Different genetic control of cutaneous and visceral disease after Leishmania major infection in mice

The mouse strains BALB/cHeA (BALB/c) and STS/A (STS) are susceptible and resistant to Leishmania major-induced disease, respectively. We analyzed this difference using recombinant congenic (RC) BALB/c-c-STS/Dem (CcS/Dem) strains that carry different random subsets of 12.5% genes of the strain STS in a BALB/c background. Previously, testing the resistant strain CcS-5, we found five novel Lmr (Leishmania major response) loci, each associated with a different combination of pathological and immunological reactions. Here we analyze the response of RC strain CcS-16, which is even more susceptible to L. major than BALB/c. In the (CcS-16 x BALB/c)F(2) hybrids we mapped three novel loci that influence cutaneous or visceral pathology. Lmr14 (chromosome 2) controls splenomegaly and hepatomegaly. On the other hand Lmr15 (chromosome 11) determines hepatomegaly only, and Lmr13 (chromosome 18) determines skin lesions only. These data confirm the complex control of L. major-induced pathology, where cutaneous and visceral pathology are controlled by different combinations of genes. It indicates organ-specific control of antiparasite responses. The definition of genes controlling these responses will permit a better understanding of pathways and genetic diversity underlying the different disease phenotypes.     

Separation and mapping of multiple genes that control IgE level in Leishmania major infected mice

The strain BALB/cHeA (BALB/c) is a high producer, and STS/A (STS) a low producer of IgE after Leishmania major infection. We analyzed this strain difference using 20 recombinant congenic (RC) BALB/c-c-STS/Dem (CcS/Dem) strains that carry different random subsets of 12.5% of genes of the strain STS on the BALB/c background. Strains CcS-16 and -20 exhibit a high and a low IgE level, respectively. In their F(2) hybrids with BALB/c we mapped nine Leishmania major response (Lmr) loci. Two of them we previously found to influence IgE level in CcS-5. IgE production in CcS-16 is controlled by loci on chromosomes 2, 10, 16 and 18 and in CcS-20 by loci on chromosomes 1, 3, 4, 5 and 8. The STS alleles of loci on chromosomes 1, 4, 5, 8 and 10 were associated with a low, whereas the STS alleles on chromosomes 16 and 18 with a high IgE production. The loci on chromosomes 2 and 3 have no apparent individual effect, but interact with the loci on chromosomes 10 and 1, respectively. The loci on chromosomes 10 and 18 were mapped in the regions homologous with the human regions containing genes that control total serum IgE and intensity of infection by Schistosoma mansoni, suggesting that some Lmr loci may participate in the pathways influencing atopic reactions and responses to several parasites. The definition of genes controlling anti-parasite responses will permit a better understanding of pathways and genetic diversity underlying the disease phenotypes.     

Interleukin-4-independent acceleration of cutaneous leishmaniasis in susceptible BALB/c mice following treatment with anti-CTLA4 antibody

BALB/c mice are susceptible to progressive infection with Leishmania major due to the preferential development of CD4(+) T cells that secrete Th2 cytokines. Although Th2 cell development and susceptibility are disrupted by blockade of CD86 function early in infection, CD28-deficient BALB/c mice remain susceptible to leishmaniasis. We therefore examined whether the alternative CD86 ligand, CTLA4, contributes to the expression of susceptibility. BALB/c mice treated for 2 weeks of infection with anti-CTLA4 monoclonal antibody developed more rapidly progressive disease than sham-treated mice, whereas normally resistant C57BL/6 mice were unaffected. The draining lymph node cells of anti-CTLA4-treated BALB/c mice produced up to sixfold more interleukin-4 (IL-4) and IL-13 than control mice in the first 2 weeks of infection, but IFN-gamma synthesis was reciprocally decreased. Anti-CTLA4 treatment of BALB/c mice pretreated with neutralizing anti-IL-4 antibody or genetically deficient in IL-4 also caused significant worsening of leishmaniasis. Exacerbation in IL-4 KO mice was associated with increased IL-13 and decreased gamma interferon (IFN-gamma) and inducible nitric oxide synthase (iNOS) mRNA expression in vivo. These data indicate that anti-CTLA4 antibody induced earlier and more-polarized Th2 responses in susceptible BALB/c mice infected with L. major. The mechanism of disease worsening was partially IL-4 independent, indicating that increased IL-13 and/or decreased IFN-gamma production may have disrupted nitric oxide-based microbicidal responses. We conclude that CTLA4 significantly modulates Th2 development in murine leishmaniasis and that the Th2-polarizing effects of anti-CTLA4 treatment result in IL-4-independent exacerbation of disease.     

