Factors associated with the development of neonatal tolerance after the administration of a plasmid DNA vaccine.
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A plasmid DNA vaccine encoding the circumsporozoite protein of malaria (pCSP) induces tolerance rather than immunity when administered to newborn mice. We find that this tolerance persists for >1 yr after neonatal pCSP administration and interferes with the induction of protective immunity in animals challenged with live sporozoites. Susceptibility to tolerance induction wanes rapidly with age, disappearing within 1 wk of birth. Higher doses of plasmid are more tolerogenic, and susceptibility to tolerance is not MHC-restricted. CD8+ T cells from tolerant mice suppress the in vitro Ag-specific immune response of cells from adult mice immunized with pCSP. Similarly, CD8+ T cells from tolerant mice transfer nonresponsiveness to naive syngeneic recipients. These findings clarify the cellular basis and factors contributing to the development of DNA vaccine-induced neonatal tolerance. (+info)
Adjuvant-guided type-1 and type-2 immunity: infectious/noninfectious dichotomy defines the class of response.
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Traditionally, protein Ags have been injected in CFA (oil with inactivated mycobacteria) to induce immunity and with IFA (oil alone) to induce tolerance. We report here that injection of hen eggwhite lysozyme, a prototypic Ag, in CFA-induced and IFA-induced pools of hen eggwhite lysozyme-specific memory T cells of comparable fine specificity, clonal size, and avidity spectrum, but with type-1 and type-2 cytokine signatures, respectively. This adjuvant-guided induction of virtually unipolar type-1 and type-2 immunity was observed with seven protein Ags and in a total of six mouse strains. Highly polarized type-1 and type-2 immunity are thus readily achievable through the choice of adjuvant, irrespective of the genetic bias of the host and of the nature of the protein Ag. This finding should have far-reaching implications for the development of vaccines against infectious and autoimmune diseases. Furthermore, our demonstration that Ag injected with IFA is as strongly immunogenic for T cells as it is with CFA shows that the presence of the mycobacteria determines not the priming of naive T cells through the second-signal link but the path of downstream differentiation toward CD4 memory cells that express either type-1 or type-2 cytokines. (+info)
Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection.
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The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host. (+info)
Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.
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NK cells constitutively express monocyte-derived cytokine (monokine) receptors and secrete cytokines and chemokines following monokine stimulation, and are therefore a critical component of the innate immune response to infection. Here we compared the effects of three monokines (IL-18, IL-15, and IL-12) on human NK cell cytokine and chemokine production. IL-18, IL-15, or IL-12 alone did not stimulate significant cytokine or chemokine production in resting NK cells. The combination of IL-18 and IL-12 induced extremely high amounts of IFN-gamma protein (225 +/- 52 ng/ml) and a 1393 +/- 643-fold increase in IFN-gamma gene expression over those in resting NK cells. IL-15 and IL-12 induced less IFN-gamma protein (24 +/- 10 ng/ml; p < 0.007) and only a 45 +/- 19-fold increase in IFN-gamma gene expression over those in resting NK cells. The CD56bright NK cell subset produced significantly more IFN-gamma following IL-18 and IL-12 compared with CD56dim NK cells (p < 0.008). However, the combination of IL-15 and IL-12 was significantly more potent than that of IL-18 and IL-12 for NK cell production of IL-10, macrophage inflammatory protein-1alpha, macrophage inflammatory protein-1beta, and TNF-alpha at the protein and transcript levels. Granulocyte-macrophage CSF was optimally induced by IL-15 and IL-18. Resting CD56+ NK cells expressed IL-18R transcript that was up-regulated by IL-12 or IL-15. Our results show that distinct cytokine and chemokine patterns are induced in NK cells in response to different costimulatory signals from these three monokines. This suggests that NK cell cytokine production may be governed in part by the monokine milieu induced during the early proinflammatory response to infection and by the subset of NK cells present at the site of inflammation. (+info)
DNA vaccination against the idiotype of a murine B cell lymphoma: mechanism of tumor protection.
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Several studies have shown that immunization with DNA, which encodes the idiotypic determinants of a B cell lymphoma, generates tumor-specific immunity. Although induction of antiidiotypic Abs has correlated with tumor protection, the effector mechanisms that contribute to tumor protection have not been clearly identified. This study evaluated the tumor protective effects of humoral and cellular immune mechanisms recruited by idiotype-directed DNA vaccines in the 38C13 murine B cell lymphoma model. Antiidiotypic Abs induced by DNA vaccination supported in vitro complement-mediated cytotoxicity of tumor cells, and simultaneous transfer of tumor cells and hyperimmune sera protected naive animals against tumor growth. However, in vitro stimulation of immune splenocytes with tumor cells failed to induce idiotype-specific cytotoxicity, and following vaccination, depletion of CD4 or CD8 T cell subsets did not compromise protection. Furthermore, protection of naive recipients against tumor challenge could not be demonstrated either by a Winn assay approach or by adoptive transfer of spleen and lymph node cells. Thus, in this experimental model, current evidence suggests that the tumor-protective effects of DNA vaccination can be largely attributed to idiotype-specific humoral immunity. (+info)
Role of the C-C chemokine, TCA3, in the protective anticryptococcal cell-mediated immune response.
