Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.

IL-12p70 induced IFN-γ is required to control Mycobacterium tuberculosis growth; however, in the absence of IL-12p70, an IL-12p40-dependent pathway mediates induction of IFN-γ and initial bacteriostatic activity. IL-23 is an IL-12p40-dependent cytokine containing an IL-12p40 subunit covalently bound to a p19 subunit that is implicated in the induction of CD4 T cells associated with autoimmunity and inflammation. We show that in IL-23 p19-deficient mice, mycobacterial growth is controlled, and there is no diminution in either the number of IFN-γ-producing Ag-specific CD4 T cells or local IFN-γ mRNA expression. Conversely, there is an almost total loss of both IL-17-producing Ag-specific CD4 T cells and local production of IL-17 mRNA in these mice. The absence of IL-17 does not alter expression of the antimycobacterial genes, NO synthase 2 and LRG-47, and the absence of IL-23 or IL-17, both of which are implicated in mediating inflammation, fails to substantially affect the granulomatous response to M. tuberculosis infection of the lung. Despite this redundancy, IL-23 is required to provide a moderate level of protection in the absence of IL-12p70, and this protection correlates with a requirement for IL-23 in the IL-12p70-independent induction of Ag-specific, IFN-γ-producing CD4 T cells. We also show that IL-23 is required for the induction of an IL-17-producing Ag-specific phenotype in naive CD4 T cells in vitro and that absence of IL-12p70 promotes an increase in the number of IL-17-producing Ag-specific CD4 T cells both in vitro and in vivo.

Migration of dendritic cells (DCs) to the draining lymph node (DLN) is required for the activation of naive T cells. We show here that migration of DCs from the lung to the DLN after Mycobacterium tuberculosis (Mtb) exposure is defective in mice lacking interleukin (IL)-12p40. This defect compromises the ability of IL-12p40–deficient DCs to activate naive T cells in vivo; however, DCs that express IL-12p40 alone can activate naive T cells. Treatment of IL-12p40–deficient DCs with IL-12p40 homodimer (IL-12(p40)2) restores Mtb-induced DC migration and the ability of IL-12p40–deficient DCs to activate naive T cells. These data define a novel and fundamental role for IL-12p40 in the pathogen-induced activation of pulmonary DCs.

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Axial walking is the cumulative axial displacement of a complete flowline length occurring over a number of start up and shut in cycles, which may lead to excessive end movement and ultimately the failure of tie-in jumper/spool connection. The phenomenon shall be evaluated for the relatively short deep water flowlines which are operated under the following conditions:very soft clay soilhigh slope seabed profilesteep temperature gradient during start up and shut down This paper addresses a study of deep water flowline walking through detailed finite element simulation with ABAQUS. The nonlinearity of pipe-soil friction and pipe material, the seabed profile, the pressure and temperature profile, and the connected PLET resistance are considered. The effects of different parameters on the pipeline axial walking are studied, especially for the pipe-soil friction models which are critical and heavily dependent on the embedment for the deep water flowline. A range of friction curves (LB, BE and UB) and mobilization distances are considered due to the uncertainty and complexities involved in the deep water soil properties. Possible mitigation methods for axial walking are further discussed. The advantage and disadvantages of each option are compared with respect to cost, possibility of success and conditions. The suitability of each mitigation method for the case study is analyzed. The work presented in this paper is intended to help raise awareness of axial walking for the design of deep water flowlines and shows the importance of the decision making process of the mitigation method to achieve an optimum balance between economical and technical constraints. Introduction In recent years, much attention has been focused on pipeline axial walking which is the cumulative axial displacement of a relatively short pipeline occurring over a number of start up and shut in cycles. The mechanism leading to axial walking has been studied in detail (Knut Tørnes et. al, 2000). An analytical equation predicting the rate of axial walking has been presented by SAFEBUCK JIP (M. Carr et. al, 2006). The mitigation measures for deep water pipeline instability including axial walking induced by pressure and temperature variations have been discussed (D. Perinet and I. Frazer, 2006). Axial walking itself, will not cause the pipeline failure if the pipeline is not susceptible to buckling. However, as a result of the accumulated global displacement over a number of cycles, axial walking may cause the failure of tie-in jumpers/spools. It may also increase the loading within a lateral buckle causing localized failure. Therefore, it is necessary to address this problem at a conceptual design stage since its occurrence may have a major influence on the field layout, which can have a huge impact on the project cost and development. Pipe walking is a complex aspect in regard to the pipe/soil interaction especially in high plasticity clay deposits so often found in deep fields. The analysis that is typically used especially for cohesive soils, is a very simplified constant residual friction and elastic soil, mobilisation and recovery axial resistance model. In reality, there are a lot of parameter non-linearities, most crucial perhaps, being the suction force between embedded pipe and surficial liquid soil which is probably re-set in very short period following pipe breakout and soil disturbance. Actual axial restraint is probably very much a function of the time between heat-up and cool down cycles, pipe coating type, soil contact area and adhesion force with variable embedment and associated varying force mobilisation distance.