Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study examines whether genetic susceptibility vs genetic resistance to experimental autoimmune uveoretinitis (EAU) are connected to a predisposition to mount a Th1-dominated (IFN-gamma high, IL-4 low) vs a Th2-dominated (IL-4 high, lFN-gamma low) response. Lewis rats developed disease with high incidence after immunization with the uveitogenic peptide R16, whereas F344 rats were resistant. Primed lymph node cells from both strains proliferated in culture in response to R16. However, while the Lewis cultures transferred EAU to syngeneic recipients, those of F344 did not. The Lewis cultures produced substantially more IFN-gamma mRNA and protein in response to R16, than did those of F344. Both strains made low levels of IL-10 mRNA and IL-4 mRNA. Unlike the primary cultures, long-term (R16-specific) T cell lines derived from each of the strains transferred EAU equally well to their respective recipients, and produced similar, high levels of IFN-gamma mRNA and protein. Treatment of F344 with Bordetella pertussis toxin concurrently with immunization abrogated its resistance, enhanced Ag-specific IFN-gamma production in culture, and yielded a primed cell population capable of transferring EAU. Conversely, immunization of Lewis rats with R16 in IFA induced little or no disease; the primed cells produced minimal amounts of IFN-gamma and did not transfer EAU. However, addition of IL-12 into the culture resulted in a highly pathogenic, IFN-gamma-producing cell population. We conclude that genetic susceptibility to ocular autoimmunity in this model is connected to an elevated Th1 response. Genetic resistance, however, does not seem to involve an elevated Th2 response, but rather an inhibited development of Th1-like effector cells.
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PMID:Genetic susceptibility to experimental autoimmune uveoretinitis in the rat is associated with an elevated Th1 response. 880 72

Splenocyte cultures from BALB/c mice were treated with THC and mitogen and shown to produce less Th1 cytokine, IFN gamma, and more Th2 cytokines, IL-4 and IL-10. This suggested that drug treatment caused a shift in the development of Th1 and Th2 cells. In studies designed to look at molecular mechanisms, the CBI antagonist, SR141716A, did not attenuate the THC enhancement of IL-4 production, but pertussis toxin attenuated the drug effect and the CB2 agonist, JWH-051, increased IL-4 production similar to THC. These results suggest that cannabinoids may increase Th2 development and IL-4 production in cultured immune cells through the activity of the CB2 receptor subtype. Studies are currently in progress to further define the molecular and cellular mechanisms involved.
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PMID:Cannabinoid receptors and the cytokine network. 966 74

IL-12 plays a critical role in protective immunity against intracellular pathogens by promoting the development of Th1 cells. Here we demonstrate that filamentous hemagglutinin (FHA), a virulence factor of Bordetella pertussis, is capable of suppressing IL-12 production by macrophages. FHA inhibited IL-12 secretion by a macrophage cell line or ex vivo alveolar macrophages in response to Escherichia coli or B. pertussis lipopolysaccharide (LPS) and IFN-gamma. Antibodies to FHA or denaturation of FHA abrogated the inhibitory effect. Injection of mice with FHA suppressed IL-12 and IFN-gamma levels in the serum in response to i. v. injection of LPS in a model of septic shock. The suppressive effect of FHA was specific for IL-12, since the production of TNF-alpha, IL-6 and IL-10 was not suppressed, and production of IL-6 and IL-10 was up-regulated. Antibody blocking studies revealed that the inhibitory effect of FHA on IL-12 production was dependent on IL-10. Since FHA is secreted at high levels and local T cell responses are suppressed during B. pertussis infection, the findings suggest that FHA may be a critical virulence factor in facilitating pathogen persistence in the respiratory tract by suppressing or delaying the development of cell-mediated immunity.
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PMID:Direct anti-inflammatory effect of a bacterial virulence factor: IL-10-dependent suppression of IL-12 production by filamentous hemagglutinin from Bordetella pertussis. 1067 Nov 96

