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1.
Q fever is a worldwide zoonosis caused by Coxiella burnetii, a strictly intracellular bacterium that is a potential bioweapon. Humans usually acquires Q fever after inhalation of dust infected by subclinical animals. We used an aerosol exposure apparatus to challenge immunocompetent (BALB/c) and severe combined immunodeficient (SCID) mice with two different strains (strain Nine Mile and strain Q 212) of C. burnetii at two different inocula. Pathological lesions and dissemination of the bacteria were related to the size of the inoculum. SCID mice showed major pulmonary lesions, whereas similarly infected BALB/c mice were more able to eliminate the bacteria. Pathological differences were found between the strains, with Nine Mile showing more severe histological lesions and quantified spread of bacteria. Our animal model could provide a new tool for the study of acute Q fever pneumonia, the development of Q fever in immunodeficient hosts, and the differentiation of pathogenicity among C. burnetii isolates.  相似文献   

2.
We examined the mechanism of resistance against reactivation of infection with Toxoplasma gondii in the brain. BALB/c-background gamma interferon (IFN-gamma)-knockout (IFN-gamma(-/-)) and control mice were infected and treated with sulfadiazine beginning 4 days after infection for 3 weeks. After discontinuation of treatment, IFN-gamma(-/-) mice succumbed to toxoplasmic encephalitis (TE) and died, whereas control animals did not develop TE and survived. Adoptive transfer of immune spleen cells from infected control mice did not prevent development of TE or mortality in the IFN-gamma(-/-) mice. To examine whether the failure of the cell transfer to protect against TE is unique to IFN-gamma(-/-) mice, athymic nude and SCID mice that lack T cells were infected and injected with the immune spleen or T cells in the same manner as IFN-gamma(-/-) mice. Whereas control nude and SCID mice that had not received the immune cells developed severe TE and died after discontinuation of sulfadiazine, those that had received the cells did not develop TE and survived. Before cell transfer, IFN-gamma mRNA was detected in brains of infected nude and SCID but not in brains of IFN-gamma(-/-) mice. IFN-gamma mRNA was also detected in brains of infected SCID mice depleted of NK cells by treatment with anti-asialo GM1 antibody, and such animals did not develop TE after receiving immune T cells. Thus, IFN-gamma production by non-T cells, in addition to T cells, is required for prevention of reactivation of T. gondii infection in the brain. The IFN-gamma-producing non-T cells do not appear to be NK cells.  相似文献   

3.
Q fever, a worldwide zoonosis caused by Coxiella burnetii, has many manifestations in humans. Endocarditis is the most serious complication of Q fever. Animal models are limited to acute pulmonary or hepatic disease and reproductive disorders. An appropriate experimental animal model for Q fever endocarditis does not yet exist. In this study, severe combined immunodeficient (SCID) mice infected with C. burnetii showed persistent clinical symptoms and died, whereas immunocompetent mice similarly infected became asymptomatic and survived. The SCID mice examined in this study had severe chronic lesions in their primary organs: the heart, lung, spleen, liver, and kidney. The heart lesions of the SCID mice were similar to those in humans with chronic Q fever endocarditis: they had focal calcification and expanded macrophages containing C. burnetii. The 50% lethal dose of C. burnetii in SCID mice was at least 10(8) times less than that in immunocompetent mice. The SCID mouse is highly susceptible to C. burnetii, and the immunodeficiency of the host enhances the severity of Q fever. This animal model could provide a new tool for the study of chronic Q fever and Q fever in immunodeficient hosts.  相似文献   

