheritance of high resistance as well as the MHC linkage of the trait. These data indicate that the MHC locus exerts a quantitative influence on vaccine induced resistance in certain inbred mouse strains and provide further support for the concept that the protection elicited by irradiated cercariae is the manifestation of a specific host immune response.     

Genetic control of immunity to parasites: adoptive transfer of immunity between inbred strains of mice characterized by rapid and slow immune expulsion of Trichinella spiralis

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-2^q) 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-2^q) 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-2^q may determine a rapid response. Comparisons are made with the genetic control of resistance to Listeria monocytogenes and possible mechanisms are discussed.     

Nematospiroides dubius in the mouse: evidence that adult worms depress the expression of homologous immunity

Summary Mice immunized by a single infection with irradiated (25 krad) larvae of N. dubius were very resistant to subsequent challenge. However, when normal larvae were administered together with irradiated larvae at immunization, the acquired immunity expressed against a challenge infection was markedly depressed. It was found that as few as 50 normal N. dubius larvae interfered with the immunity that would have otherwise been elicited by the concurrently administered irradiated larvae, but this depressed response was totally alleviated when the normal worms were removed after completing their development in the intestinal mucosa and before they reached adulthood. Adult TV. dubius were transplanted directly into the intestines of mice either 7 days before or after immunization by irradiated larvae; it was shown that the recipient mice were less resistant to challenge than mice which had been sham operated. Transplanted adult worms themselves stimulated very little resistance to challenge in recipient mice. These results established that adult parasites are capable of depressing the expression of homologous immunity in the mouse. The possible mechanisms by which JV. dubius might modulate the host's immunological activity at the intestinal level are discussed and it is proposed that this mechanism is of benefit to the parasite in preventing the host from eliminating the worms during a chronic primary function.     

Susceptibility to experimental interstitial lung disease is modified by immune- and non-immune-related genes

To evaluate the concept that genetic factors modulate susceptibility to agents that cause interstitial lung disease, animal models of interstitial lung disease caused by bleomycin or by inhalation of organic particulates (ovalbumin or bovine gamma globulin after specific immunization) were studied in strains of mice with different genetic backgrounds. Because immune processes have been implicated in modulating the susceptibility to agents that cause interstitial lung disease, we also compared congenic, resistant strains (strains with the same background but with different H-2 haplotypes) for their sensitivity to the same agents. In bleomycin-induced disease, the degree of lung disease was different in some of the different strains of mice and, in some strains, was related to H-2 locus genes since all strains with H-2b haplotypes were high responders, whereas most of the strains with H-2a, H-2d, and H-2k haplotypes were low responders. However, some of the strains of mice with the same H-2 haplotype but otherwise different genetic backgrounds had different responses to bleomycin, suggesting that there is also a role for non-H-2 genetic factors in modulating the response to this experimental interstitial lung disease. In the ovalbumin-induced lung disease model, as in bleomycin-induced lung disease, there were different strain susceptibilities: 2 of the 3 strains in the H-2b group were high responders, as was 1 of the 3 strains in the H-2k group. Interestingly, evaluation of the congenic, resistant strains showed that on the same backgrounds the H-2-related genes were able to modulate the degree of lung lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Suppression of mucosal mastocytosis by Nematospiroides dubius results from an adult worm-mediated effect upon host lymphocytes

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 genetic control of host responses to Dipetalonema viteae (Filarioidea) infections in mice

Dipetalonema 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. C57Bl/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 C57Bl/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 histocompatibility 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 C57bl/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.     

Resistance to Listeria monocytogenes in mice: genetic control by genes that are not linked to the H-2 complex.

After mice of several inbred strains were injected with Listeria monoyctogenes, two parameters of resistance, the 50% lethal dose and the suppression of bacterial proliferation in spleen, were determined. The strains of mice tested could be segregated into two groups: the resistant C57BL/10Sn mice and the sensitive A/J and DBA/2J mice. Congenic resistant strains of mice were used because they would express the H-2 haplotype of the sensitive strains (H-2a or H-2d) on the background of a resistant strain, C57BL/10Sn. Both the B10.A/SgSn (H-2a) and the B10.D2/Sn (H-2d) mice were as resistant as mice from their background strain and were significantly more resistant than the strains that donated their H-2 locus (A/J or DBA/2J). Therefore, the resistance of mice to Listeria, although genetically controlled, is not controlled by gene (s) linked to the H-2 haplotype. On the other hand, the level of specific immunity to listeria antigens (as indicated by the footpad reaction) was higher in the C57BL/10Sn (H-2b) mice than in either the A/J and B10.A/SgSn (H-2a) mice or the DBA/2J and B10.D2/Sn (H-2d) mice. This observation suggests an H-2 linkage of specific immunity to Listeria.     