Interleukin-12 regulation of host defenses against Coccidioides immitis.

We have previously reported on the alternate regulation of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) in inbred mouse strains which differ in their susceptibility to Coccidioides immitis. The genetically resistant DBA/2 mice manifest a predominant T-helper 1 (Th1) response, with early production of IFN-gamma, whereas susceptible BALB/c mice show an early production of the Th2 cytokine IL-4. Since IL-12 is one cytokine that can act early during host defenses to promote the differentiation of cytokine production towards IFN-gamma and thus may promote expression of a protective immune response, we investigated the role of IL-12 in resistance to C. immitis. Administration of recombinant IL-12 to the susceptible mouse strain before and after systemic (intraperitoneal) challenge with C. immitis significantly ameliorated the course of the disease, as measured by a reduction in the fungal load in the lungs, liver, and spleen. Analysis of the cytokine mRNA in lungs from infected BALB/c mice revealed that the protective effect of recombinant IL-12 was accompanied by a shift from a Th2 to a Th1 response. The importance of IL-12 in resistance to this fungus was further established by showing that neutralization of endogenous IL-12 in the resistant DBA/2 mouse strain led to a significant increase in the fungal burden in pulmonary and extrapulmonary tissues. These results establish that IL-12 plays a pivotal role in the host defense against systemic challenge with C. immitis.     

Cytokine responses in mice infected with<Emphasis Type="Italic"> Clonorchis sinensis</Emphasis>

FVB and BALB/c mice show different morbidity, development of Clonorchis sinensis, and pathological changes following C. sinensis infection. FVB mice are susceptible and BALB/c mice are relatively more resistant to C. sinensis infection. To investigate the relationship between cytokine reaction and susceptibility to C. sinensis infection in FVB and BALB/c mice, we described both the patterns and kinetics of Th1 cytokines and Th2 cytokines in spleen cell culture. Interleukin (IL)-4 and IL-10 cytokine production in the culture supernatants of the concanavalin-A-stimulated spleen cells increased at 2–3 weeks post-infection in both strains. IL-5 production increased between 2 and 5 weeks post-infection in both strains, and reached a peak level at 2 weeks post-infection in BALB/c mice and 4 weeks post-infection in FVB mice. In contrast, gamma interferon (IFN-) production decreased between 2 and 4 weeks in both strains. IL-2 production increased slightly in BALB/c mice following infection, but was unchanged in FVB mice. IL-4 production over preinfection levels was significantly higher in FVB mice, whereas IFN-, IL-2, and IL-10 production were significantly higher in BALB/c mice. The levels of serum immunoglobulin E (IgE) and blood eosinophils in both mouse strains significantly increased between 3 and 6 weeks postinfection. Serum IgE levels were significantly higher in FVB mice than in BALB/c mice. The results of this study suggest that susceptibility to C. sinensis infection is associated with Th2 cytokine production, especially IL-4 which is predominant in relatively susceptible FVB mice.     

Site-specific immunity to Leishmania major in SWR mice: the site of infection influences susceptibility and expression of the antileishmanial immune response.