To elucidate the factor(s) accelerating the autoimmune disease processes, we induced two types of experimental autoimmune encephalomyelitis (EAE), severe and very mild, in F344 rats by immunization with myelin basic protein (MBP) plus pertussis toxin (PT) (PT+) or with MBP alone (PT-) and compared the differences between the two. Immunohistochemical examinations showed that although the nature of inflammation was essentially the same between the two groups, the proportion of Vbeta8.2(+) T cells in the CNS lesion of PT (+) rats was larger than that of PT (-) rats. Cytokine analysis by competitive PCR revealed that IL-10 mRNA in the lymphoid organ was significantly suppressed in the PT(+) group, whereas levels of IFN-gamma,TNF-alpha and TGF-beta mRNA were insignificantly different after PT administration. In addition, T cells taken from PT (+) rats proliferated well in response to MBP, while those from PT (-) rats showed a marginal response to the same antigen. However, this finding does not indicate the switching of non-encephalitogenic to encephalitogenic T cells upon PT administration because PT (-) rats contained encephalitogenic T cells and/or their precursor cells as revealed by adoptive transfer experiments. Taken together, these findings suggest that suppression of IL-10 by PT administration is the major factor contributing to the exacerbation of EAE in PT(+) rats.
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PMID:Analysis of experimental autoimmune encephalomyelitis induced in F344 rats by pertussis toxin administration. 1068 10

In this study, mouse recombinant IFN-beta was shown to favor PLP139-151-specific Th2 responses in vitro, by inhibiting IFN-gamma production and stimulating IL-4 and IL-10 production. IFN-beta (5000 U/day) failed to prevent the development or severity of EAE induced with PLP139-151. Whereas efficacy of IL-10 was found in the B. pertussis assisted but not in the pertussigen-assisted EAE model, both models appeared insensitive to IFN-beta. Also the combination of (suboptimal) IL-10 and IFN-beta appeared ineffective in inhibiting disease. However, the PLP139-151-specific IL-10 production by T cells from these mice appeared significantly more sensitive to the stimulatory effect of IFN-beta in vitro. It is concluded that despite its Th2 promoting effects, IFN-beta is not effective in inhibiting EAE in this study.
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PMID:IFN-beta modulates specific T cell responses in vitro but does not affect Experimental Autoimmune Encephalomyelitis in the SJL mouse. 1069 29

We explored the role of Gi protein signaling in the regulation of interleukin (IL)-12 production and T helper cell type 1 (Th1) T cell differentiation. In initial studies, we showed that treatment of normal mice with pertussis toxin (PT), which inhibits Gi protein signaling, enhanced the capacity of splenocytes to produce IL-12 in response to both microbial and nonmicrobial stimuli. In addition, PT treatment increased the production of tumor necrosis factor (TNF)-alpha and IL-10 by stimulated cells. These findings were corroborated by the fact that untreated Gi2alpha(2/-) mice exhibited enhanced production of IL-12 and TNF-alpha by splenocytes, and of IL-12 p40 by purified spleen CD8alpha(+) lymphoid dendritic cells. Finally, we showed that while normal BALB/c mice infected with Leishmania major exhibited a nonhealing phenotype, those treated with PT when infection was initiated exhibited a healing phenotype along with an enhancement of leishmania-specific Th1 responses in draining lymph nodes. Further, healing was prevented by coadministration of anti-IL-12 and PT. These data demonstrate that endogenous Gi protein signaling has a primary role in the regulation of IL-12 production and the induction of Th1 responses in vivo.
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PMID:Primary role for Gi protein signaling in the regulation of interleukin 12 production and the induction of T helper cell type 1 responses. 1079 Apr 34

Immune responses to exogenous antigens in infant experimental animals display various degrees of Th2 polarization. Preliminary evidence from small human studies suggest a similar age-dependent response pattern to vaccines, but detailed investigations on vaccine immunity during infancy have not yet been undertaken. We report below the results of a comprehensive prospective study on responses to the tetanus component of the diphtheria, tetanus, acellular pertussis (DTaP) vaccine in a cohort of 55 healthy children, employing peripheral blood mononuclear cells (PBMC) collected at the 2-, 4-, and 6-month vaccinations and at 12 months. Antigen-specific production of interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, IL-13, and gamma interferon (IFN-gamma) was determined at each sample point, in parallel with polyclonal (phytohemagglutinin PHA-induced) cytokine responses. Our results indicate early and persistent Th2 responses to the vaccine, in contrast to a more delayed and transient pattern of IFN-gamma production. This initial disparity between the Th1 and Th2 components of the vaccine response was mirrored by patterns of polyclonally induced cytokine production, suggesting that the delayed maturation of the Th1 component of the vaccine response during infancy is secondary to developmental processes occurring within the overall Th cell system.
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PMID:Antigen-specific responses to diphtheria-tetanus-acellular pertussis vaccine in human infants are initially Th2 polarized. 1085 97

