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Identification of key processes that control tumor necrosis factor availability in a tuberculosis granuloma.

Fallahi-Sichani M, Schaller MA, Kirschner DE, Kunkel SL, Linderman JJ - PLoS Comput. Biol. (2010)

Bottom Line: We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads.Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry.Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
Tuberculosis (TB) granulomas are organized collections of immune cells comprised of macrophages, lymphocytes and other cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF). To characterize mechanisms that control TNF availability within a TB granuloma, we developed a multi-scale two compartment partial differential equation model that describes a granuloma as a collection of immune cells forming concentric layers and includes TNF/TNF receptor binding and trafficking processes. We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads. Using our model, we then demonstrated that the organization of immune cells within a TB granuloma as well as TNF/TNF receptor binding and intracellular trafficking are two important factors that control TNF availability and may spatially coordinate TNF-induced immunological functions within a granuloma. Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry. To further elucidate the role of TNF in the process of granuloma development, our modeling and experimental findings on TNF-associated molecular scale aspects of the granuloma can be incorporated into larger scale models describing the immune response to TB infection. Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.

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Spatial coordination of the TNF-induced immunological functions in a classical granuloma composed of a core of macrophages and DCs surrounded by a ring of lymphocytes.Great availability of TNF in the core of granuloma (together with TNF-induced TNFR2 activation) can turn on the TNFR1-dependent caspase-mediated apoptotic pathway that favors antigen cross-presentation as well as elimination of the pathogen inside the granuloma. Low level of TNF availability in the mantle of granuloma is sufficient to turn on the NF-κB signaling which favors cell survival and expression of pro-inflammatory genes but not the apoptotic pathway.
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pcbi-1000778-g008: Spatial coordination of the TNF-induced immunological functions in a classical granuloma composed of a core of macrophages and DCs surrounded by a ring of lymphocytes.Great availability of TNF in the core of granuloma (together with TNF-induced TNFR2 activation) can turn on the TNFR1-dependent caspase-mediated apoptotic pathway that favors antigen cross-presentation as well as elimination of the pathogen inside the granuloma. Low level of TNF availability in the mantle of granuloma is sufficient to turn on the NF-κB signaling which favors cell survival and expression of pro-inflammatory genes but not the apoptotic pathway.

Mentions: The hypothesis of differential induction of TNF-mediated signaling pathways for classical granulomas such as ones observed particularly in human, nonhuman primate and guinea pig models of TB [9], [10] has immunological implications. Whereas TNF-induced apoptosis of granuloma core macrophages that contain pathogenic mycobacteria is required for antigen cross-presentation and subsequent T cell priming and helps eliminate the pathogen [77], [78], lymphocyte (especially CD4 and CD8 T cell) death by TNF-induced apoptosis has been reported as one of the important components of an ineffective immune response against mycobacterial infections [79], [80]. However, the TNF-induced survival signaling pathway is required for retaining T cells at the developing granuloma site where they produce IFN-γ, activating macrophages in synergy with TNF to kill intracellular infections [81]. Thus, our novel hypothesis is that a separate cellular organization in the granuloma may favor an efficient immune response via spatially coordinating the TNF-induced immunological functions in the granuloma (Figure 8). Consistent with our hypothesis, very few apoptotic lymphocytes in classical TB granulomas induced in the guinea pig have been detected and most apoptotic cells have been seen close to the core of granulomas [82]. Further, because cellular organization undergoes dynamic changes with granuloma development and at different stages of immune response (innate versus adaptive) to TB infection, it can be a factor controlling the diverse activities of TNF according to the stage of infection in the lung tissue.


Identification of key processes that control tumor necrosis factor availability in a tuberculosis granuloma.