Inbred strains of mice usually develop either of two divergent patterns of infection in response to Leishmania major. Resistant mice, which develop self-limiting infections, respond immunologically with the activation of gamma interferon-secreting Th1 helper T cells, while nonhealing infections in susceptible mice are characterized by the proliferation of interleukin-4-secreting Th2 cells. Development of these divergent responses is dependent primarily on the strain of mouse infected, although factors such as the infective dose, species, and strain of parasite can also influence the degree of resistance. In this study, we show that a single mouse strain, SWR, can develop totally divergent patterns of infection depending on the site of parasite inoculation. Both SWR mice and highly susceptible BALB/c mice developed progressive, ultimately fatal disease when inoculated in the dorsal skin over the base of the tail. However, SWR mice infected in the hind footpad developed far less severe infections, which were for the most part controlled, whereas BALB/c mice infected in this site developed severe, nonhealing lesions. Production of gamma interferon and interleukin-4 and measurement of immunoglobulin E levels in serum were used to assess the degree of Th1 and Th2 cell activation in infected mice. Cytokine profiles early in infection had characteristics of a mixed Th1-Th2 response and were similar in SWR mice infected at either site. These early cytokine responses were not predictive of the ultimate disease outcome, since lymph node cells from healing mice eventually produced higher levels of gamma interferon than did those from nonhealing mice, and healing mice had lower levels of immunoglobulin E in serum, suggesting a functional bias toward Th1 cell activity in these animals. The differential ability of SWR mice to heal infections at different cutaneous sites provides a new model for the study of resistance to cutaneous leishmaniasis. Unlike traditional models of infection in which resistant and susceptible strains of mice are compared, this model allows for the study of factors that contribute to healing and nonhealing infections in a genetically identical strain of mouse.     

Dissociation of disease susceptibility, inflammation and cytokine profile in lmr1/2 congenic mice infected with Leishmania major

Severity of disease caused by Leishmania major depends on the genetics of the host. Early induction of T helper cell type 1 (Th1)-type responses in resistant C57BL/6 mice and T helper cell type 2 (Th2) in susceptible BALB/c mice is thought to determine cure or disease respectively. We have mapped three loci that confer susceptibility or resistance upon congenic mice on the C57BL/6 or BALB/c backgrounds. Here we examine the histopathology and production of interleukin 4 (IL-4) and interferon gamma (IFN-gamma) in the skin and draining lymph nodes in the congenic and parental mice. We show an evolving granuloma with a staged infiltration of inflammatory cells, but no difference between the groups. As an indication of an early-polarised Th1/Th2 response we measured IFN-gamma and IL-4 in the lymph nodes and found no difference between any of the mice during the first 48 h. During infection, the level of IL-4 correlated with the lesion size, indicating that IL-4 reflects the disease severity rather than controls it. Considering this effect, B6.C(lmr1,lmr2) mice had similar cytokine levels to the parental C57BL/6 mice despite increased susceptibility and C.B6(lmr1,lmr2) were similar to BALB/c despite increased resistance. We conclude that the lmr loci affect disease severity by a mechanism independent of conventional helper T-cell responses.     

Chromosomes X, 9, and the H2 locus interact epistatically to control Leishmania major infection.

As in other infectious diseases, the outcome of a Leishmania major infection is closely tied to the T helper cell response type; progressive disease is associated with a predominant Th2 lymphocyte response, healing with a Th1 response. In mice, susceptibility is genetically con trolled, with BALB/c (C) mice being susceptible and C57BL/6 (B) mice being resistant. Using a genome-wide scan on two large populations of F2 mice created from these strains, we have shown previously that susceptibility to infection with L. major is controlled by two autosomal loci: lmr1 at the H2 locus, and lmr2 on chromosome 9. Employing a strategy to identify loci that interact, we show here that lmr1 and lmr2 interact synergistically, and we describe a new locus lmr3, lying on the X chromosome, whose effect depends on a specific lmr1 haplotype.     

