scholarly journals Gamma Interferon Dominates the Murine Cytokine Response to the Agent of Human Granulocytic Ehrlichiosis and Helps To Control the Degree of Early Rickettsemia

2000 ◽  
Vol 68 (4) ◽  
pp. 1827-1833 ◽  
Author(s):  
Mustafa Akkoyunlu ◽  
Erol Fikrig
Keyword(s):  
Gamma Interferon ◽  
Cytokine Response ◽  
Interleukin 4 ◽  
Infection Model ◽  
Granulocytic Ehrlichiosis ◽  
Human Granulocytic Ehrlichiosis ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT The cytokine response to the agent of human granulocytic ehrlichiosis (HGE) was assessed in a murine infection model and the role of gamma interferon (IFN-γ), a cytokine that is crucial for host defenses against intracellular pathogens, was investigated by using IFN-γ-deficient mice. The agent of HGE (aoHGE) is an obligate intracellular bacterium that survives within neutrophils: morulae (vacuoles containing HGE organisms) are evident in polymorphonuclear leukocytes of experimentally infected immunocompetent mice for 1 to 2 weeks. We now show that IFN-γ levels increase during early infection of C3H/HeN or C57BL/6 mice with HGE bacteria. Moreover, in response to aoHGE extracts or concanavalin A, splenocytes from ehrlichia-infected mice produced more IFN-γ and less interleukin-4 than controls, suggesting that aoHGE partially skewed the immune response towards a Th1 phenotype. Absolute concentration of morulae containing neutrophils in blood was 122 ± 22 cells/μl on day 8. The bacterial DNA burden was also highest on day 8 and then declined after IFN-γ levels peaked. In contrast, IFN-γ-deficient mice had a markedly elevated HGE bacteria burden with morulae concentration of 282 ± 48 cells/μl on day 5 (P = 0.004) and 242 ± 63 cells/μl on day 8 (P = 0.005). Rickettsemia resolved in immunocompetent and IFN-γ deficient mice after 2 weeks, while both the immunocompetent and the IFN-γ-deficient mice had increased serum antibodies against aoHGE antigens at this time point. These data demonstrate that the HGE agent elicits a prominent IFN-γ response in mice and that IFN-γ is important in controlling the degree of rickettsemia during the early phase of infection, while IFN-γ independent mechanisms play a role at later time points.

scholarly journals Role of Gamma Interferon in the Pathogenesis of Severe Schistosomiasis in Interleukin-4-Deficient Mice

2001 ◽  
Vol 69 (12) ◽  
pp. 7445-7452 ◽  
Author(s):  
Anne Camille La Flamme ◽  
Elisabeth A. Patton ◽  
Edward J. Pearce
Keyword(s):  
Severe Disease ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
No Production ◽  
Wild Type ◽  
Fatal Disease ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT In the absence of interleukin-4 (IL-4), infection withSchistosoma mansoni leads to a severe fatal disease rather than the chronic survivable condition that occurs in wild-type (WT) mice. Because the sustained production of NO most closely correlates to weight loss and fatality in infected IL-4−/− mice and because gamma interferon (IFN-γ) is an important inducer of inducible NO synthase, infected IL-4−/− mice were treated with anti-IFN-γ antibodies to determine the role of IFN-γ during schistosomiasis in WT and IL-4−/− animals. When IFN-γ was neutralized, Th2 responses were enhanced and NO production was reduced in both WT and IL-4−/− mice. The decreased NO production correlated with a rescue of proliferation in splenocytes from infected IL-4−/− mice. Furthermore, the neutralization of IFN-γ in vivo improved the gross appearance of the liver and led to a reduction in granuloma size in infected IL-4−/− but not WT mice. However, the neutralization of IFN-γ in vivo did not affect the development of severe disease in infected IL-4−/− mice. These results suggest that while the increased production of IFN-γ does lead to some of the pathology observed in infected IL-4−/− mice, it is not ultimately responsible for cachexia and death.

