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ABSTRACT: Trichinella spiralis larvae incubated with a rabbit antiserum raised against the larval surface coat bound murine macrophages to the parasite surface. Cell binding was not observed without the antisurface coat serum, or with incubation of larvae in normal rabbit serum, or with antibodies to keyhole limpet haemocyanin which identify a cryptic T. spiralis larval antigen. Cell adherence to the larval surface was lost by treatment of the cells with the lysosomotropic drug primaquine, implicating a receptor-mediated mechanism. Cells adhering to the parasite surface internalized parasite surface coat material, which was subsequently concentrated into endosomes. Culture supernatants from these cells contained enhanced levels of IL-12. Thus, the initial Th1 response to T. spiralis infection may be explained by these data.
Parasite Immunology 04/2000; 22(3):115-20. · 2.60 Impact Factor
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ABSTRACT: IL-18, formerly designated IFN-inducing factor, is a novel cytokine produced by activated macrophages. It synergizes with IL-12 in the induction of the development of Th1 cells and NK cells. To define the biological role of IL-18 in vivo, we have constructed a strain of mice lacking IL-18. Homozygous IL-18 knockout (-/-) mice are viable, fertile, and without evident histopathologic abnormalities. However, in contrast to the heterozygous (+/-) or wild-type (+/+) mice, which are highly resistant to the infection of the protozoan parasite Leishmania major, the IL-18-/- mice are uniformly susceptible. The infected IL-18-/- mice produced significantly lower levels of IFN-gamma and larger amounts of IL-4 compared with similarly infected +/- and +/+ mice. In contrast, when infected with the extracellular Gram-positive bacteria Staphylococcus aureus, the IL-18-/- mice developed markedly less septicemia than similarly infected wild-type (+/+) mice. However, the mutant mice developed significantly more severe septic arthritis than the control wild-type mice. This was accompanied by a reduction in the levels of Ag-induced splenic T cell proliferation, decreased IFN-gamma and TNF-alpha synthesis, but increased IL-4 production by the mutant mice compared with the wild-type mice. These results therefore provide direct evidence that IL-18 is not only essential for the host defense against intracellular infection, but it also plays a critical role in regulating the synthesis of inflammatory cytokines, and therefore could be an important target for therapeutic intervention.
The Journal of Immunology 10/1999; 163(5):2821-8. · 5.79 Impact Factor
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ABSTRACT: We have previously shown that mice lacking inducible NO synthase are markedly more susceptible to Leishmania major infection but developed a significantly enhanced Th1 cell response compared with wild-type mice. Furthermore, at high concentrations, NO inhibited IL-12 synthesis by activated macrophages, thereby indirectly suppressing the expansion of Th1 cells. We report here that at low concentrations, NO selectively enhanced the induction of Th1 cells and had no effect on Th2 cells. NO exerted this effect in synergy with IL-12 during Th1 cell differentiation and had no effect on fully committed Th1 cells. NO appears to affect CD4(+) T cells directly and not at the antigen-presenting cells. These results therefore provide an additional pathway by which NO modulates the immune response and contributes to the homeostasis of the immune system.
European Journal of Immunology 09/1999; 29(8):2498-505. · 5.10 Impact Factor
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ABSTRACT: To develop an effective vaccine against the intracellular protozoan parasite Leishmania spp., we investigated the feasibility of expression library immunization (ELI) in the mouse. Genomic expression libraries of L. major were constructed and used to immunize mice. One of the three libraries (L1, with 10(5) clones) induced a significant protective immune response and delayed the onset of lesion development in highly susceptible BALB/c mice after i.m. immunization, compared with control mice immunized with the empty vector (EV). L1 was then divided into five sublibraries of approximately 2 x 10(4) clones each. Mice immunized with one of the sublibraries (SL1A) developed an even stronger protective effect than that induced by L1. SL1A was further divided into 20 sublibraries (SL2) of approximately 10(3) clones each. One of the SL2 libraries (SL2G) induced a strong protective effect against L. major infection. In direct comparative studies, the protective effect of the sublibraries was in the order of SL2G > SL1A > L1. Lymphoid cells from mice vaccinated with SL2G produced more IFN-gamma and NO, compared with cells from control mice injected with EV. Serum from the vaccinated mice also contained more parasite-specific IgG2a Ab, compared with controls. Therefore, these data demonstrate that ELI is feasible against this complex intracellular parasitic infection, by preferentially inducing the development of Th1 responses. Furthermore, by sequential division of the libraries, this approach may be used to enrich and identify protective genes for effective gene vaccination against other parasitic infections.