Cryptosporidium infection in major histocompatibility complex congeneic strains of mice: variation in susceptibility and the role of T-cell cytokine responses

Studies with murine infection models have shown that immunity to the protozoan parasite Cryptosporidium involves T-cells and interferon-gamma (IFN-γ) activity. The present study was performed to compare the course of infection of Cryptosporidium muris in major histocompatibility complex (MHC) congeneic strains of mice and examine the relationship between susceptibility to infection and production of T-cell cytokines. In experiments with BALB mice, the BALB/c strain (H-2 ^d) produced significantly fewer oocysts and recovered from infection sooner than the BALB/B (H-2 ^b) or BALB/K (H-2 ^k) strains. BALB/B X BALB/c F1 hybrid mice were found to express the more susceptible phenotype of the BALB/B parent strain, indicating that the gene(s) in the H-2 locus conferring increased susceptibility to C. muris infection was dominant. At different times during infection of the resistant BALB/c strain and the susceptible BALB/B strain, splenocytes were cultured with soluble parasite antigen and measurements were made of production of a number of T-cell cytokines. Similar patterns of increasing levels of IFN-γ and interleukin 2 (IL-2) were observed in both the resistant and susceptible strains during the patent stage of infection, indicating that production of these type 1 T-helper-cell (TH1) cytokines (i.e. involved in cell-mediated responses) correlated with the development of immunity. This also suggested that the increased susceptibility of BALB/B mice was not associated with a defective TH1 cytokine response. In the study of TH2 cytokines (involved in induction of an antibody response), low levels of IL-10 were detected during infection of BALB/c and BALB/B mice. In contrast, although IL-4 was released by splenocytes of both strains, significantly larger amounts were obtained from cells of the susceptible BALB/B mice in the early stages of infection. Thus, the H-2-dependent variation in susceptibility to infection between these BALB strains correlated with a difference in the pattern of IL-4 secretion. Received: 11 July 1996 / Accepted: 15 September 1996     

Leishmania major-infected murine langerhans cell-like dendritic cells from susceptible mice release IL-12 after infection and vaccinate against experimental cutaneous Leishmaniasis

Leishmania major-infected C57BL / 6 skin-dendritic cells (DC) are activated and release cytokines (including IL-12 p70), and likely initiate protective Th1 immunity in vivo (von Stebut, E. et al., J. Exp. Med. 188: 1547 - 1552). To characterize differences in DC function in mice that are genetically susceptible (BALB / c) and resistant (C57BL / 6) to cutaneous leishmaniasis, we analyzed the effects of L. major on Langerhans cell-like, fetal skin-derived DC (FSDDC) from both strains. BALB / c- and C57BL / 6-FSDDC ingested similar numbers of amastigotes, but did not ingest metacyclic promastigotes. Like C57BL / 6-FSDDC, infection of BALB / c-FSDDC led to up-regulation of MHC class I and II antigens, CD40, CD54, and CD86 within 18 h. L. major-induced BALB / c DC activation also led to the release of TNF-alpha, IL-6 and IL-12 p40 into 18-h supernatants. Infected BALB / c- and C57BL / 6-DC both released small amounts of IL-12 p70 within 72 h. Additional stimulation with IFN-gamma and / or anti-CD40 induced the release of more IL-12 p70 from infected BALB / c-DC than C57BL / 6-DC. Co-culture of control or infected BALB / c- and C57BL / 6-DC with naive syngeneic CD4(+) T cells and soluble anti-CD3 resulted in mixed, IFN-gamma-predominant responses after restimulation with immobilized anti-CD3. Finally, syngeneic L. major-infected DC effectively vaccinated BALB / c mice against cutaneous leishmaniasis. Genetic susceptibility to L. major that results from induction of Th2 predominant immune responses after infection does not appear to reflect failure of skin DC to internalize or respond to parasites, or the inability of BALB / c T cells to mount a Th1 response to DC-associated Leishmania antigens.     

Roles of gamma interferon and interleukin-4 in genetically determined resistance to Coccidioides immitis.

