scholarly journals Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway

2011 ◽  
Vol 208 (9) ◽  
pp. 1863-1874 ◽  
Author(s):  
Julius A. Potian ◽  
Wasiulla Rafi ◽  
Kamlesh Bhatt ◽  
Amanda McBride ◽  
William C. Gause ◽  
...  
Keyword(s):  
Alternative Activation ◽  
Intestinal Helminth ◽  
Nippostrongylus Brasiliensis ◽  
Th2 Response ◽  
Alternatively Activated Macrophages ◽  
Cellular Immune Responses ◽  
Helminthic Infections ◽  
Cellular Immune ◽  
The Impact ◽  
Alternatively Activated

Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Rα exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Rα−/− mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Rα−/− macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Rα signaling pathway.

scholarly journals Thioredoxin Peroxidase Secreted by Fasciola hepatica Induces the Alternative Activation of Macrophages

2005 ◽  
Vol 73 (1) ◽  
pp. 166-173 ◽  
Author(s):  
Sheila Donnelly ◽  
Sandra M. O'Neill ◽  
Mary Sekiya ◽  
Grace Mulcahy ◽  
John P. Dalton
Keyword(s):  
Fasciola Hepatica ◽  
Interleukin 10 ◽  
Alternative Activation ◽  
Parasitic Infections ◽  
Prostaglandin E ◽  
Th2 Response ◽  
Alternatively Activated Macrophages ◽  
Thioredoxin Peroxidase ◽  
Alternatively Activated

ABSTRACT Alternatively activated macrophages (AAMφ) are primarily associated with the chronic stages of parasitic infections and the development of a polarized Th2 response. We have shown that Fasciola hepatica infection of BALB/c mice induces a polarized Th2 response during both the latent and chronic stage of disease. The activation status of macrophages was analyzed in this model of helminth infection by evaluating the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arg1. AAMφ were recruited to the peritoneum of mice within 24 h of F. hepatica infection and after intraperitoneal injection of parasite excretory-secretory (ES) products. Administration of a recombinant antioxidant thioredoxin peroxidase (TPx), which is contained within the ES products, also induced the recruitment of AAMφ to the peritoneum. In vitro studies showed that this recombinant TPx directly converts RAW 264.7 macrophages to an alternatively activated phenotype characterized by the production of high levels of interleukin-10 (IL-10), prostaglandin E2, corresponding with low levels of IL-12. Our data suggest that the Th2 responses induced by the helminth F. hepatica are mediated through the secretion of molecules, one of which is TPx, that induce the recruitment and alternative activation of macrophages.

scholarly journals Induction of Broad-Based Immunity and Protective Efficacy by Self-amplifying mRNA Vaccines Encoding Influenza Virus Hemagglutinin

2015 ◽  
Vol 90 (1) ◽  
pp. 332-344 ◽  
Author(s):  
Michela Brazzoli ◽  
Diletta Magini ◽  
Alessandra Bonci ◽  
Scilla Buccato ◽  
Cinzia Giovani ◽  
...  
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Immune Responses ◽  
Upper Respiratory Tract ◽  
Vaccine Platform ◽  
Major Health Problem ◽  
Cellular Immune Responses ◽  
Influenza Virus Hemagglutinin ◽  
Cellular Immune ◽  
The Impact

ABSTRACTSeasonal influenza is a vaccine-preventable disease that remains a major health problem worldwide, especially in immunocompromised populations. The impact of influenza disease is even greater when strains drift, and influenza pandemics can result when animal-derived influenza virus strains combine with seasonal strains. In this study, we used the SAM technology and characterized the immunogenicity and efficacy of a self-amplifying mRNA expressing influenza virus hemagglutinin (HA) antigen [SAM(HA)] formulated with a novel oil-in-water cationic nanoemulsion. We demonstrated that SAM(HA) was immunogenic in ferrets and facilitated containment of viral replication in the upper respiratory tract of influenza virus-infected animals. In mice, SAM(HA) induced potent functional neutralizing antibody and cellular immune responses, characterized by HA-specific CD4 T helper 1 and CD8 cytotoxic T cells. Furthermore, mice immunized with SAM(HA) derived from the influenza A virus A/California/7/2009 (H1N1) strain (Cal) were protected from a lethal challenge with the heterologous mouse-adapted A/PR/8/1934 (H1N1) virus strain (PR8). Sera derived from SAM(H1-Cal)-immunized animals were not cross-reactive with the PR8 virus, whereas cross-reactivity was observed for HA-specific CD4 and CD8 T cells. Finally, depletion of T cells demonstrated that T-cell responses were essential in mediating heterologous protection. If the SAM vaccine platform proves safe, well tolerated, and effective in humans, the fully synthetic SAM vaccine technology could provide a rapid response platform to control pandemic influenza.IMPORTANCEIn this study, we describe protective immune responses in mice and ferrets after vaccination with a novel HA-based influenza vaccine. This novel type of vaccine elicits both humoral and cellular immune responses. Although vaccine-specific antibodies are the key players in mediating protection from homologous influenza virus infections, vaccine-specific T cells contribute to the control of heterologous infections. The rapid production capacity and the synthetic origin of the vaccine antigen make the SAM platform particularly exploitable in case of influenza pandemic.