We have examined the roles of enzyme activity and the nontoxic AB complex of heat-labile toxin (LT) from Escherichia coli on its adjuvant and immunomodulatory properties. LTK63, an LT mutant that is completely devoid of enzyme activity, enhanced Th1 responses to coinjected Ags at low adjuvant dose. In contrast, LTR72, a partially detoxified mutant, enhanced Th2 responses and when administered intranasally to mice before infection with Bordetella pertussis suppressed Th1 responses and delayed bacterial clearance from the lungs. LTR72 or wild-type LT inhibited Ag-induced IFN-gamma production by Th1 cells, and LT enhanced IL-5 production by Th2 cells in vitro. Each of the toxins enhanced B7-1 expression on macrophages, but enhancement of B7-2 expression was dependent on enzyme activity. We also observed distinct effects of the nontoxic AB complex and enzyme activity on inflammatory cytokine production. LT and LTR72 suppressed LPS and IFN-gamma induced TNF-alpha and IL-12 production, but enhanced IL-10 secretion by macrophages in vitro and suppressed IL-12 production in vivo in a murine model of LPS-induced shock. In contrast, LTK63 augmented the production of IL-12 and TNF-alpha. Furthermore, LTK63 enhanced NF-kappaB translocation, whereas low doses of LTR72 or LT failed to activate NF-kappaB, but stimulated cAMP production. Thus, E. coli LT appears to be capable of suppressing Th1 responses and enhancing Th2 responses through the modulatory effects of enzyme activity on NF-kappaB activation and IL-12 production. In contrast, the nontoxic AB complex can stimulate acquired immune responses by activating components of the innate immune system.
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PMID:Modulation of innate and acquired immune responses by Escherichia coli heat-labile toxin: distinct pro- and anti-inflammatory effects of the nontoxic AB complex and the enzyme activity. 1106 33

As there is still a high mortality of the large cell anaplastic non Hodgkin lymphoma (ALCL) (between 40-70%, depending on prognostic factors) there is a need for new therapeutic approaches. Therefore, we studied different strategies for cancer immunotherapy in an immunogenic ALCL tumor model system: A murine IL-9 dependent T cell line was transfected with IL-9 cDNA, resulting in an autonomous growing T cell line designated G6BB, which had a high tumor incidence after injecting of as few as 10(4) cells subcutaneously into syngeneic C57Bl/6 mice. Tumor growth, dissemination, histology, and immunohistochemistry were similar to human ALCL. This mouse model provides an immunogenic in vivo system to investigate antitumor immunotherapies. In order to increase antigen recognition by T cells and T cell activation, we administered tumor bearing mice cell-based cancer vaccines with irradiated tumor cells alone or in combination with immunostimulating CpG-Oligonucleotides, a combination of Th1 cytokines and Th2 cytokine antibodies (IL-12, IFN-gamma, GM-CSF, Anti-IL-10) (after detecting a Th2 cytokine profile in G6BB), or the recall antigens diphtheria, pertussis, and tetanus.
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PMID:[New immunotherapeutic approaches for the treatment of anaplastic large cell lymphoma in a mouse model]. 1121 40

Together with macrophages and dendritic cells, mast cells have recently been shown to interact with certain pathogenic bacteria and present microbial antigens to the immune system. We show here that Bordetella pertussis can adhere to and be phagocytosed by mast cells. In addition, mast cells are able to process and present B. pertussis antigens to T lymphocytes. Furthermore, exposure of mast cells to B. pertussis induced the release of the proinflammatory cytokines tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). The release of IL-6 was strongly reduced by pertussis toxin expressed by B. pertussis. The production of IL-10, but not that of IL-4, by mast cells was also inhibited by pertussis toxin. Depletion of mast cells in vivo resulted in significant reduction of early TNF-alpha production in bronchoalveolar lavage (BAL) fluids of B. pertussis-infected mice. These data suggest that mast cells may play a role in the induction of immune responses against B. pertussis through the release of cytokines, especially TNF-alpha.
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PMID:Interaction of Bordetella pertussis with mast cells, modulation of cytokine secretion by pertussis toxin. 1126 Jan 41


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