The profiles of gamma interferon (IFN-gamma) and interleukin-4 (IL-4) production were evaluated during the course of coccidioidomycosis in two inbred mouse strains which differ in their susceptibility to Coccidioides immitis. Cytokine responses, measured at the molecular and protein levels, showed increased levels of IFN-gamma in lung extracts from mice of the resistant DBA/2 strain after a pulmonary challenge, whereas the susceptible BALB/c strain manifested a predominant IL-4 response. The importance of these cytokines in host defense against C. immitis was established by treating the mice with recombinant cytokines or neutralizing anticytokine monoclonal antibodies. Treatment of the susceptible BALB/c mice with recombinant murine IFN-gamma significantly protected mice against systemic challenge, and in the reciprocal experiment, the administration of an anti-IFN-gamma monoclonal antibody to the resistant DBA/2 mice significantly decreased their capacity to control disease. Although the treatment of DBA/2 mice with recombinant IL-4 did not alter the disease, neutralization of endogenous IL-4 in infected BALB/c mice by administration of a neutralizing anti-IL-4 antibody led to a significant reduction in the fungal load in their tissues. These results, taken together, establish that IFN-gamma plays a pivotal role in resistance to C. immitis, whereas IL-4 down-regulates protective immunity against C. immitis.     

Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis

Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c.DBA/2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3?Mbp (11.8?Mbp with flanking regions) in size and contained gene(s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (～3?Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6?Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.     

Genetic control of murine listeriosis expressed in the macrophage response

Susceptibility to murine listeriosis is genetically regulated. For example, A/J, C3H, CBA, DBA/1, DBA/2 and 129/J mouse strains are classed as susceptible and demonstrate an early net bacterial growth rate which is significantly higher than that seen in strains classed as resistant, namely, C57BL-derived strains, NZB and SJL. These strain differences in susceptibility are expressed during the phase of natural resistance, as a property of the macrophage response. Genetic analysis in progeny derived from resistant C57BL-derived strains and susceptible A/J or BALB/c strain mice has indicated that a major gene is responsible for determining resistance/susceptibility to listeria. The genetic advantage of the resistant phenotype is attributed to a prompt influx of young (radiosensitive) inflammatory macrophages which control the early bacterial multiplication in infective sites. Such cells reportedly have superior listericidal activity in vitro, as compared to mature macrophages. Mononuclear phagocyte production, emigration and accumulation at infective foci are all increased in resistant C57BL, but not in susceptible A/J mice, shortly following infection. Thus, resistance to listeriosis is associated with an efficient macrophage inflammatory response and, conversely, susceptibility is attributed to a sluggish response. Genetic studies have demonstrated linkage between these two traits (listeria resistance/susceptibility and the macrophage inflammatory response). In all probability, different gene loci are responsible for susceptibility amongst the various mouse strains. In A/J mice, susceptibility is attributed to C5 deficiency (specified by Hc locus) while, for C5-sufficient strains, another genetic defect is presumably responsible.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistance ranking of some common inbred mouse strains to Mycobacterium tuberculosis and relationship to major histocompatibility complex haplotype and Nramp1 genotype.

Six common inbred strains of mice and their F1 hybrids were examined for resistance to infection with the H37Rv strain of Mycobacterium tuberculosis. According to survival times after inoculation of 10(5) CFU intravenously (i.v.), the mice could be classified as being either highly susceptible (CBA, DBA/2, C3H, 129/SvJ) or highly resistant (BALB/c and C57BL/6). F1 hybrids of susceptible and resistant strains were resistant. Although an examination of a limited number of H-2 congenic strains showed that the H-2k haplotype could confer susceptibility on a resistant strain, it was evident that non-major histocompatibility complex (MHC) genes were much more important. Resistant strains all possessed the susceptibility allele of the anti-microbial resistance gene, Nramp1. Results obtained with selected strains infected with 10(2) CFU of M. tuberculosis by aerosol agreed with the results obtained with mice infected i.v. The size of the bacterial inoculum was important in distinguishing between resistant and susceptible strains, in that a 10(7) inoculum overcame the resistance advantage of one strain over another.     

An in vitro model for infection with Leishmania major that mimics the immune response in mice.