The Journal of Immunology 08/1999; 163(3):1467-72. · 5.79 Impact Factor
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D Piedrafita,
L Proudfoot,
A V Nikolaev,
D Xu,
W Sands,
G J Feng,
E Thomas,
J Brewer,
M A Ferguson,
J Alexander,
F Y Liew
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ABSTRACT: It is now generally accepted that IFN-gamma, secreted by Th1 cells, is the most potent cytokine leading to macrophage activation and host resistance against infection with the intracellular protozoan parasite Leishmania. It is also established that IL-12 is a critical cytokine involved in the differentiation and expansion of Th1 cells. Therefore, the ability of Leishmania parasites to actively suppress IL-12 production by host macrophages may be an important strategy for parasite survival. Here we report that a major parasite cell surface molecule, phosphoglycan (PG), of Leishmania could selectively inhibit the synthesis of IL-12(p40, p70) by activated murine macrophages. Furthermore, synthetic PG (sPG) was able to inhibit IL-12 release in a dose-dependent manner. Inhibition was dependent on the galactose(beta1-4)mannose(alpha1)-PO4 repeating units and not the glycophosphoinositol lipid anchor of lipophosphoglycan. At the concentration used, sPG had no effect on the release of TNF-alpha or IL-6 in activated macrophages. The inhibition of IL-12(p40) production was at the transcriptional level, but was not mediated through NF kappaB inhibition. These data demonstrate that PG may be an important molecule for the establishment and survival of the parasite in permissive hosts.
European Journal of Immunology 02/1999; 29(1):235-44. · 5.10 Impact Factor
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ABSTRACT: Nitric oxide is a labile molecule involved in a diverse range of biological functions including host defence against infection by pathogens. Oxidative deamination of the amino acid L-arginine, catalysed by a group of enzymes called nitric oxide synthases, results in the formation of L-citrulline and nitric oxide. A large number of pathogens, including bacteria, yeasts and multicellular parasites are susceptible to nitric oxide-mediated toxicity in vitro suggesting that nitric oxide is potentially an important molecule in host defence. Recent studies in vivo have demonstrated that infection of a host by micro-organisms can result in the induction of nitric oxide synthase, release of high levels of nitric oxide by inflammatory cells and resolution of the infection. However, the persistent production of high levels of nitric oxide in chronic disease states, can result in immune suppression, pathological changes and even host death. Whether nitric oxide is predominantly an immunoprotective or host-damaging agent, following infection, may depend on the host-pathogen equilibrium. This review discusses the role of nitric oxide both as a protective and pathogenic molecule in disease.
(C) Williams & Wilkins 1998. All Rights Reserved.
Reviews in Medical Microbiology 09/1998; 9(4). · 0.37 Impact Factor
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ABSTRACT: T helper cell type 1 (Th1) and 2 (Th2) are central to immune regulation. However, no stable cell surface marker capable of distinguishing and separating these two subsets of CD4(+) cells has yet been found. Using differential display PCR, we have identified a gene encoding a cell membrane bound molecule, originally designated ST2L, T1, DER4, or Fit, expressed constitutively and stably on the surface of murine Th2s, but not Th1s even after stimulation with a range of immunological stimuli. Antibody against a peptide derived from ST2L strongly and stably labeled the surface of cloned Th2s but not Th1s, and Th2s but not Th1s derived from naive T cells of ovalbumin T cell receptor-alpha/beta transgenic mice. Three-color single cell flow cytometric analysis shows that cell surface ST2L coexpressed with intracellular interleukin (IL)-4, but not with interferon (IFN)-gamma. The antibody selectively lysed Th2s in vitro in a complement-dependent manner. In vivo, it enhanced Th1 responses by increasing IFN-gamma production and decreasing IL-4 and IL-5 synthesis. It induced resistance to Leishmania major infection in BALB/c mice and exacerbated collagen-induced arthritis in DBA/1 mice. Thus, ST2L is a stable marker distinguishing Th2s from Th1s and is also associated with Th2 functions. Hence, it may be a target for therapeutic intervention.
Journal of Experimental Medicine 04/1998; 187(5):787-94. · 13.85 Impact Factor