Prolonged renal allograft survival by donor interleukin-6 deficiency: association with decreased alloantibodies and increased intragraft T regulatory cells

2012 ◽  
Vol 302 (2) ◽  
pp. F276-F283 ◽  
Author(s):  
Hao Wang ◽  
Qiunong Guan ◽  
Zhu Lan ◽  
Shuyuan Li ◽  
Wei Ge ◽  
...  
Keyword(s):  
Renal Allograft ◽  
T Regulatory Cells ◽  
Treg Cells ◽  
Renal Tubules ◽  
Allograft Survival ◽  
Cellular Immune Responses ◽  
Forkhead Box ◽  
Cellular Immune ◽  
The Impact ◽  
Cellular Rejection

Both humoral and cellular immune responses are involved in renal allograft rejection. Interleukin (IL)-6 is a regulatory cytokine for both B and Foxp3 (forkhead box P3)-expressing regulatory T (Treg) cells. This study was designed to investigate the impact of donor IL-6 production on renal allograft survival. Donor kidneys from IL-6 knockout (KO) vs. wild-type (WT) C57BL/6 mice (H-2b) were orthotopically transplanted to nephrotomized BALB/c mice (H-2d). Alloantibodies and Treg cells were examined by fluorescence-activated cell sorting analysis. Graft survival was determined by the time to graft failure. Here, we showed that a deficiency in IL-6 expression in donor kidneys significantly prolonged renal allograft survival compared with WT controls. IL-6 protein was upregulated in renal tubules and endothelium of renal allografts following rejection, which correlated with an increase in serum IL-6 compared with that in those receiving KO grafts or naive controls. The absence of graft-producing IL-6 or lower levels of serum IL-6 in the recipients receiving IL-6 KO allografts was associated with decreased circulating anti-graft alloantibodies and increased the percentage of intragraft CD4+CD25+Foxp3+ Treg cells compared with those with WT allografts. In conclusion, the lack of graft-producing IL-6 significantly prolongs renal allograft survival, which is associated with reduced alloantibody production and/or increased intragraft Treg cell population, implying that targeting donor IL-6 may effectively prevent both humoral and cellular rejection of kidney transplants.

scholarly journals Signal Transducer and Activator of Transcription Factor 6 Signaling Contributes to Control Host Lung Pathology but Favors Susceptibility againstToxocara canisInfection

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Berenice Faz-López ◽  
Yadira Ledesma-Soto ◽  
Yolanda Romero-Sánchez ◽  
Elsa Calleja ◽  
Pablo Martínez-Labat ◽  
...  
Keyword(s):  
Toxocara Canis ◽  
Lung Pathology ◽  
Activated Macrophages ◽  
Wild Type ◽  
Gastrointestinal Helminths ◽  
Th2 Response ◽  
Alternatively Activated Macrophages ◽  
Severe Pathology ◽  
Alternatively Activated

UsingSTAT6−/−BALB/c mice, we have analyzed the role of STAT6-induced Th2 response in determining the outcome of experimental toxocariasis caused by embryonated eggs of the helminth parasiteToxocara canis. FollowingT. canisinfection wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, and IL-4, recruited alternatively activated macrophages, and displayed a moderate pathology in the lungs; however, they harbored heavy parasite loads in different tissues. In contrast, similarly infectedSTAT6−/−BALB/c mice mounted a weak Th2-like response, did not recruit alternatively activated macrophages, displayed a severe pathology in the lungs, but efficiently controlledT. canisinfection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to larval stage ofT. canis. Furthermore, they also indicate that unlike most gastrointestinal helminths, immunity against larvae ofT. canisis not mediated by a Th2-dominant response.

scholarly journals The skin is an important bulwark of acquired immunity against intestinal helminths

2013 ◽  
Vol 210 (12) ◽  
pp. 2583-2595 ◽  
Author(s):  
Kazushige Obata-Ninomiya ◽  
Kenji Ishiwata ◽  
Hidemitsu Tsutsui ◽  
Yuichiro Nei ◽  
Soichiro Yoshikawa ◽  
...  
Keyword(s):  
Lung Injury ◽  
Intestinal Helminth ◽  
Nippostrongylus Brasiliensis ◽  
Arginase 1 ◽  
Helminthic Infections ◽  
Selective Ablation ◽  
Helminthic Infection ◽  
Worm Expulsion ◽  
Deficient Mice ◽  
Infected Skin