By using a primary in vitro response specific for Leishmania major, normal T cells from resistant CBA/CaH-T6J and susceptible BALB/c mice commit to a Th1 and a Th2 response, respectively. Since commitment occurred, we measured the production of gamma interferon (IFN-gamma), interleukin-1 (IL-1), IL-2, IL-4, IL-5, IL-10, and IL-12, prostaglandin E2 (PGE2), transforming growth factor beta (TGF-beta), and nitric oxide in the first 7 days of the response to identify factors that are critical for Th1 and Th2 development. While cells from resistant CBA mice produced more IFN-gamma, IL-10, and nitric oxide, cells from susceptible BALB/c mice produced more IL-1alpha, IL-5, PGE2, and TGF-beta. Although substantial amounts of IL-12 were detected, IL-12 did not associate with either Th1 or Th2 development. We did not anticipate that cells from resistant CBA mice would make more IL-10 in vitro. However, this also occurred in vivo since CBA mice produced substantial amounts of IL-10 following infection with L. major. Moreover, adding anti-IL-10 to primary in vitro responses enhanced production of IFN-gamma and nitric oxide by cells from CBA and BALB/c mice. Therefore, IL-10 cannot be regarded as a cytokine that associates with susceptibility to infection with L. major. Finally, the data presented here suggest that a collection of factors that can be produced by accessory cells influence Th commitment (e.g., IL-1, PGE2, and TGF-beta favor Th2 development).     

Acquired immunity to Salmonella typhimurium and delayed (footpad) hypersensitivity in BALB/c mice.

BALB/c mice are extremely susceptible to salmonella infections. Previous reports have suggested that this natural susceptibility is due to a defect in cell-mediated immunity (CMI) which correlates with their inability to develop a delayed (footpad) hypersensitivity reaction to a salmonella extract when immunized with attenuated salmonellae. We have shown that mice thus immunized are in fact highly resistant to superinfecting intravenous challenge with virulent organisms, at a time when the footpad test is still negative. The footpad test becomes positive 2-3 weeks later, after the appearance of CMI, which is already present at 1 week as measured by determining the fate of a superinfecting challenge in the RES. The positive footpad reactions that develop in BALB/c mice--and also in B10, and CBA and (B10XA/J)F1 mice--are transferable to normal recipients by thetasensitive spleen cells. However, although B10 mice give positive delayed hypersensitivity (DH) reactions, they are more susceptible to salmonellae of intermediate virulence than the DH negative BALB/c strain. We have also shown that previous reports which suggested that susceptible mice did not develop immunity when vaccinated with live organisms are probably due to the salmonella strain used for vaccination, which does not establish a carrier state. A strain which does establish a carrier state effectively immunizes the susceptible BALB/c strain against virulent challenge, indicating that natural susceptibility does not preclude the development of acquired immunity to reinfection. X     

Genetic susceptibility to food allergy is linked to differential TH2-TH1 responses in C3H/HeJ and BALB/c mice

BACKGROUND: Although food allergy is a serious health problem in westernized countries, factors influencing the development of food allergy are largely unknown. Appropriate murine models of food allergy would be useful in understanding the mechanisms underlying food allergy in human subjects. OBJECTIVE: We sought to determine the susceptibility of different strains of mice to food hypersensitivity. METHODS: C3H/HeJ and BALB/c mice were sensitized to cow's milk (CM) or peanut by means of intragastric administration, with cholera toxin as a mucosal adjuvant. Mice were then challenged with CM or peanut. Antigen-specific IgE levels, anaphylactic symptoms, plasma histamine levels, and splenocyte cytokine profiles of these 2 strains were compared. RESULTS: CM-specific IgE levels were significantly increased only in the C3H/HeJ strain, 87% of which exhibited systemic anaphylactic reactions accompanied by significantly increased plasma histamine levels in response to challenge. BALB/c mice exhibited no significant CM-specific IgE response, increased plasma histamine levels, or anaphylactic symptoms. After peanut challenge, 100% of peanut-sensitized C3H/HeJ mice exhibited high levels of peanut-specific IgE and anaphylactic symptoms. In contrast, no hypersensitivity reactions were detected in BALB/c mice, despite the presence of significant serum peanut-specific IgE levels. Splenocytes from CM- and peanut-sensitized C3H/HeJ mice exhibited significantly increased IL-4 and IL-10 secretion, whereas splenocytes from BALB/c mice exhibited significantly increased IFN-gamma secretion. CONCLUSION: Induction of food-induced hypersensitivity reactions in mice is strain dependent, with C3H/HeJ mice being susceptible and BALB/c mice being resistant. This strain-dependent susceptibility to food allergy is associated with differential T(H)2-T(H)1 responses after intragastric food allergen sensitization.     