4.
The response of guinea pigs experimentally infected with Coxiella burnetii organisms, the etiologic agents of Q fever, was obtained by the measurement of fever, circulating infectious C. burnetii cells, and anti-C. burnetii antibodies. The detection of antibodies by the enzyme-linked immunosorbent assay (ELISA) and traditional methods against phase I whole cells, phase II whole cells, and phase I lipopolysaccharide (LPS-I) (a virulence marker for phase I cells) antigens in the serum samples of infected animals revealed marked differences between intrastrain phase variants. Animals infected with the phase I Nine Mile strain produced a concomitant increase in temperature, circulating infectious C. burnetii cells, and antibodies against phase II cells, phase I cells, and LPS-I. At 15 weeks, a challenge of phase I-infected animals with viable phase I cells resulted in anamnestic antibody responses to phase I cells and LPS-I but not to phase II cells. Infection of animals with the phase II Nine Mile strain produced antibodies against only phase II cells. The challenge of phase II-infected animals at 15 weeks with viable phase II cells resulted in anamnestic antibody responses to phase I and phase II cells but not to LPS-I. Suppression of anti-phase II responses by the phase I challenge was apparent with only the ELISA, because the immunofluorescence, microagglutination, and complement fixation assays were insensitive to these changes. The sensitivity and specificity of the ELISA with whole-cell and the LPS-I antigens in the detection of phase-specific antibody revealed that avirulent phase II cells induced an immune response to phase I antigenic epitopes. Although the avirulent phase II cells were rapidly cleared by the host immune responses, they were sufficiently infective to induce antibody responses to both phase variants. Thus, in the occurrence of Q fever, any conventional serological technique that uses only phase II antigens may not provide a true incidence of naturally acquired infection with both phase I and II C. burnetii organisms.  相似文献   

5.
Vaccination with an inactivated, whole cell, Q fever vaccine (Q-vax) induces lasting antibody conversion and a positive delayed-type hypersensitivity (DTH) skin reaction in about 60% of recipients but a long-lasting positive lymphoproliferative or mitogenic response to C. burnetii antigens with peripheral blood mononuclear cells (PBMC) in 85-95% of subjects. Analysis of the lymphoproliferative response to C. burnetii antigens has now been made by fractionation-reconstitution experiments with PBMC from vaccines, from past infections, and from healthy controls. The major contributor to the response in immune subjects proved to be the T lymphocyte. T cells were stimulated by both the phase I and phase II antigens of two prototype strains of C. burnetii and responses were greatly amplified by addition of IL-2. Similar T lymphocyte stimulation profiles were obtained with the 'Priscilla' strain of C. burnetii which represents a different biotype of Coxiella isolated from Q fever endocarditis; Q-vax is therefore likely to protect against endocarditis strains. Fractionation-reconstitution experiments with T and B cells from vaccines and subjects infected in the past, using various antigenic or haptenic fractions from C. burnetii indicate that protein, non-lipopolysaccharide components of the organism are responsible for the mitogenic response of immune T cells. However, the role of the lipopolysaccharide in the protective immunogen has still to be defined.  相似文献   

6.
To investigate the role of IFN-gamma in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4+ T cells from either wild-type (WT) or IFN-gamma-deficient (IFN-gammaKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-alpha), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4+ blasts induced a lethal IBD, whereas IFN-gammaKO blasts induced a less severe intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4+ T cells positive for TNF-alpha, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4-positive cells was found in IFN-gammaKO-transplanted SCID mice. Flow cytometric analyses showed strong up-regulation of MHC class II expression of colonic epithelial cells of WT-CD4+ T cell-transplanted compared with IFN-gammaKO-transplanted SCID mice. A significantly higher fraction of CD4+ LPL were found to enter the cell cycle, i.e. to incorporate bromo-deoxy-uridine, and to undergo apoptosis in vivo in WT-transplanted compared with IFN-gammaKO-transplanted SCID mice. These data point towards an important role for IFN-gamma in the development of IBD in SCID mice. The inflammation might be initiated and subsequently enhanced by the ability of IFN-gamma to induce de novo MHC class II expression in the colonic epithelium, a change which could lead to increased antigen processing and production of local proinflammatory cytokines, CD4+ T cell turnover and thereby to exaggeration of disease.  相似文献   

7.
Severe experimental infections with Cryptosporidium parvum have been reported in immunocompromised animals such as SCID mice (mice without functional T cells and B cells). In a C. parvum infection with 1 x 10(6) oocysts/mouse in SCID beige (SCIDbg) mice (SCID mice lacking functional NK cells), oocyst shedding was first demonstrated 18 days after infection. However, shedding was shown as early as 3 days after the same infection in SCIDbgMN mice. All of the SCIDbgMN mice died within 16 days of C. parvum infection, while 100% of the SCIDbg mice exposed to the parasite survived. SCIDbgMN mice are SCIDbg mice depleted of functional macrophages (Mphi) and neutrophils (PMN), suggesting that the severity early after C. parvum infection is strongly influenced by the functions of Mphi and PMN. All SCIDbgMN mice orally infected with a lethal dose of C. parvum survived after they were inoculated with Mphi from SCIDbg mice exposed to C. parvum (CP-Mphi) or resident Mphi previously cultured with PMN from C. parvum-infected SCIDbg mice (CP-PMN). However, all SCIDbgMN mice inoculated with CP-PMN alone or resident Mphi alone died after C. parvum infection. CP-Mphi were identified as classically activated Mphi (M1Mphi), and CP-PMN were characterized as PMN-I. In in vitro studies, resident Mphi converted to M1Mphi after transwell cultivation with CP-PMN. These results indicate that the resistance of SCIDbg mice early after C. parvum infection is displayed through the function of M1Mphi which are converted from resident Mphi influenced by CP-PMN (PMN-I).  相似文献   