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Activated T lymphocytes play a crucial role in orchestrating cellular infiltration during a cell-mediated immune (CMI) reaction. TCA3, a C-C chemokine, is produced by Ag-activated T cells and is chemotactic for neutrophils and macrophages, two cell types in a murine CMI reaction. Using a gelatin sponge model for delayed-type hypersensitivity (DTH), we show that TCA3 is a component of the expression phase of an anticryptococcal CMI response in mice. TCA3 mRNA levels are augmented in anticryptococcal DTH reactions at the same time peak influxes of neutrophils and lymphocytes are observed. Neutralization of TCA3 in immunized mice results in reduced numbers of neutrophils and lymphocytes at DTH reaction sites. However, when rTCA3 is injected into sponges in naive mice, only neutrophils are attracted into the sponges, indicating TCA3 is chemotactic for neutrophils, but not lymphocytes. We show that TCA3 is indirectly attracting lymphocytes into DTH-reactive sponges by affecting at least one other chemokine that is chemotactic for lymphocytes. Of the two lymphocyte-attracting chemokines assessed, monocyte-chemotactic protein-1 and macrophage-inflammatory protein-1alpha (MIP-1alpha), only MIP-1alpha was reduced when TCA3 was neutralized, indicating that TCA3 affects the levels of MIP-1alpha, which attracts lymphocytes into the sponges. TCA3 also plays a role in protection against Cryptococcus neoformans in the lungs and brains of infected mice, as evidenced by the fact that neutralization of TCA3 results in increased C. neoformans CFU in those two organs. (+info)
IFN-gamma mediates crescent formation and cell-mediated immune injury in murine glomerulonephritis.
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Features of crescentic glomerulonephritis suggest that it results from a T helper 1 (Th1) nephritogenic immune response. Interferon-gamma (IFN-gamma), produced by Th1 cells, is involved in T cell-directed macrophage activation in effector Th1 responses. The hypothesis that endogenous IFN-gamma contributes to the development of crescentic glomerulonephritis was tested by comparing the development of glomerulonephritis (induced by a planted antigen) and immune responses in normal C57BL/6 mice (IFN-gamma +/+) and in mice genetically deficient in IFN-gamma (IFN-gamma -/-). Ten days after the initiation of glomerulonephritis, IFN-gamma -/- mice developed fewer glomerular crescents (5+/-1% versus 26+/-3%, P<0.005), less severe glomerular injury, and less renal impairment. Effectors of delayed-type hypersensitivity (CD4+ T cells, macrophages, and fibrin) in glomeruli were reduced in IFN-gamma -/- mice. Skin delayed-type hypersensitivity to sheep globulin was reduced. Total antigen-specific Ig and splenocyte interleukin-2 production were unchanged, but antigen-specific serum IgG2a was reduced. Markers of an antigen-specific Th2 response (serum IgG1, splenocyte interleukin-4) were unchanged. Studies 22 d after the initiation of glomerulonephritis showed that IFN-gamma -/- mice still had fewer crescents (11+/-2% versus 22+/-3%, P = 0.02) and glomerular CD4+ T cells and macrophages than IFN-gamma +/+ mice. These studies demonstrate that endogenous IFN-gamma mediates crescentic glomerulonephritis by promoting cell-mediated immune injury. They support the hypothesis that crescentic glomerulonephritis is a manifestation of a Th1 nephritogenic immune response. (+info)
The cellular immunology of multiple sclerosis.
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Multiple sclerosis (MS) is a neurological disease that affects the central nervous system (brain and spinal cord) resulting in debilitating motor and sensory dysfunction. Its mean age of onset is 30 years and, with the exception of trauma, MS remains the most frequent cause of neurological disabilities for young adults. The disease is highly variable in its onset and progression. It may not be easily diagnosed, at least in its earliest stages. Significant disability is a hallmark of MS. Indeed, up to 50% of patients require walking aids and 10% are wheelchair-bound at 15 years after an initial diagnosis. Clinical features include deficits in sensory (parasthesias and numbness), motor (difficulties with fine movements and gait), balance, bladder, and sexual functions. Although the etiology for MS is not yet known, it is thought to be related to microbial, genetic, and/or environmental factors. Pathologically, MS is characterized by inflammation. An influx of mononuclear cells occurs through a disrupted blood-brain barrier into an immune-privileged central nervous system. The secretion of a variety of inflammatory cytokines and chemokines from glial cells leads to loss of myelin, disruption of oligodendrocyte integrity, and axonal loss. These events, in large measure, affect progressive neural atrophy. How brain inflammatory activities affect transendothelial migration of leukocytes into the brain and alter the process of myelination are the focal points for MS research activities. (+info)