Susceptibility or resistance to Leishmania infection is dictated by the macrophages evolved under the influence of IL-3 or GM-CSF.

Although enhanced monocytopoiesis is a hallmark of leishmaniasis, its significance in determining the course of the disease has not been addressed. While the number of granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting cells increases in the draining lymph nodes in a resistant mouse strain (C57BL/6) during disease, in a susceptible strain (BALB/c) the number of interleukin-3 (IL-3)-secreting cells increases. Treatment of BALB/c mice with anti-IL-3 antibody significantly reduces the disease score. Bone marrow macrophages derived under stimulation with IL-3 (IL-3-Mphi) or GM-CSF (GM-Mphi) differ functionally. GM-Mphi are significantly more responsive to IFN-gamma-induced augmentation and more refractory to IL-4-mediated suppression of anti-leishmanial activity than IL-3-Mphi. LPS-induced IL-12 and TNF-alpha secretion by both the susceptible and resistant strain-derived macrophage subsets are down-regulated. Despite down-regulation of IL-12 secretion, GM-Mphi favor expansion of IFN-gamma-secreting cells and IL-3-Mphi favor IL-6-dependent expansion of the IL-4-secreting Th subset. Adoptive transfer of leishmanial antigen-pulsed IL-3-Mphi and GM-Mphi prior to infection either aggravated or reduced the disease score, respectively, in BALB/c mice. Anti-IL-6 treatment reverted the Th subset profile not only in vitro but also in vivo, resulting in a reduced disease score in both infected BALB/c mice and IL-3-Mphi recipients. The disease score in IL-3-Mphi recipients is also reduced significantly after anti-IL-4 treatment.     

ECTV Abolishes the Ability of GM-BM Cells to Stimulate Allogeneic CD4 T Cells in a Mouse Strain-Independent Manner

Ectromelia virus (ECTV) is the etiological agent of mousepox, an acute and systemic disease with high mortality rates in susceptible strains of mice. Resistance and susceptibility to mousepox are triggered by the dichotomous T-helper (Th) immune response generated in infected animals, with strong protective Th1 or nonprotective Th2 profile, respectively. Th1/Th2 balance is influenced by dendritic cells (DCs), which were shown to differ in their ability to polarize naïve CD4⁺ T cells in different mouse strains. Therefore, we have studied the inner-strain differences in the ability of conventional DCs (cDCs), generated from resistant (C57BL/6) and susceptible (BALB/c) mice, to stimulate proliferation and activation of Th cells upon ECTV infection. We found that ECTV infection of GM-CSF-derived bone marrow (GM-BM) cells, composed of cDCs and macrophages, affected initiation of allogeneic CD4⁺ T cells proliferation in a mouse strain-independent manner. Moreover, infected GM-BM cells from both mouse strains failed to induce and even inhibited the production of Th1 (IFN-γ and IL-2), Th2 (IL-4 and IL-10) and Th17 (IL-17A) cytokines by allogeneic CD4⁺ T cells. These results indicate that in in vitro conditions ECTV compromises the ability of cDCs to initiate/polarize adaptive antiviral immune response independently of the host strain resistance/susceptibility to lethal infection.