Fallahi-Sichani M, Schaller MA, Kirschner DE, Kunkel SL, Linderman JJ - PLoS Comput. Biol. (2010)

Spatial coordination of the TNF-induced immunological functions in a classical granuloma composed of a core of macrophages and DCs surrounded by a ring of lymphocytes.Great availability of TNF in the core of granuloma (together with TNF-induced TNFR2 activation) can turn on the TNFR1-dependent caspase-mediated apoptotic pathway that favors antigen cross-presentation as well as elimination of the pathogen inside the granuloma. Low level of TNF availability in the mantle of granuloma is sufficient to turn on the NF-κB signaling which favors cell survival and expression of pro-inflammatory genes but not the apoptotic pathway.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2865521&req=5

pcbi-1000778-g008: Spatial coordination of the TNF-induced immunological functions in a classical granuloma composed of a core of macrophages and DCs surrounded by a ring of lymphocytes.Great availability of TNF in the core of granuloma (together with TNF-induced TNFR2 activation) can turn on the TNFR1-dependent caspase-mediated apoptotic pathway that favors antigen cross-presentation as well as elimination of the pathogen inside the granuloma. Low level of TNF availability in the mantle of granuloma is sufficient to turn on the NF-κB signaling which favors cell survival and expression of pro-inflammatory genes but not the apoptotic pathway.
Mentions: The hypothesis of differential induction of TNF-mediated signaling pathways for classical granulomas such as ones observed particularly in human, nonhuman primate and guinea pig models of TB [9], [10] has immunological implications. Whereas TNF-induced apoptosis of granuloma core macrophages that contain pathogenic mycobacteria is required for antigen cross-presentation and subsequent T cell priming and helps eliminate the pathogen [77], [78], lymphocyte (especially CD4 and CD8 T cell) death by TNF-induced apoptosis has been reported as one of the important components of an ineffective immune response against mycobacterial infections [79], [80]. However, the TNF-induced survival signaling pathway is required for retaining T cells at the developing granuloma site where they produce IFN-γ, activating macrophages in synergy with TNF to kill intracellular infections [81]. Thus, our novel hypothesis is that a separate cellular organization in the granuloma may favor an efficient immune response via spatially coordinating the TNF-induced immunological functions in the granuloma (Figure 8). Consistent with our hypothesis, very few apoptotic lymphocytes in classical TB granulomas induced in the guinea pig have been detected and most apoptotic cells have been seen close to the core of granulomas [82]. Further, because cellular organization undergoes dynamic changes with granuloma development and at different stages of immune response (innate versus adaptive) to TB infection, it can be a factor controlling the diverse activities of TNF according to the stage of infection in the lung tissue.

Bottom Line: We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads.Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry.Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, USA.

ABSTRACT
Tuberculosis (TB) granulomas are organized collections of immune cells comprised of macrophages, lymphocytes and other cells that form in the lung as a result of immune response to Mycobacterium tuberculosis (Mtb) infection. Formation and maintenance of granulomas are essential for control of Mtb infection and are regulated in part by a pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF). To characterize mechanisms that control TNF availability within a TB granuloma, we developed a multi-scale two compartment partial differential equation model that describes a granuloma as a collection of immune cells forming concentric layers and includes TNF/TNF receptor binding and trafficking processes. We used the results of sensitivity analysis as a tool to identify experiments to measure critical model parameters in an artificial experimental model of a TB granuloma induced in the lungs of mice following injection of mycobacterial antigen-coated beads. Using our model, we then demonstrated that the organization of immune cells within a TB granuloma as well as TNF/TNF receptor binding and intracellular trafficking are two important factors that control TNF availability and may spatially coordinate TNF-induced immunological functions within a granuloma. Further, we showed that the neutralization power of TNF-neutralizing drugs depends on their TNF binding characteristics, including TNF binding kinetics, ability to bind to membrane-bound TNF and TNF binding stoichiometry. To further elucidate the role of TNF in the process of granuloma development, our modeling and experimental findings on TNF-associated molecular scale aspects of the granuloma can be incorporated into larger scale models describing the immune response to TB infection. Ultimately, these modeling and experimental results can help identify new strategies for TB disease control/therapy.

Show MeSH
Related in: MedlinePlus