8.
The ability of various strains of Coxiella burnetii (C.b.) and their phase I and II lipopolysaccharides (LPSs) to induce tumor necrosis factor alpha (TNF-alpha) in peritoneal Balb/c mouse macrophages in vitro was investigated. Considerable differences in the induction ability were observed in dependence on the strain applied. In a TNF-alpha bioassay, the most effective inducers were both corpuscles and LPSs of the strains Priscilla and Scurry, followed by Nine Mile, Luga, and Henzerling I. In contrast, in ELISA, the most effective inducers were LPSs of the strains Luga and Henzerling, followed by Nine Mile, Priscilla, and Scurry. The role of toll-like receptor 4 (TLR4) in the induction was confirmed by the use of C3H/HeJ mouse macrophages. Thus, the induction of TNF-alpha was much higher in Balb/c mouse macrophages than that in TLR4-deficient C3H/HeJ mouse macrophages. Differences in the results of the bioassay and those of ELISA suggest a role of another secreted factor(s) induced with C.b. in murine macrophages that could act synergically with TNF-alpha in L929 cells in the bioassay. The observed differences in TNF-alpha induction might play a role in the pathobiology of Q fever.  相似文献   

9.
The mechanism of immune defense against pathogens in the lung, has so far been poorly understood. Here, we show that human type II alveolar epithelial cells play a key role in defense via interactions between B7 homolog (B7h), also known as ICOS ligand, and its receptor ICOS expressed on activated T cells. The A549 alveolar type II cell line abundantly expresses B7-H2, CD40 and B7-1, but not B7-2 or hGL50. TNF-alpha significantly induced B7-H2 and CD40 expression by A549 cells, but had no effect on B7-1 or B7-2 expression. TNF-alpha-deficient mice exhibited low B7-H2 expression on alveolar epithelial cells in comparison with wild-type mice. Co-culture of TNF-alpha pre-stimulated A549 cells with CD4+ T cells promoted CD154 expression, CD4+ T cell proliferation and cytokine production, especially IFN-gamma. Monocyte-derived TNF-alpha in combination with IFN-gamma and LPS markedly induced B7-H2 expression in A549 cells. This study thus identifies a unique costimulatory pathway via alveolar epithelial type II cells that preferentially affects T helper cell function, implying that alveolar epithelial type II cells play a crucial role in innate immunity in the lung by regulating IFN-gamma-synthesis via B7-H2/ICOS interactions.  相似文献   

10.
Coxiella burnetii, phase I and II, cells cultivated in the yolk sac of chicken embryos were separated from host cell components by two cycles of isopycnic Renografin gradient centrifugation. Initial steps in the purification of viable C. burnetii involved differential centrifugation and sedimentation through an aqueous solution of 30% sucrose and 7.6% Renografin. After the first, but not the second, cycle of Renografin gradient centrifugation, the cells were passed through microfilter glass filters which facilitated the removal of host components. The integrity of morphologically different cell variants was maintained during purification procedures by suspending highly purified C. burnetii in phosphate-buffered saline-sucrose solutions. C. burnetii, phases I and II, obtained by these methods appeared to be free from host cell components by serological methods while retaining morphological integrity and infectivity for yolk sacs and experimental animals. Average yields of C. burnetii were 2.83, 1.5, and 0.84 mg (dry weight) per yolk sac of the Ohio strain (phase I), 9 Mile strain (phase I), and 9 Mile strain (phase II), respectively. Recovery of phase I cells averaged about 70%, whereas the recovery of phage II cells was approximately 40%. The temporal sequence of phase I and II antibody response was demonstrated in infected and vaccinated animals. Also, no antibody response in mice and guinea pigs to yolk sac antigens was detectable after two injections of vaccine or viable cells. Importantly, this is the first report of the separation of viable phase II cells of C. burnetii free of host components.  相似文献   