scholarly journals Gamma Interferon Produced by Antigen-Specific CD4+ T Cells Regulates the Mucosal Immune Responses to Citrobacter rodentium Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2653-2666 ◽  
Author(s):  
Hideyuki Shiomi ◽  
Atsuhiro Masuda ◽  
Shin Nishiumi ◽  
Masayuki Nishida ◽  
Tetsuya Takagawa ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Gamma Interferon ◽  
Immune Defense ◽  
Interleukin 4 ◽  
Mucosal Inflammation ◽  
Citrobacter Rodentium ◽  
Macrophage Phagocytosis ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Citrobacter rodentium, a murine model pathogen for enteropathogenic Escherichia coli, colonizes the surface of intestinal epithelial cells and causes mucosal inflammation. This bacterium is an ideal model for investigating pathogen-host immune interactions in the gut. It is well known that gene transcripts for Th1 cytokines are highly induced in colonic tissue from mice infected with C. rodentium. However, it remains to be seen whether the Th1 or Th2 cytokines produced by antigen-specific CD4+ T cells provide effective regulation of the host immune defense against C. rodentium infection. To investigate the antigen-specific immune responses, C. rodentium expressing ovalbumin (OVA-C. rodentium), a model antigen, was generated and used to define antigen-specific responses under gamma interferon (IFN-γ)-deficient or interleukin-4 (IL-4)-deficient conditions in vivo. The activation of antigen-specific CD4+ T cells and macrophage phagocytosis were evaluated in the presence of IFN-γ or IL-4 in vitro. IFN-γ-deficient mice exhibited a loss of body weight and a higher bacterial concentration in feces during OVA-C. rodentium infection than C57BL/6 (wild type) or IL-4-deficient mice. This occurred through the decreased efficiency of macrophage phagocytosis and the activation of antigen-specific CD4+ T cells. Furthermore, a deficiency in antigen-specific CD4+ T-cell-expressed IFN-γ led to a higher susceptibility to mucosal and gut-derived systemic OVA-C. rodentium infection. These results show that the IFN-γ produced by antigen-specific CD4+ T cells plays an important role in the defense against C. rodentium.

scholarly journals Aberrant Contraction of Antigen-Specific CD4 T Cells after Infection in the Absence of Gamma Interferon or Its Receptor

2006 ◽  
Vol 74 (11) ◽  
pp. 6252-6263 ◽  
Author(s):  
Jodie S. Haring ◽  
John T. Harty
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Interleukin 2 ◽  
Gamma Interferon ◽  
Model Systems ◽  
Important Regulator ◽  
Ifn Γ ◽  
And Function ◽  
Deficient Mice

ABSTRACT Several lines of evidence from different model systems suggest that gamma interferon (IFN-γ) is an important regulator of T-cell contraction after antigen (Ag)-driven expansion. To specifically investigate the role of IFN-γ in regulating the contraction of Ag-specific CD4 T cells, we infected IFN-γ−/− and IFN-γR1−/− mice with attenuated Listeria monocytogenes and monitored the numbers of Ag-specific CD4 T cells during the expansion, contraction, and memory phases of the immune response to infection. In the absence of IFN-γ or the ligand-binding portion of its receptor, Ag-specific CD4 T cells exhibited normal expansion in numbers, but in both strains of deficient mice there was very little decrease in the number of Ag-specific CD4 T cells even at time points later than day 90 after infection. This significant delay in contraction was not due to prolonged infection, since mice treated with antibiotics to conclusively eliminate infection exhibited the same defect in contraction. In addition to altering the number of Ag-specific CD4 T cells, the absence of IFN-γ signaling also changed the phenotype of cells generated after infection. IFN-γR1−/− Ag-specific CD4 T cells reacquired expression of CD127 more quickly than wild-type cells, and more IFN-γR1−/− CD4 T cells were capable of producing both IFN-γ and interleukin 2 following Ag stimulation. From these data we conclude that IFN-γ regulates the contraction, phenotype, and function of Ag-specific CD4 T cells generated after infection.

