The<i>in vivo</i>immunomodulatory effect of recombinant tumour necrosis factor-alpha in guinea pigs vaccinated with<i>Mycobacterium bovis</i>bacille Calmette–Guérin

Kramp, J. C.; McMurray, David N.; Formichella, Cathryn R.; Jeevan, Amminikutty

doi:10.1111/j.1365-2249.2011.04406.x

Cited by 7 publications

(6 citation statements)

References 50 publications

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“…Furthermore, modulating IL-10 levels in the context of other important immune molecules (e.g. TNF or IFN-γ) could prove to be beneficial in controlling lesion outcome, but have yet to be explored (83–85). Unfortunately, these strategies may lack clinical relevance in humans because the short window where IL-10 treatments could be effective is at odds with the long-time-to-diagnosis in clinics.…”

Section: Discussionmentioning

confidence: 99%

Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity–Mediated Antimicrobial Responses with Caseation duringMycobacterium tuberculosisInfection

Cilfone

Ford

Marino

et al. 2015

The Journal of Immunology

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Although almost a third of the world’s population is infected with the bacterial pathogen Mycobacterium tuberculosis (Mtb), our understanding of the functions of many immune factors involved in fighting infection is limited. Determining the role of the immunosuppressive cytokine interleukin-10 (IL-10) at the level of the granuloma has proven difficult due to lesional heterogeneity and the limitations of animal models. Here we take an in silico approach and, through a series of virtual experiments, we predict several novel roles for IL-10 in TB granulomas: (1) decreased levels of IL-10 lead to increased numbers of sterile lesions, but at the cost of early increased caseation, (2) small increases in early antimicrobial activity cause this increased lesion sterility, (3) IL-10 produced by activated macrophages is a major mediator of early antimicrobial activity and early host-induced caseation and (4) increasing levels of infected macrophage derived IL-10 promotes bacterial persistence by limiting the early antimicrobial response and preventing lesion sterilization. Our findings, currently only accessible using an in silico approach, suggest that IL-10 at the individual granuloma scale is a critical regulator of lesion outcome. These predictions suggest IL-10 related mechanisms that could be used as adjunctive therapies during TB.

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Section: Discussionmentioning

confidence: 99%

Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity–Mediated Antimicrobial Responses with Caseation duringMycobacterium tuberculosisInfection

Cilfone

Ford

Marino

et al. 2015

The Journal of Immunology

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“…One possible modulatory or comodulatory cytokine that is also disrupted in TLR3-deficient OE cells is TNF-␣. The role of TNF-␣ as an immunomodulatory cytokine has been described in experiments demonstrating TNF-␣'s direct role in regulating the synthesis of inflammatory mediators, including TGF-␤, IL-12p40, and IL-10, in the guinea pig model for tuberculosis infection (25,31). Others have described a comodulatory role for TNF-␣ by demonstrating that TNF-␣ works synergistically with IFN-␤ in order to sufficiently induce the synthesis of indoleamine 2,3-dioxygenase (IDO) production during Haemophilus ducreyi infection of human DCs (29).…”

Section: Discussionmentioning

confidence: 99%

Identifying a Role for Toll-Like Receptor 3 in the Innate Immune Response to Chlamydia muridarum Infection in Murine Oviduct Epithelial Cells

et al. 2012

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Because epithelial cells are the major cell type productively infected with Chlamydia during genital tract infections, the overall goal of our research was to understand the contribution of infected epithelial cells to the host defense. We previously showed that Toll-like receptor 3 (TLR3) is the critical pattern recognition receptor in oviduct epithelial (OE) cells that is stimulated during Chlamydia infection, resulting in the synthesis of beta interferon (IFN-␤). Here, we present data that implicates TLR3 in the expression of a multitude of other innate-inflammatory immune modulators including interleukin-6 (IL-6), CXCL10, CXCL16, and CCL5. We demonstrate that Chlamydia-induced expression of these cytokines is severely disrupted in TLR3-deficient OE cells, whereas Chlamydia replication in the TLR3-deficient cells is more efficient than in wild-type OE cells. Pretreatment of the TLR3-deficient OE cells with 50 U of IFN-␤/ml prior to infection diminished Chlamydia replication and restored the ability of Chlamydia infection to induce IL-6, CXCL10, and CCL5 expression in TLR3-deficient OE cells; however, CXCL16 induction was not restored by IFN-␤ preincubation. Our findings were corroborated in pathway-focused PCR arrays, which demonstrated a multitude of different inflammatory genes that were defectively regulated during Chlamydia infection of the TLR3-deficient OE cells, and we found that some of these genes were induced only when IFN-␤ was added prior to infection. Our OE cell data implicate TLR3 as an essential inducer of IFN-␤ and other inflammatory mediators by epithelial cells during Chlamydia infection and highlight the contribution of TLR3 to the inflammatory cytokine response.

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“…The in vivo effect of rgpMCP-1 on infiltration of macrophages in the guinea pig skin will be assessed as reported before [24]. We previously reported the in vivo effects of rgpTNF-α [38]. Future studies will focus on generation of polyclonal antibodies for both rgpIL-1β and MCP-1 and in vivo neutralization experiments involving anti-IL-1β and anti-MCP-1 will be performed in a similar manner as that done for anti-TNF-α by our group [12, 39].…”

Section: Discussionmentioning

confidence: 99%

Prokaryotic Expression and In Vitro Functional Analysis of IL-1β and MCP-1 from Guinea Pig

Dirisala

Jeevan

et al. 2012

Mol Biotechnol

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The Guinea pig (Cavia porcellus) is an excellent animal model for studying human tuberculosis (TB) and also for a number of other infectious and non-infectious diseases. One of the major roadblocks in effective utilization of this animal model is the lack of readily available immunological reagents. In order to address this issue, guinea pig interleukin 1 beta (IL-1β) and monocyte chemo attractant protein-1 (MCP-1) were efficiently cloned and expressed in a prokaryotic expression vector (pET-30a) and the expressed proteins in soluble form from both the genes were confirmed by N-terminal sequencing. The biological activity of recombinant guinea pig IL-1β was demonstrated by its ability to drive proliferation in thymocytes and the recombinant guinea pig MCP-1 exhibited chemotactic activity for guinea pig resident peritoneal macrophages. These biologically active recombinant guinea pig proteins will facilitate an in-depth understanding of the role they play in the immune responses of the guinea pig to TB and other diseases.

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Thein vivoimmunomodulatory effect of recombinant tumour necrosis factor-alpha in guinea pigs vaccinated withMycobacterium bovisbacille Calmette–Guérin

Cited by 7 publications

References 50 publications

Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity–Mediated Antimicrobial Responses with Caseation duringMycobacterium tuberculosisInfection

Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity–Mediated Antimicrobial Responses with Caseation duringMycobacterium tuberculosisInfection

Identifying a Role for Toll-Like Receptor 3 in the Innate Immune Response to Chlamydia muridarum Infection in Murine Oviduct Epithelial Cells

Prokaryotic Expression and In Vitro Functional Analysis of IL-1β and MCP-1 from Guinea Pig

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