11.
Hair growth abnormalities in mice usually are accompanied by histologic abnormalities as well. Recently, however, we reported a mouse model in which an arrest of the hair cycle and diffuse shedding of the hair without pathologic features induced alopecia in interferon-gamma(-/-) (IFN-gamma(-/-)) C57BL/6 (B6) mice. Here, we explored the cellular origin of IFN-gamma. When bone marrow from IFN-gamma(-/-) B6 mice was transplanted into lethally irradiated IFN-gamma(+/+) B6 mice, the level of IFN-gamma mRNA expression in the skin or peripheral blood mononuclear cells (PBMCs) of recipient mouse was markedly reduced, suggesting that IFN-gamma is normally produced by bone marrow-derived cells. Although severe combined immunodeficiency (SCID) mice lack mature T cells and B cells, IFN-gamma-dependent hair regrowth was induced in SCID mice by depilation, which caused alopecia in IFN-gamma(-/-) B6 mice. Consistently, IFN-gamma mRNA expression in the skin or PBMC from SCID mice was comparable to that from their genetic counterpart (BALB/c mice), suggesting IFN-gamma production by non-T cells. RT-PCR analyses after separation of PBMC from SCID mice into eight fractions by a cell sorter revealed that Mac-1(+) cells were the major origin of IFN-gamma.  相似文献   

12.
We examined the role of mouse CD8+ CD122+ T cells, which increase in number with age, in the generalized Shwartzman reaction. This reaction was induced by IL-12 priming and subsequent LPS challenge (after 24 h) in mice of various ages (4-50 weeks of age). Although most young mice (4 or 6 weeks of age) survived, mortality essentially increased with increasing age of the mice, and all mice of 20 weeks of age or older died within 48 h. Serum TNF-alpha levels after LPS challenge also increased age dependently. The neutralization of either IL-12-induced IFN-gamma or LPS-induced TNF-alpha improved the survival of middle-aged (25-week-old) mice. Both IFN-gamma production after IL-12 priming and TNF-alpha production from the liver mononuclear cells after LPS challenge were also prominent in the middle-aged mice. CD8+CD122+ T cells cultured with IL-12 produced a much larger amount of IFN-gamma than CD8+CD122- T cells. Although the depletion of NK/NK T cells did not decrease the IFN-gamma or TNF-alpha production in the Shwartzman reaction of the middle-aged mice, an additional depletion of CD8+CD122+ T cells did decrease such production and also improved mouse survival. Furthermore, young mice transferred with CD8+CD122+ T cells from aged B6 nude mice showed an enhanced Shwartzman reaction.  相似文献   

13.
We explored the mechanisms of class B CpG-oligodeoxynucleotide-induced antitumour effects against weakly immunogenic tumours. Treatment with CpG-oligodeoxynucleotide 1826 (CpG) induced similar antitumour effects in B16 melanoma-bearing immunocompetent C57BL/6 mice and T-cell-deficient severe combined immunodeficient (SCID) mice, and NXS2 neuroblastoma-bearing T-cell-depleted A/J mice. Both macrophages (Mphi) and natural killer (NK) cells from CpG-treated C57BL/6 mice could mediate cytotoxicity in vitro, suggesting that these cell types might control tumour growth in vivo. However, CpG treatment of SCID/beige mice or T-cell-depleted and NK-cell-depleted A/J mice still induced antitumour effects in vivo, arguing against a major role of NK cells in the antitumour effects of CpG in the absence of T cells. In contrast, CpG treatment of interferon-gamma knockout (IFN-gamma(-/-)) C57BL/6 mice resulted in no antitumour effects in vivo and no Mphi-mediated tumoristasis in vitro despite unaltered cytolytic function of NK cells in vitro. Moreover, Mphi inactivation by silica substantially reduced CpG-induced suppression of tumour growth in vivo, revealing an important role of Mphi in CpG-induced antitumour effects. The in vitro tumouritoxicity by CpG-stimulated Mphi (CpG-Mphi) correlated with tumour cell mitochondria dysfunction and involved nitric oxide (NO), tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma, whereas interleukin-1alpha (IL-1alpha), IL-1beta, IFN-alpha, TNF-related apoptosis-inducing ligand and Fas ligand played insignificant roles in CpG-Mphi tumouritoxicity. Taken together, our results indicate that the growth control of weakly immunogenic tumours during CpG-immunotherapy is mediated predominantly by Mphi, rather than T cells or NK cells.  相似文献   