scholarly journals Role of Interleukin-4 (IL-4), IL-12, and Gamma Interferon in Primary and Vaccine-Primed Immune Responses to Friend Retrovirus Infection

2001 ◽  
Vol 75 (2) ◽  
pp. 654-660 ◽  
Author(s):  
Ulf Dittmer ◽  
Karin E. Peterson ◽  
Ron Messer ◽  
Ingunn M. Stromnes ◽  
Brent Race ◽  
...  
Keyword(s):  
Immune Responses ◽  
Gamma Interferon ◽  
Immunoglobulin M ◽  
Friend Virus ◽  
T Helper ◽  
Friend Retrovirus ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Helper Type

ABSTRACT The immunological resistance of a host to viral infections may be strongly influenced by cytokines such as interleukin-12 (IL-12) and gamma interferon (IFN-γ), which promote T helper type 1 responses, and IL-4, which promotes T helper type 2 responses. We studied the role of these cytokines during primary and secondary immune responses against Friend retrovirus infections in mice. IL-4- and IL-12-deficient mice were comparable to wild-type B6 mice in the ability to control acute and persistent Friend virus infections. In contrast, more than one-third of the IFN-γ-deficient mice were unable to maintain long-term control of Friend virus and developed gross splenomegaly with high virus loads. Immunization with a live attenuated vaccine virus prior to challenge protected all three types of cytokine-deficient mice from viremia and high levels of spleen virus despite the finding that the vaccinated IFN-γ-deficient mice were unable to class switch from immunoglobulin M (IgM) to IgG virus-neutralizing antibodies. The results indicate that IFN-γ plays an important role during primary immune responses against Friend virus but is dispensable during vaccine-primed secondary responses.

scholarly journals Role of Gamma Interferon and Interleukin-4 in Host Defense against the Human Filarial Parasite Brugia malayi

2000 ◽  
Vol 68 (5) ◽  
pp. 3034-3035 ◽  
Author(s):  
Subash Babu ◽  
Lisa M. Ganley ◽  
Thomas R. Klei ◽  
Leonard D. Shultz ◽  
T. V. Rajan
Keyword(s):  
Host Defense ◽  
Brugia Malayi ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Canonical Type ◽  
Time Required

ABSTRACT We have investigated the roles of gamma interferon (IFN-γ) and interleukin-4 (IL-4) in host defense against Brugia malayi. Our data suggest that the lack of either IFN-γ or IL-4 prolongs the time required to achieve sterile immunity, suggesting that both canonical type 1 and type 2 responses are involved in the clearance of infection.

scholarly journals Role of Interleukin-18 in Host Defense against Disseminated Candida albicans Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3284-3286 ◽  
Author(s):  
Rogier J. L. Stuyt ◽  
Mihai G. Netea ◽  
Ineke Verschueren ◽  
Giamila Fantuzzi ◽  
Charles A. Dinarello ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Protective Effect ◽  
Host Defense ◽  
Gamma Interferon ◽  
Interleukin 18 ◽  
Ifn Γ ◽  
Candida Albicans Infection ◽  
Deficient Mice

ABSTRACT In mice injected intravenously with Candida albicans, administration of anti-interleukin-18 (IL-18) antibodies increased the yeast load in the kidneys. There was no effect on the organ load with Candida when gamma interferon (IFN-γ)-deficient mice were treated with anti-IL-18 antibodies, suggesting that the protective effect of IL-18 is mediated through endogenous IFN-γ.

scholarly journals Gamma Interferon Production by Cytotoxic T Lymphocytes Is Required for Resolution of Chlamydia trachomatis Infection