Survival to patency of low level infections with Trichuris muris in mice concurrently infected with Nematospiroides dubius

Large, single-pulse laboratory infections with Trichuris muris are rejected by mice before patency, but low-level infections of fewer than 20 worms survive for long periods. Data are presented to show that the threshold at which an effective immune response takes place is significantly higher in mice concurrently infected with Nematospiroides dubius. In control CFLP mice trickle infections did not survive to maturity but in the slower responder C57 Bl10 mice egg production began on Day 35 and continued for a further seven weeks, with some mature worms present at autopsy. Concurrent infection with N. dubius resulted in trickle infections, T. muris surviving much better than in control mice, although these still showed some resistance to T. muris. It is suggested that the results support the hypothesis that T. muris elicits concomitant immunity in the host. Thus, the first worms to establish survive to patency at which time they can no longer be removed by the host, but once the immunological threshold has been exceeded incoming larvae are rejected by the host. Such a survival strategy would be very useful to T. muris in the wild.     

Genetic variation in the humoral immune responses of mice to the nematode Trichuris muris

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.     

Transfer of immunity to Nematospiroides dubius: co-operation between lymphoid cells and antibodies in mediating worm expulsion

The effect of transferring immune serum (IS) and immune mesenteric lymph node cells (IMLNC) either alone or in combination was studied in NIH mice infected with partially radiation attenuated (5 krad) N. dubius. It was demonstrated that immunity to N. dubius could be transferred with IS and with IMLNC. However, considerably greater protection was transferred to recipient mice when they received both IS + IMLNC. Animals treated in this way had fewer worms than either of the other groups from as early as day 9 onwards, suggesting that a substantial proportion of the worms in mice given IS + IMLNC was retained in the intestinal tissues. The few surviving worms which completed the tissue phase of their development were then rejected by the fourth week of infection. Dose response data showed that as few as 1 × 10⁷ IMLNC could cause a significant reduction in worm numbers when given in combination with IS. These experiments indicate that both antibodies (IS) and sensitized lymphoid cells (IMLNC) are required for effective resistance to N. dubius.     

Localization of a critical restriction site on the I-A beta chain that determines susceptibility to collagen-induced arthritis in mice

Type II collagen-induced arthritis (CIA) in mice is an autoimmune experimental model for rheumatoid arthritis. Susceptibility to CIA is associated with certain major histocompatibility complex class II haplotypes. The two very closely related haplotypes H-2q and H-2p differ in susceptibility to CIA. Only mice of H-2q (DBA/1, B10G strains) but not mice of H-2p-expressing strains (like strain B10P) develop CIA and an autoimmune response to type II collagen (CII) after immunization with CII. In contrast to H-2p, the H-2q haplotype does not express I-E molecules. The purpose of the present study was to identify, at the molecular level, the structures on major histocompatibility complex class II molecules determining susceptibility to CIA and CII responsiveness. We first excluded the possible suppressive involvement of Ep or Ap molecules by showing that F1 hybrids between H-2p and H-2q haplotype strains, expressing Ep and Ap, are responders to CII and fully susceptible to CIA. Secondly, because A alpha chains appear identical, we sequenced the A beta first-domain exons of p and q allotypes and found only four diverging amino acids in the predicted amino acid sequence. These variable residues were closely located at positions 85, 86, 88, and 89 at the end of the postulated alpha-helix, which is of importance for interactions with the antigenic peptide and the T-cell receptor. We suggest that this region is a critical major histocompatibility complex restriction site for CIA and CII responsiveness in H-2q mice as compared with H-2p mice. The CIA will now be an excellent autoimmune model for studies on interactions between autoantigenic peptide, autoreactive T cells, and a particular major histocompatibility complex molecule, as has been postulated to be the initial event also in rheumatoid arthritis.     

