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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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Cellular fractions in PPD bead granulomas at 2 and 4 days of granuloma formation in thirty CBA/J mice quantified by multi-color flow cytometry.Results are expressed as the percentage of each cell type in the total population of granuloma cells. Error bars represent standard deviation from the mean.
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pcbi-1000778-g004: Cellular fractions in PPD bead granulomas at 2 and 4 days of granuloma formation in thirty CBA/J mice quantified by multi-color flow cytometry.Results are expressed as the percentage of each cell type in the total population of granuloma cells. Error bars represent standard deviation from the mean.

Mentions: We used an artificial model of TB granuloma developed in mice following injection of PPD-coated beads to measure model parameters of interest. To identify the cellular composition of PPD bead granulomas, multi-color flow cytometry with fluorescing antibodies for specific immune cell surface markers was used as described in Methods. Figure 4 indicates experimental data on fractions of the major granuloma-comprising immune cells, including DCs, macrophages, T cells and B cells, that compose approximately 80% of the total cell population of day 2 and day 4 granulomas. Macrophages and B cells were observed to be the largest cell populations in isolated granulomas. A small but statistically significant increase (p<0.001) in the percentage of both CD4 and CD8 T cells which represent the adaptive immune response was observed in day 4 granulomas compared with day 2 granulomas. On the other hand, macrophages and DCs were shown to form a slightly smaller portion of day 4 granuloma cell population. The percentage of B cells in granulomas did not significantly change from day 2 to day 4. Cellular composition of the granuloma and the increase in the level of T cell recruitment with time are qualitatively consistent with the experimental data on the infiltration of immune cells into the lungs of mice infected with Mtb as well as data on granulomas induced in lungs of Mtb-infected monkeys, although T cell recruitment occurs in a shorter time scale for PPD bead granulomas [7], [9].


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)

Cellular fractions in PPD bead granulomas at 2 and 4 days of granuloma formation in thirty CBA/J mice quantified by multi-color flow cytometry.Results are expressed as the percentage of each cell type in the total population of granuloma cells. Error bars represent standard deviation from the mean.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000778-g004: Cellular fractions in PPD bead granulomas at 2 and 4 days of granuloma formation in thirty CBA/J mice quantified by multi-color flow cytometry.Results are expressed as the percentage of each cell type in the total population of granuloma cells. Error bars represent standard deviation from the mean.
Mentions: We used an artificial model of TB granuloma developed in mice following injection of PPD-coated beads to measure model parameters of interest. To identify the cellular composition of PPD bead granulomas, multi-color flow cytometry with fluorescing antibodies for specific immune cell surface markers was used as described in Methods. Figure 4 indicates experimental data on fractions of the major granuloma-comprising immune cells, including DCs, macrophages, T cells and B cells, that compose approximately 80% of the total cell population of day 2 and day 4 granulomas. Macrophages and B cells were observed to be the largest cell populations in isolated granulomas. A small but statistically significant increase (p<0.001) in the percentage of both CD4 and CD8 T cells which represent the adaptive immune response was observed in day 4 granulomas compared with day 2 granulomas. On the other hand, macrophages and DCs were shown to form a slightly smaller portion of day 4 granuloma cell population. The percentage of B cells in granulomas did not significantly change from day 2 to day 4. Cellular composition of the granuloma and the increase in the level of T cell recruitment with time are qualitatively consistent with the experimental data on the infiltration of immune cells into the lungs of mice infected with Mtb as well as data on granulomas induced in lungs of Mtb-infected monkeys, although T cell recruitment occurs in a shorter time scale for PPD bead granulomas [7], [9].

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