1998 ◽  
Vol 66 (11) ◽  
pp. 5457-5461 ◽  
Author(s):  
Mary F. Lampe ◽  
Christopher B. Wilson ◽  
Michael J. Bevan ◽  
Michael N. Starnbach
Keyword(s):  
Chlamydia Trachomatis ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Adoptive Transfer ◽  
Gamma Interferon ◽  
Chlamydia Trachomatis Infection ◽  
Immune Defect ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT In this study, we used mice in which the gene for gamma interferon (IFN-γ) has been disrupted (IFN-γ−/− mice) to study the role of this cytokine in the resolution of Chlamydia trachomatis infection. We show that IFN-γ−/− mice are impaired in the ability to clear infection with C. trachomatis compared to IFN-γ+/+ control mice. Activated CD8+ cytotoxic T lymphocytes (CTL) secrete IFN-γ in response to intracellular infection, and we have shown previously that a Chlamydia-specific CTL line can reduceC. trachomatis infection when adoptively transferred into infected mice. In the present study, we found that when these IFN-γ+/+ CTL lines are transferred intoChlamydia-infected IFN-γ−/− mice, the transferred CTL cannot overcome the immune defect seen in the IFN-γ−/− mice. We also show thatChlamydia-specific CTL can be cultured from IFN-γ-deficient mice infected with C. trachomatis; however, the adoptive transfer of IFN-γ−/− CTL into infected IFN-γ+/+ mice does not reduce the level of infection. These results suggest that IFN-γ production by CTL is not sufficient to overcome the defect that IFN-γ−/− mice have in the resolution of Chlamydia infection, yet IFN-γ production by CTL is required for the protective effect seen upon adoptive transfer of CTL into IFN-γ+/+ mice.

scholarly journals Increased Host Resistance against Pneumocystis carinii Pneumonia in γδ T-Cell-Deficient Mice: Protective Role of Gamma Interferon and CD8+ T Cells

2002 ◽  
Vol 70 (9) ◽  
pp. 5208-5215 ◽  
Author(s):  
Chad Steele ◽  
Mingquan Zheng ◽  
Erana Young ◽  
Luis Marrero ◽  
Judd E. Shellito ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pneumocystis Carinii ◽  
Lavage Fluid ◽  
Gamma Interferon ◽  
Host Susceptibility ◽  
T Cell Subsets ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACT Although a clear relationship between αβ T-cell receptor-positive (αβ-TCR+) CD4+ T cells and susceptibility to Pneumocystis carinii infection exists, the role of other T-cell subsets is less clearly defined. Previous studies have shown that γδ-TCR+ T cells infiltrate into the lung during P. carinii pneumonia. Therefore, the present study examined the role of γδ-TCR+ T cells in host defense against P. carinii pneumonia. C57BL/6 (control) and B6.129P2-Tcrdtm1Mom (γδ-TCR+ T-cell-deficient) mice were inoculated intratracheally with P. carinii. At specific time points, mice were sacrificed and analyzed for P. carinii burden, T-cell subsets, and cytokine levels in lung tissue. Analysis of P. carinii burden showed a more rapid and complete resolution of infection in γδ-TCR+ T-cell-deficient mice than in C57BL/6 controls. This augmented resolution was associated with elevated gamma interferon (IFN-γ) levels in bronchoalveolar lavage fluid predominantly produced by CD8+ T cells, as well as an increased recruitment of CD8+ T cells in general. In separate experiments, neutralization of IFN-γ or depletion of CD8+ T cells early during infection abolished the augmented resolution previously observed in γδ-TCR+ T-cell-deficient mice. These results show that the presence of γδ-TCR+ T cells modulates host susceptibility to P. carinii pneumonia through interactions with pulmonary CD8+ T cells and tissue production of IFN-γ.

scholarly journals Disruption of the ICOS-B7RP-1 Costimulatory Pathway Leads to Enhanced Hepatic Immunopathology and Increased Gamma Interferon Production by CD4 T Cells in Murine Schistosomiasis