Influence of genes within the MHC on mortality and brain cyst development in mice infected with Toxoplasma gondii: kinetics of immune regulation in BALB H-2 congenic mice

Previous work has shown that genes within the major histocompatibility complex (MHC) of the mouse influence resistance and susceptibility to Toxoplasma gondii infection. Initial studies presented here using B10 H-2 congenic and recombinant haplotype mice inoculated via the oral route with the low virulence Beverley strain of T. gondii confirm the D region localization of MHC-linked control of brain cyst number. All B10 mice were, however, exquisitely sensitive to minor changes in virulence of the parasite inoculum resulting in high mortality during the early acute phase of infection. Further experiments examining mortality and brain cyst number in BALB MHC congenic mice inoculated via different routes indicated that the BALB background would provide a more favourable genetic environment in which to analyse kinetics of MHC controlled immune regulation following infection via the natural (oral) route. In studies comparing d and k haplotype mice a dramatic inverse relationship between splenic CD4:CD8 T cell ratios and brain cyst number was observed, particularly in the strain (BALB/K; H-2^k) most susceptible to high brain cyst numbers and subsequent toxoplasmic encephalitis. Of particular interest was the observation that splenomegaly and the relative increase in the splenic CD8 T cell population preceded and accompanied the very dramatic and rapid increase in brain cyst formation. The results suggest that the too rapid development of a potent anti-parasite response in the viscera may drive the parasite to encyst in the brain.     

An analysis of T-cell receptor variable region gene expression in major histocompatibility complex disparate mice.

To define the impact of major histocompatibility complex (MHC)-encoded glycoproteins on the selection of the T-cell receptor repertoire, we have determined the frequency with which T-cell receptor variable region (V alpha and V beta) genes are expressed in T cells from MHC disparate mice. Approximately 500 T-cell hybridomas were generated from each of three strains of MHC congenic mice [B10 (H-2b), B10.BR (H-2k), and B10.Q (H-2q)] by fusing mitogen-stimulated lymph node T cells with the thymoma BW5147. RNA was prepared from 1629 individual hybridomas and analyzed for the expression of 10 V alpha and 16 V beta gene families. These experiments reveal significant differences in the relative contributions of 1 V alpha gene family (V alpha 3) and several V beta gene segments (V beta 5.1, -5.2, -11, and -12) to the T-cell receptor repertoire of MHC disparate mice.     

Studies on chronic versus transient intestinal nematode infections in mice I. A comparison of responses to excretory/secretory (ES) products of Nippostrongylus brasiliensis and Nematospiroides dubius worms

Summary Previous reports have demonstrated that after implantation of intestinal worms or after exposure to infective third stage larvae, the duration of infection with Nematospiroides dubius is markedly prolonged in intact mice relative to infection with Nippostrongylus brasiliensis. The rapid rejection of N. brasiliensis adults appears T-cell dependent in that adults persist for longer periods in hypothymic nude mice than in intact mice. Excretory/secretory (ES) products harvested from N. dubius or N. brasiliensis intestinal worms did not differ obviously in the following characteristics: rate of production and degree of complexity of proteins, in vitro mitogenicity, allergenicity, or in their abilities to induce or elicit delayed type hypersensitivity reactions in naive and infected mice, respectively. Two differences between N. brasiliensis- and N. dubius-infected mice were an IgG₁ hypergammaglobulinaemia and readily detected anti-ES precipitating antibodies in the circulation; both responses were confined to the chronic N. dubius infection. One difference between N. brasiliensis and N. dubius ES products was that the former, but not the latter, induced protection against homologous infection when injected with Freund's complete adjuvant. By contrast, intraperitoneal implantation of either type of adult worm induced protection against homologous infection at least in female Balb/c mice. After intestinal implantation of both N. dubius and N. brasiliensis intestinal worms, the rejection of N. brasiliensis was not influenced by, nor did it alter, persistence of N. dubius adults. In support of conclusions drawn by others, the differences in persistence of infection between these two nematodes probably reflect differences in the ability to resist both specific and nonspecific components of the complex intestinal rejection process. The chronicity of N. dubius infection and nonpersistence of N. brasiliensis     