14.
Previous studies of mice have implicated natural killer (NK) cells as mediators of protective activity against Toxoplasma gondii through their production of gamma interferon (IFN-gamma). In the present study, we have compared NK-cell activity in infected and uninfected SCID mice. Our data reveal that infection results in increased levels of IFN-gamma in serum and elevated NK-cell activity but that these NK cells were not cytotoxic for T. gondii-infected P815 cells. Treatment with anti-IFN-gamma antibody abrogated the increase in NK-cell activity and resulted in earlier mortality of infected mice. In vivo treatment with anti-asialo GM1 antiserum reduced NK cell activity and levels of IFN-gamma in serum but did not alter time to death. Spleen cells from infected mice produced higher levels of IFN-gamma than those from uninfected mice when stimulated in vitro with live T. gondii or parasite antigen preparations. Further analysis revealed that interleukin 10 (IL-10) inhibited, whereas tumor necrosis factor alpha (TNF-alpha) and IL-12 enhanced, IFN-gamma production by spleen cells from infected or uninfected mice. The combination of IL-12 and TNF-alpha induced higher levels of IFN-gamma from whole spleen cells of infected mice than from those of uninfected mice. Depletion of the adherent cell population from the spleen cells of infected mice led to a significant reduction in the levels of IFN-gamma produced after stimulation with IL-12 plus TNF-alpha. Similar results did not occur with cells from uninfected mice. These data indicate that other cytokines produced by the adherent cell population from infected mice may be involved in maximal production of IFN-gamma by NK cells stimulated with IL-12 and TNF-alpha. To assess the importance of endogenous IL-12, a polyclonal anti-IL-12 was administered to infected SCID mice. This treatment led to earlier mortality, indicating that endogenous IL-12 mediates resistance to T. gondii.  相似文献   

15.
Endocarditis is a rather frequent complication of Q fever caused by Coxiella burnetii. We examined the ability of phase I (virulent) or phase II (avirulent) C. burnetii to coagulate blood in the presence of human blood mononuclear cells in vitro. After incubation for 4 h, virulent phase I C. burnetii was an effective stimulant for mononuclear cells. Since this interaction is a potent trigger of blood coagulation through the extrinsic pathway, it could be responsible for the local deposition of fibrin on the surface of infected valves and the development of large vegetations in cases of endocarditis complicating Q fever.  相似文献   

16.
17.
Previous work in our laboratory has shown that lymphocytes from persons vaccinated with a formalin-inactivated Phase I Q fever vaccine (Q-Vax CSL Ltd) show a mitogenic response to Coxiella burnetii antigens. The mitogenic response is the sum of that from various subsets of CD4+, T helper cells, CD8+ T cells and probably B cells. It does not distinguish between T helper cell responses leading to formation of interferon-gamma (IFN-gamma)--a cytokine responsible for clearing intracellular infection with C. burnetii organisms--and responses of other T cell subsets which may produce disease-enhancing cytokines. The present study analyses (i) the capacity of Q-Vax to induce T cell sensitization which leads to IFN-gamma responses on antigen stimulation, and (ii) the immunomodulatory, (down-regulatory) effects of the Phase I lipopolysaccharide (LPS) of the organism, which interacts with monocyte/macrophages to limit IL-2 production and production of IFN-gamma by sensitized T lymphocytes.  相似文献   