2003 ◽  
Vol 71 (7) ◽  
pp. 4040-4044 ◽  
Author(s):  
Laura I. Rutitzky ◽  
Engin Özkaynak ◽  
James B. Rottman ◽  
Miguel J. Stadecker
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Costimulatory Molecule ◽  
Lymphocyte Activation ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Egg Antigen ◽  
Costimulatory Pathway

ABSTRACT Morbidity and mortality in schistosomiasis are largely due to an immune response mediated by CD4 T lymphocytes. Since lymphocyte activation is shaped by costimulatory signals, the specific functions of different costimulatory pathways are of increasing interest. We now examined the role of the inducible costimulatory molecule (ICOS) and its ligand B7-related protein 1 (B7RP-1) in the experimental murine schistosome infection by blocking this costimulatory pathway with monoclonal antibody against ICOS, administered daily by intraperitoneal injection during the patent phase of the disease. The treated mice exhibited enhanced hepatic immunopathology characterized by enlarged egg granulomas and pronounced parenchymal inflammation with hepatocellular necrosis, resulting in elevated liver enzyme levels in serum. Most strikingly, there was a sharp increase in gamma interferon (IFN-γ) production by schistosome egg antigen-stimulated granuloma cells, bulk mesenteric lymph node (MLN) cells, and purified MLN CD4 T cells, which contrasted with a more discreet change in the Th2-type cytokines interleukin 4 (IL-4) and IL-10. These findings suggest that the ICOS-B7RP-1 costimulatory pathway serves primarily to control IFN-γ production, thereby promoting a cytokine environment conducive to limited hepatic damage.

scholarly journals Interleukin-4 and Interleukin-10 Are Involved in Host Resistance to Staphylococcus aureus Infection through Regulation of Gamma Interferon

2000 ◽  
Vol 68 (5) ◽  
pp. 2424-2430 ◽  
Author(s):  
Sanae Sasaki ◽  
Shinsuke Nishikawa ◽  
Tomisato Miura ◽  
Mayuko Mizuki ◽  
Kyogo Yamada ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Survival Rates ◽  
Interleukin 10 ◽  
Protective Role ◽  
Gamma Interferon ◽  
Interleukin 4 ◽  
T Helper 1 ◽  
Th2 Response ◽  
Ifn Γ

ABSTRACT Our previous study showed that gamma interferon (IFN-γ), a T-helper 1 (Th1)-type cytokine, plays a detrimental role inStaphylococcus aureus infection in mice. In this study, the role of Th2-type cytokines such as interleukin-4 (IL-4) and IL-10 inS. aureus infection was investigated. IL-10 mRNA was induced in parallel with IFN-γ in the spleens and kidneys of mice during S. aureus infection, whereas IL-4 mRNA was induced in the spleens but not in the kidneys of these animals. Spleen cells obtained from S. aureus-infected mice produced lower titers of IFN-γ and higher titers of IL-4 and IL-10 in response to heat-killed S. aureus than did those from uninfected mice. Administration of anti-IL-4 monoclonal antibody (MAb) or anti-IL-10 MAb inhibited the elimination of S. aureus cells from the kidneys of mice. IFN-γ mRNA expression was enhanced in the spleens of anti-IL-4 MAb- or anti-IL-10 MAb-treated mice and also in the kidneys of anti-IL-4 MAb-treated animals. Next, we evaluated the role of IFN-γ in S. aureus infection in IFN-γ−/−mice. An increase in survival rates, a decrease in bacterial numbers in the kidneys, and an amelioration of histologic abnormalities in these organs were observed in IFN-γ−/− mice compared with those in IFN-γ+/+ mice. Administration of MAb against IL-4 or IL-10 failed to affect bacterial growth in the spleens and kidneys of IFN-γ−/− mice irrespective of the expression of Th2 response. These results suggest that S. aureusinfection induced a Th2 response and that IL-4 and IL-10 might play a protective role through the regulation of IFN-γ in S. aureus infection.

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