Once animals have experienced a helminthic infection, they often show stronger protective immunity against subsequent infections. Although helminthic infections are well known to elicit Th2-type immune responses, it remains ill-defined where and how acquired protection is executed. Here we show that skin-invading larvae of the intestinal helminth Nippostrongylus brasiliensis are surrounded by skin-infiltrating cells and are prevented from migrating out of infected skin during the second but not the first infection. B cell– or IgE receptor FcεRI–deficient mice showed impaired larval trapping in the skin. Selective ablation of basophils, but not mast cells, abolished the larval trapping, leading to increased worm burden in the lung and hence severe lung injury. Skin-infiltrating basophils produced IL-4 that in turn promoted the generation of M2-type macrophages, leading to the larval trapping in the skin through arginase-1 production. Basophils had no apparent contribution to worm expulsion from the intestine. This study thus reveals a novel mode of acquired antihelminth immunity, in which IgE-armed basophils mediate skin trapping of larvae, thereby limiting lung injury caused by larval migration.

scholarly journals Cellular Immune Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent HPV Vaccine in Fijian Girls and Subsequent Responses to a Dose of Bivalent HPV Vaccine

2018 ◽  
Vol 5 (7) ◽  
Author(s):  
Zheng Quan Toh ◽  
Kathleen Wen Bei Cheow ◽  
Fiona M Russell ◽  
Edwin Hoe ◽  
Rita Reyburn ◽  
...  
Keyword(s):  
Cellular Immunity ◽  
Hpv Vaccine ◽  
Peripheral Blood Mononuclear ◽  
Cellular Immune Responses ◽  
Reduced Dose ◽  
Specific Cellular Immune Response ◽  
Hpv Types ◽  
Cellular Immune ◽  
The Impact ◽  
High Disease Burden

Abstract Background This study examined the cellular immunity of 0, 1, 2, and 3 doses of Gardasil vaccine (4vHPV) in girls after 6 years and their responses to a subsequent dose of Cervarix vaccine (2vHPV). Methods A subset of girls (n = 59) who previously received 0, 1, 2, or 3 doses of 4vHPV 6 years earlier were randomly selected from a cohort study of Fijian girls (age 15–19 years). Blood was collected before and 28 days after a dose of 2vHPV. The HPV16- and HPV18-specific cellular immune response was determined by IFNγ-ELISPOT and by measurement of cytokines in peripheral blood mononuclear cell supernatants. Results Six years after 4vHPV vaccination, HPV18-specific responses were significantly lower in the 1- (1D) or 2-dose (2D) recipients compared with 3-dose recipients (2D: IFNγ-ELISPOT: P = .008; cytokines, IFNγ: P = .002; IL-2: P = .022; TNFα: P = .016; IL-10: P = .018; 1D: IL-2: P = .031; IL-10: P = .014). These differences were no longer significant post-2vHPV. No significant differences in HPV16 responses (except IL-2, P < .05) were observed between the 2- or 1-dose recipients and 3-dose recipients. Conclusions These data suggest that cellular immunity following reduced-dose schedules was detectable after 6 years, although the responses were variable between HPV types and dosage groups. The clinical significance of this is unknown. Further studies on the impact of reduced dose schedules are needed, particularly in high–disease burden settings.

scholarly journals Identification of Caspase-6 as a New Regulator of Alternatively Activated Macrophages

2016 ◽  
Vol 291 (33) ◽  
pp. 17450-17466 ◽  
Author(s):  
Yongfang Yao ◽  
Qian Shi ◽  
Bing Chen ◽  
Qingsong Wang ◽  
Xinda Li ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Protein Composition ◽  
Alternative Activation ◽  
Activated Macrophages ◽  
Alternatively Activated Macrophages ◽  
Protein Levels ◽  
Caspase 6 ◽  
Alternatively Activated

Alternatively activated macrophages (AAMs) play essential roles in the promotion of tissue remodeling, vasculogenesis, and tumor progression; however, the detailed mechanisms underlying the activation of AAMs remain largely unknown. Here, by using quantitative proteomic analysis, we identified 62 proteins that were up-regulated in IL-4-induced macrophages. Among these, Caspase-6 was increased significantly. Caspase-6 is important in the apoptotic signaling pathway; however, its role in non-apoptosis is also reported. Here, we first examined the non-apoptotic role of Caspase-6 in the alternative activation of macrophages after administration of IL-4, 4T1 tumor conditional medium, or co-culture with 4T1 cells. Both treatments promoted alternative activation of RAW264.7 cells and primary macrophages, whereas disruption of caspase-6 expression and activity could markedly suppress the biomarker levels of AAMs. Overexpression of Caspase-6 could significantly promote the activation of AAMs. Importantly, we further present evidence that caspase-6 could regulate breast cancer cell invasion by modulating MMP-2 and MMP-9 expression in 4T1 tumor-associated macrophages, as ablation of protein levels or activity of caspase-6 suppressed tumor cell invasion in vitro. In conclusion, the observed results markedly expanded our views of the dynamic changes in protein composition during alternative activation of macrophages, and they revealed a critical new role of caspase-6 in regulating this cellular biological process, which suggested that caspase-6 might be a key nod molecule to regulate immunological steady-state and be a therapeutic candidate for tumor immunotherapy.

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