18.
We previously showed the requirement of both T cells and gamma interferon (IFN-gamma)-producing non-T cells for the genetic resistance of BALB/c mice to the development of toxoplasmic encephalitis (TE). In order to define the role of IFN-gamma production and the perforin-mediated cytotoxicity of T cells in this resistance, we obtained immune T cells from spleens of infected IFN-gamma knockout (IFN-gamma(-/-)), perforin knockout (PO), and wild-type BALB/c mice and transferred them into infected and sulfadiazine-treated athymic nude mice, which lack T cells but have IFN-gamma-producing non-T cells. Control nude mice that had not received any T cells developed severe TE and died after discontinuation of sulfadiazine treatment due to the reactivation of infection. Animals that had received immune T cells from either wild-type or PO mice did not develop TE and survived. In contrast, nude mice that had received immune T cells from IFN-gamma(-/-) mice developed severe TE and died as early as control nude mice. T cells obtained from the spleens of animals that had received either PO or wild-type T cells produced large amounts of IFN-gamma after stimulation with Toxoplasma gondii antigens in vitro. In addition, the amounts of IFN-gamma mRNA expressed in the brains of PO T-cell recipients did not differ from those in wild-type T-cell recipients. Furthermore, PO mice did not develop TE after infection, and their IFN-gamma production was equivalent to or higher than that of wild-type animals. These results indicate that IFN-gamma production, but not perforin-mediated cytotoxic activity, by T cells is required for the prevention of TE in genetically resistant BALB/c mice.  相似文献   

19.
Respiratory syncytial virus (RSV) infection is ubiquitous and leads to various outcomes between immunocompetent and immunocompromised individuals. This study aimed to compare RSV infection and inflammatory responses between immunocompetent BALB/c mice and immunodeficient nude mice. RSV titers in both infected BALB/c mice and nude mice peaked on the third day post-inoculation, but the nude mice had longer lasting and higher levels of viral replication. RSV infection induced a more severe grade of pulmonary histopathology and larger numbers of leukocytes in airways of nude mice than that of BALB/c mice. RSV infection increased pulmonary macrophages and natural killer (NK) cells in both strains of mice. Furthermore, infected nude mice had larger numbers of pulmonary macrophages and NK cells than infected BALB/c mice. Whereas the RSV infected BALB/c mice secreted more tumor necrosis factor -alpha (TNF-alpha), interleukin-12 (IL-12), interferon-gamma (IFN-gamma) and IL-10 than control BALB/c mice, the infected nude mice had higher levels of TNF-alpha, IL-12 and IL-10 than the infected BALB/c mice. The inflammation induced by RSV infection did not correspond with the immune response of T cells. Macrophages and NK cells were potent immunocytes and inflammatory cells in RSV infection especially when T lymphocytes were deficient. Therefore, nude mice may be a good model for severe and persistent RSV infection in immunocompromised hosts.  相似文献   

20.
Recent experiments have shown that gamma interferon (IFN-gamma), either administered or induced in vivo, e.g., by certain bacteria, is a key mediator in inducing hypersensitivity to bacterial lipopolysaccharides. The source of endogenous IFN-gamma in this context (natural killer versus TH1 cells) has not been investigated yet. In order to investigate the role of antigen-specific, IFN-gamma-producing TH1 cells in murine Pseudomonas aeruginosa infection, a murine TH1 cell line was propagated in vitro by using recombinant P. aeruginosa outer membrane protein I. Adoptive transfer experiments were performed by intravenous injection of various amounts of TH1 cells into P. aeruginosa-challenged SCID mice. Adoptive transfer of 5 x 10(6) T cells into SCID mice followed by an intraperitoneal challenge with 1.4 x 10(6) CFU of live P. aeruginosa resulted in the rapid death of the animals within 12 h postchallenge, whereas transfer of lower T-cell doses and saline as a control did not cause any detrimental effects. After challenge with 2.8 x 10(6) CFU of P. aeruginosa, similar results were obtained 18 h postchallenge; however, at the end of the 72-h observation period, no significant differences in survival rates were obtained between the groups treated with different amounts of T cells. The rapid death of mice treated with 5 x 10(6) T cells was reflected by 860-fold-elevated levels of tumor necrosis factor alpha (TNF-alpha) present in serum 2 h postchallenge, whereas no significant differences in TNF-alpha serum levels were detectable in mice treated with lower doses of T cells or with saline. Pretreatment of T-cell-reconstituted SCID mice with neutralizing anti-IFN-gamma monoclonal antibodies completely protected mice from bacterial challenge and reduced TNF-alpha levels in serum. We conclude that under the experimental conditions described here, IFN-gamma- and interleukin-2-producing TH1 cells represent an important trigger mechanism inducing TNF-alpha-mediated hypersensitivity to bacterial endotoxin.  相似文献   

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