scholarly journals Characterization and Modulation of the Immunosuppressive Phase of Sepsis

2010 ◽  
Vol 78 (4) ◽  
pp. 1582-1592 ◽  
Author(s):  
Jared T. Muenzer ◽  
Christopher G. Davis ◽  
Kathy Chang ◽  
Robert E. Schmidt ◽  
W. Michael Dunne ◽  
...  
Keyword(s):  
Immune Response ◽  
Proinflammatory Cytokines ◽  
Secondary Infection ◽  
Survival Rates ◽  
Cecal Ligation ◽  
Decisive Role ◽  
Lavage Fluid ◽  
Interleukin 10 ◽  
Secondary Injury ◽  
Ifn Γ

ABSTRACT Sepsis continues to cause significant morbidity and mortality in critically ill patients. Studies of patients and animal models have revealed that changes in the immune response during sepsis play a decisive role in the outcome. Using a clinically relevant two-hit model of sepsis, i.e., cecal ligation and puncture (CLP) followed by the induction of Pseudomonas aeruginosa pneumonia, we characterized the host immune response. Second, AS101 [ammonium trichloro(dioxoethylene-o,o′)tellurate], a compound that blocks interleukin 10 (IL-10), a key mediator of immunosuppression in sepsis, was tested for its ability to reverse immunoparalysis and improve survival. Mice subjected to pneumonia following CLP had different survival rates depending upon the timing of the secondary injury. Animals challenged with P. aeruginosa at 4 days post-CLP had ∼40% survival, whereas animals challenged at 7 days had 85% survival. This improvement in survival was associated with decreased lymphocyte apoptosis, restoration of innate cell populations, increased proinflammatory cytokines, and restoration of gamma interferon (IFN-γ) production by stimulated splenocytes. These animals also showed significantly less P. aeruginosa growth from blood and bronchoalveolar lavage fluid. Importantly, AS101 improved survival after secondary injury 4 days following CLP. This increased survival was associated with many of the same findings observed in the 7-day group, i.e., restoration of IFN-γ production, increased proinflammatory cytokines, and decreased bacterial growth. Collectively, these studies demonstrate that immunosuppression following initial septic insult increases susceptibility to secondary infection. However, by 7 days post-CLP, the host's immune system has recovered sufficiently to mount an effective immune response. Modulation of the immunosuppressive phase of sepsis may aid in the development of new therapeutic strategies.

Cytokines and chemokines triggered by Chikungunya virus infection in human patients during the very early acute phase

2019 ◽  
Vol 113 (11) ◽  
pp. 730-733 ◽  
Author(s):  
Ithallo S B Tanabe ◽  
Elane C Santos ◽  
Eloiza L L Tanabe ◽  
Stephannie J M Souza ◽  
Fabio E F Santos ◽  
...  
Keyword(s):  
Immune Response ◽  
Acute Phase ◽  
Chikungunya Virus ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Interferon Α ◽  
Monocyte Chemoattractant Protein 1 ◽  
Illness Onset ◽  
Ifn Γ ◽  
C5a Anaphylatoxin

Abstract Background The immune response against the Chikungunya virus (CHIKV) during the very early acute phase is not fully elucidated. Therefore we explored the cytokine and chemokine profile triggered by CHIKV in infected patients. Methods Cytokines, chemokines and C5a anaphylatoxin were analysed in serum from CHIKV-infected patients during the viraemic phase (mean 2.97±1.27 d after illness onset) compared with a healthy group. Results CHIKV-infected patients had a significant increase of interferon-α (IFN-α), interleukin-6 (IL-6), interleukin-8 (CXCL8/IL-8), interleukin-10 (IL-10), interferon-γ (IFN-γ), monokine induced by interferon-γ (CXCL9/MIG), monocyte chemoattractant protein-1 (CCL2/MCP-1), interferon-γ-induced protein-10 (CXCL10/IP-10) and complement C5a anaphylatoxin. Conclusions The very early acute immune response triggered against CHIKV leads to an increase in pro-inflammatory immune mediators such as IFN-γ and its induced chemokines, and a high level of C5a anaphylatoxin as a result of complement activation.

scholarly journals Interleukin-10 Has Different Effects on Proliferation of Listeria monocytogenes in Livers and Spleens of Mice

2000 ◽  
Vol 68 (8) ◽  
pp. 4666-4672 ◽  
Author(s):  
Janneke N. Samsom ◽  
Akke Annema ◽  
Minke F. Geertsma ◽  
Jan A. M. Langermans ◽  
Paul H. P. Groeneveld ◽  
...  
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Primary Infection ◽  
Secondary Infection ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Number Of Bacteria