MHC-restricted antibody responses to Trichuris muris excretory/secretory (E/S) antigen

Two panels of H-2 recombinant mice were used in a detailed serological study to analyse the role of H-2-linked genes in the control of the antibody response to excretory/secretory (E/S) antigens of Trichuris muris. An apparent H-2q (I-Aq) restriction on the early development of high levels of IgG1 antibody to E/S antigen was revealed by ELISA. No such restriction was demonstrated for the specific IgG2a response patterns. Recognition of two high molecular weight antigens (90-95 kDa, 105-110 kDa) by IgG antibodies was also shown to be almost exclusively H-2q restricted and may be related at least in part to the high antibody levels seen for H-2q strains of mice. Immune serum from resistant (B10.BRxB10.G) F1 hybrid mice (H-2q/k) containing high levels of IgG1 antibodies specific for T. muris E/S and IgG antibodies which recognized the 90-95 kDa and 105-110 kDa E/S antigens was effective in transferring protection to the non-responsive B10.BR mouse strain as seen on day 35 post-infection (p.i.). It is suggested that the IgG responses described for the generally very resistant H-2q mouse strains may contribute to, but not be an absolute requirement for, protective immunity, antibody-mediated damage facilitating a subsequent cellular attack in certain strains of mice.     

The development of resistance in different inbred strains of mice to infection with Nematospiroides dubius

Infection by the intestinal nematode parasite Nematospiroides dubius was studied in seven different inbred mouse strains. Although there was some minor variation in the susceptibility of the different strains to a primary infection there were marked differences in their ability to develop resistance to infection following repeated exposure to infective larvae. The strains of mice which developed the best resistance also expelled adult worms arising from the previous infections. The adult worms resulting from a primary infection were slowly eliminated in two inbred strains studied whereas no loss occurred from outbred LACA mice. Although males and females of two strains, C3H/HeJ and CBA/H were equally susceptible to a primary infection, the females developed better resistance than the male mice following two oral administrations of third stage larvae. Infected mice of every strain and both sexes contained high levels of IgG1 in the serum.     

Immunoregulation of genetically controlled acquired responses to Leishmania donovani infection in mice: the effects of parasite dose, cyclophosphamide and sublethal irradiation

On a B10 (Lshs) genetic background, the development of acquired T cell mediated immunity to Leishmania donovani infection in mice is under H-2 linked genetic control. Following intravenous inoculation of 10(7) amastigotes three phenotypic patterns of recovery have been described: 'early cure' (H-2r,s), 'cure' (H-2b) and 'non-cure' (H-2d,q,f). In an attempt to determine the immunological basis for this H-2 linked genetic control the effects of varying parasite dose (5 x 10(3) to 5 x 10(7) amastigotes) and of pre-treatments with cyclophosphamide (50 or 200 mg/kg body weight CY) or sublethal irradiation (100 or 550 rad) on the course of infection, and on circulating anti-leishmanial IgG levels, were examined in strains representative of the three phenotypes: B10.D2/n (H-2d), C57BL/10ScSn (H-2b) and B10.RIII (H-2r). It was found that with low parasite doses (5 x 10(3) or 5 x 10(4)) 'non-cure' mice presented a 'cure' profile whilst raising the dose (5 x 10(7)) caused some perturbation of the normal self-curing response in 'cure' (but not 'early cure') mice. The highest dose did not, however, lead to progressive disease in the genetically non-cure strain. For the parasite dose experiments circulating anti-leishmanial IgG levels were higher in the early cure and cure strains than in the H-2d non-cure strain. The higher doses of CY and sublethal irradiation administered prior to infection had a clear prophylactic effect on the non-cure strain with some effect also observed in cure and early cure strains. This was thought to be due to deletion of the precursors of T suppressor (TS) cells suppressing cell-mediated immunity. Resolution of the liver parasite load in pre-treated mice took place despite minimal or undetectable levels of circulating anti-leishmanial IgG. Similarly, the earlier resolution of parasite load in pre-treated cure and early cure mice occurred even though the antibody response was severely reduced. This suggests that the high antibody responses observed in early cure and cure strains do not normally mediate cure and may simply reflect the independent effect of H-2 on T helper function or the humoral response.