ABSTRACT The aim of this study was to investigate the effect of interleukin-10 (IL-10) on the course of Listeria monocytogenes infection in naive and immune mice. Treatment with IL-10 during the course of a primary infection significantly decreased the number of bacteria in the spleen and did not affect the number in the liver. During a secondary infection in immune mice treated with IL-10, the number of bacteria was significantly lower in the spleen but significantly higher in the liver in comparison to mock-treated immune mice. IL-10 treatment during a primary Listeria infection decreased the concentration of gamma interferon (IFN-γ) in plasma and the toxoplasmastatic activity of macrophages, whereas it increased the percentage of mildly CD3-positive T cells in the spleen. During a secondary infection, the concentration of IFN-γ in plasma was decreased on day 1 but remained unaffected during later days of infection. From these results, we conclude that IL-10 has different effects on the proliferation of L. monocytogenes in the spleen and liver during primary and secondary Listeriainfections.

scholarly journals Expression of Toll-Like Receptor 2 by Dendritic Cells Is Essential for the DnaJ-ΔA146Ply-Mediated Th1 Immune Response against Streptococcus pneumoniae

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Xiaofang Wang ◽  
Taixian Yuan ◽  
Jun Yuan ◽  
Yufeng Su ◽  
Xiaoyu Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Protective Immunity ◽  
Survival Rates ◽  
Pneumococcal Infection ◽  
Toll Like Receptor ◽  
Pneumococcal Strain ◽  
Ifn Γ ◽  
Subcutaneous Immunization ◽  
Th1 Immune Response

ABSTRACT The fusion protein DnaJ-ΔA146Ply could induce cross-protective immunity against pneumococcal infection via mucosal and subcutaneous immunization in mice in the absence of additional adjuvants. DnaJ and Ply are both Toll-like receptor 4 (TLR4) but not TLR2 ligands. However, we found that TLR2 −/− mice immunized subcutaneously with DnaJ-ΔA146Ply showed significantly lower survival rates and higher bacterial loads in nasal washes than did wild-type (WT) mice after being challenged with pneumococcal strain D39 or 19F. The gamma interferon (IFN-γ) level in splenocytes decreased in TLR2 −/− mice, indicating that Th1 immunity elicited by DnaJ-ΔA146Ply was impaired in these mice. We explored the mechanism of protective immunity conferred by DnaJ-ΔA146Ply and the role of TLR2 in this process. DnaJ-ΔA146Ply effectively promoted dendritic cell (DC) maturation via TLR4 but not the TLR2 signaling pathway. In a DnaJ-ΔA146Ply-treated DC and naive CD4 + T cell coculture system, the deficiency of TLR2 in DCs resulted in a significant decline of IFN-γ production and Th1 subset differentiation. The same effect was observed in adoptive-transfer experiments. In addition, TLR2 −/− DCs showed remarkably lower levels of the Th1-polarizing cytokine IL-12p70 than did WT DCs, suggesting that TLR2 was indispensable for DnaJ-ΔA146Ply-induced IL-12 production and Th1 proliferation. Thus, our findings illustrate that dendritic cell expression of TLR2 is essential for optimal Th1 immune response against pneumococci in mice immunized subcutaneously with DnaJ-ΔA146Ply.

scholarly journals Vaccination with Lentiviral Vector Expressing thenfa1Gene Confers a Protective Immune Response to Mice Infected with Naegleria fowleri

2013 ◽  
Vol 20 (7) ◽  
pp. 1055-1060 ◽  
Author(s):  
Jong-Hyun Kim ◽  
Hae-Jin Sohn ◽  
Jinyoung Lee ◽  
Hee-Jong Yang ◽  
Yong-Joon Chwae ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Viral Vector ◽  
Lentiviral Vector ◽  
Survival Rates ◽  
Dna Vaccination ◽  
Naegleria Fowleri ◽  
Content Type ◽  
Ifn Γ ◽  
Nægleria Fowleri

ABSTRACTNaegleria fowleri, a pathogenic free-living amoeba, causes fatal primary amoebic meningoencephalitis (PAM) in humans and animals. Thenfa1gene (360 bp), cloned from a cDNA library ofN. fowleri, produces a 13.1-kDa recombinant protein which is located on pseudopodia, particularly the food cup structure. Thenfa1gene plays an important role in the pathogenesis ofN. fowleriinfection. To examine the effect ofnfa1DNA vaccination againstN. fowleriinfection, we constructed a lentiviral vector (pCDH) expressing thenfa1gene. For thein vivomouse study, BALB/c mice were intranasally vaccinated with viral particles of a viral vector expressing thenfa1gene. To evaluate the effect of vaccination and immune responses of mice, we analyzed the IgG levels (IgG, IgG1, and IgG2a), cytokine induction (interleukin-4 [IL-4] and gamma interferon [IFN-γ]), and survival rates of mice that developed PAM. The levels of both IgG and IgG subclasses (IgG1 and IgG2a) in vaccinated mice were significantly increased. The cytokine analysis showed that vaccinated mice exhibited greater IL-4 and IFN-γ production than the other control groups, suggesting a Th1/Th2 mixed-type immune response. In vaccinated mice, high levels of Nfa1-specific IgG antibodies continued until 12 weeks postvaccination. The mice vaccinated with viral vector expressing thenfa1gene also exhibited significantly higher survival rates (90%) after challenge withN. fowleritrophozoites. Finally, thenfa1vaccination effectively induced protective immunity by humoral and cellular immune responses inN. fowleri-infected mice. These results suggest that DNA vaccination using a viral vector may be a potential tool againstN. fowleriinfection.

scholarly journals Gamma Interferon Does Not Enhance Clearance of Pseudomonas aeruginosa but Does Amplify a Proinflammatory Response in a Murine Model of Postseptic Immunosuppression

2004 ◽  
Vol 72 (12) ◽  
pp. 6892-6901 ◽  
Author(s):  
E. D. Murphey ◽  
David N. Herndon ◽  
Edward R. Sherwood
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Opportunistic Infections ◽  
Cecal Ligation ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Causative Organism ◽  
Bacterial Clearance ◽  
Proinflammatory Response ◽  
Cytokine Balance ◽  
Ifn Γ

ABSTRACT Patients that have suffered a major injury may sustain a period of immunocompromise and altered Th1/Th2 cytokine balance that can predispose them to opportunistic infections. Pseudomonas aeruginosa is frequently a causative organism for nosocomial infections in critically ill patients and is associated with high mortality. We previously mimicked this clinical scenario by challenging mice with P. aeruginosa 5 days after a cecal ligation and puncture (CLP) procedure. Mice that were subjected to CLP had reduced ability to clear bacteria, significantly lower gamma interferon (IFN-γ) concentrations in plasma, and significantly elevated levels of interleukin 10 (IL-10) in plasma in response to the Pseudomonas challenge compared to uninjured control mice. We investigated the significance of the alteration in IFN-γ by administering recombinant IFN-γ to post-CLP mice at the time of Pseudomonas challenge and by challenging IFN-γ knockout (IFN-γ KO) mice with Pseudomonas. Administration of IFN-γ to post-CLP mice attenuated IL-10 secretion and enhanced IL-12 secretion but did not improve bacterial clearance or survival after Pseudomonas challenge. Furthermore, IFN-γ KO mice had significantly higher plasma IL-10 concentrations but did not exhibit impaired bacterial clearance or increased mortality following Pseudomonas challenge. These data indicate that systemic administration of IFN-γ effectively reverses alterations in immune function that are commonly associated with immunosuppression in critically injured mice but does not improve bacterial clearance or survival following Pseudomonas challenge. Further, endogenous IFN-γ does not appear to contribute significantly to early clearance of Pseudomonas bacteremia, nor does it affect the mortality rate after a lethal Pseudomonas challenge.

scholarly journals CD4+ Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

2007 ◽  
Vol 75 (6) ◽  
pp. 3021-3026 ◽  
Author(s):  
Brandon T. Leader ◽  
Charmie Godornes ◽  
Wesley C. VanVoorhis ◽  
Sheila A. Lukehart
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Rabbit Model ◽  
Treponema Pallidum ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Mrna Levels ◽  
Ifn Γ

ABSTRACT The clearance of Treponema pallidum subsp. pallidum from early syphilis lesions involves infiltration of a large number of mononuclear cells and is characteristic of a cell-mediated immune response. In the present study, we sought to determine the relative abundance of different T-lymphocyte populations and Th1/Th2-associated cytokines present in testicular lesions following experimental infection with the Chicago strain of T. pallidum. Using flow cytometry, we examined the proportion of CD4+ and CD8+ T cells present throughout the progression and resolution of primary syphilis in the rabbit model. We related these findings to the results of real-time reverse transcription-PCR quantification of treponemal and cytokine mRNA levels. Treponemal mRNA levels reached peak values on day 18 postinfection, coincident with an initial peak in the level of T cells, which were primarily CD4+ T cells. T-cell levels increased again during resolution of orchitis, and there was an increased proportion of CD8+ T cells. The maximum gamma interferon (IFN-γ) and interleukin-10 (IL-10) mRNA levels were observed on days 11 and 18, respectively, while only negligible amounts of IL-4 and IL-2 were detected throughout the infection. In addition to showing the temporal relationship between treponemal burden and T-cell responses during lesion progression, our results also demonstrate that the composition of the T-cell population changes during lesion resolution. The presence of the mRNA for IFN-γ, but not IL-4, is consistent with cytokine expression in human syphilis and provides further support for the hypothesis that there is a Th1 predominance during the early immune response to T. pallidum.

scholarly journals Evidence that Development of Severe Cardiomyopathy in Human Chagas' Disease Is Due to a Th1-Specific Immune Response

2003 ◽  
Vol 71 (3) ◽  
pp. 1185-1193 ◽  
Author(s):  
J. A. S. Gomes ◽  
L. M. G. Bahia-Oliveira ◽  
M. O. C. Rocha ◽  
O. A. Martins-Filho ◽  
G. Gazzinelli ◽  
...  
Keyword(s):  
Immune Response ◽  
Chagas Disease ◽  
Cardiac Disease ◽  
Interleukin 10 ◽  
Flow Cytometry Analysis ◽  
Peripheral Blood Mononuclear ◽  
Th1 Response ◽  
Indeterminate Form ◽  
Ifn Γ

ABSTRACT The role of interleukin 10 (IL-10) and gamma interferon (IFN-γ) on the development of pathology in human Chagas' disease was investigated. Two categories of patients, low and high producers of IFN-γ, were identified based on the levels of secretion of this cytokine in the supernatant of peripheral blood mononuclear cell (PBMC) cultures. Eighty-three percent of the patients presenting with cardiac disease (CARD) of different degrees and 59% of the patients with the indeterminate form of disease (IND) were identified as high IFN-γ producers. PBMC from IND patients classified as low IFN-γ producers secreted significantly higher amounts of IL-10 than did those from other groups. Flow cytometry analysis demonstrated that in PBMC from the IND group, the majority of the IL-10-producing cells were monocytes (CD14High+ cells), whereas in the CARD group, the major sources of IFN-γ were T lymphocytes (CD3+ CD4+ cells). These results suggest an association between the production of IFN-γ by CD3+ CD4+ cells and morbidity in Chagas' disease, whereas the production of IL-10 by macrophages/monocytes leads to regulation of the immune response in IND patients. We hypothesize that an exacerbated production of IFN-γ against Trypanosoma cruzi antigens favors the development of a strong Th1 response in CARD patients, which leads to progression of heart disease.

scholarly journals Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein

2021 ◽  
Vol 22 (13) ◽  
pp. 6892
Author(s):  
Ekaterina I. Lesnova ◽  
Olga V. Masalova ◽  
Kristina Yu. Permyakova ◽  
Vyacheslav V. Kozlov ◽  
Tatyana N. Nikolaeva ◽  
...  
Keyword(s):  
Immune Response ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Suppressor Cells ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
Immunomodulatory Activity ◽  
Polyamine Biosynthesis ◽  
Ifn Γ ◽  
Ns5b Protein

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.

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.

scholarly journals Proinflammatory cytokine changes in bronchoalveolar lavage fluid cells isolated from pigs infected solely with porcine reproductive and respiratory syndrome virus or co-infected with swine influenza virus

2019 ◽  
Vol 63 (4) ◽  
pp. 489-495 ◽  
Author(s):  
Ewelina Czyżewska-Dors ◽  
Małgorzata Pomorska-Mól ◽  
Arkadiusz Dors ◽  
Aneta Pluta ◽  
Katarzyna Podgórska ◽  
...  
Keyword(s):  
Immune Response ◽  
Influenza Virus ◽  
Bronchoalveolar Lavage ◽  
Bronchoalveolar Lavage Fluid ◽  
Swine Influenza Virus ◽  
Swine Influenza ◽  
Lavage Fluid ◽  
Respiratory Syndrome Virus ◽  
Ifn Γ ◽  
Time Point

AbstractIntroductionThe study evaluated the patterns of local innate immune response in bronchoalveolar lavage fluid (BALF) cells of pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV) alone or co-infected with swine influenza virus (SIV).Material and MethodsThe study was performed on 26 seven-week-old pigs in three groups: PRRSV-infected (n = 11), PRRSV and SIV-infected (n = 11), and control (n = 4). BALF was collected post euthanasia at 2 and 4 dpi (three piglets per inoculated group) and at 21 dpi (all remaining pigs). Expression of IFN-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 mRNA was quantified in BALF cells. PRRSV RNA was quantified in BALF samples using a commercial real-time RT-PCR kit.ResultsThe three cytokines IFN-α, IFN-γ, and IL-1β presented significant expression changes in all experimental pigs. In PRRSV-infected animals IL-8 also did, but in co-infected subjects IL-6 and IL-10 were the additional upregulated cytokines. The highest number of differentially expressed genes was observed at 4 dpi, and significant differences in cytokine gene expression did not occur between the experimental groups at any other time point. The mean PRRSV load in the BALF of PRRSV-infected pigs was higher than that of co-infected pigs at each time point, having statistical significance only at 4 dpi.ConclusionThe results of the study indicate that infection with PRRSV alone as well as with SIV interferes with innate and adaptive immune response in the infected host. They also showed that co-infection demonstrates additive effects on IL-6 and IL-10 mRNA expression levels.

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