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The 4-trifluoromethyl analog 4c shown moderate activity against Pim-1, but was surprisingly effective when tested against Pim-3 (residual activities 51% and 24%, respectively) The overall yield for the preparation of the C8 methyl derivative 17 from the common aldehyde starting material was 18%

The expression of mRNA encoding IL-23a was assessed by real-time PCR and normalized to the expression of HPRT. and lung tissue damage. This pathological response is definitely abrogated in mice deficient in the gene encoding IL-23p19 or in the presence of IL-17Cobstructing antibody. This finding that repeated exposure to mycobacterial antigen promotes enhanced IL-17Cdependent pathological consequences offers important implications for the design of effective vaccines against Mtb. Tuberculosis (TB) remains one of the main risks to mankind. Despite the efforts of the medical community toward understanding this disease, 9 million active TB instances and 2 million deaths occur every year (Dye et al., 1999; Dye, 2006). Although immune cell activation is required to limit the growth of (Mtb), if uncontrolled it can damage host cells. The balance between safety and pathological effects is the crux of TB pathogenesis. It is therefore essential to understand and discriminate the components of the immune response that are protecting from those that are damaging to efficiently intervene in TB. Indeed, the hope for improved vaccination relies on the possibility that these reactions can be individually manipulated. The discrimination between protecting and pathological components of the immune response during TB is particularly important because bacille Calmette-Gurin (BCG), currently the only available vaccine against TB, has variable effectiveness (ranging from 0 to 80%; Colditz et al., 1994) and its safety may last for only 10 yr (Sterne et al., 1998; Weir et al., 2008). As a result of this apparent loss of activity, revaccination with BCG, DNA vaccines, or subunit vaccines is considered as a potential control strategy; Tyclopyrazoflor however, the security of this strategy in a highly revealed human population is not yet fully defined. The issue of safety occurs because of the fact that repeated exposure of Mtb-infected animals to mycobacterial antigens can initiate immune-mediated pathology. Specifically, the exposure of Mtb-infected guinea pigs to either live mycobacteria or mycobacterial antigens results in necrotic swelling at the site of challenge, a response that has been termed the Koch trend (Koch, 1891). Even though cellular and molecular determinants of this response are undefined, it appears that the severity of the Koch trend depends on the dose of antigen, as lower doses of antigen are used to induce a delayed-type hypersensitivity response; this is the basis for the current skin test for detecting latently infected individuals (High, 1944). A damaging focal response at the site of initial illness can also be induced by repeated vaccine (BCG or DNA) challenge of Mtb-infected animals. This prospects to the development of severe pathology, including necrosis and improved granulocyte influx in preexisting lesions in the lung (Turner et al., 2000; Moreira et al., 2002; Taylor et al., 2003). The perceived Tyclopyrazoflor risk of improved pathological consequences as a result of Tyclopyrazoflor vaccination in previously revealed humans has lead to initial safety screens becoming performed on novel vaccine candidates (Sander et al., 2009). However, results from these types of studies should be interpreted cautiously, as the degree of repeated antigen exposure will differ greatly depending on the level of disease in the community. Therefore, there is a concern that adult postexposure vaccination to prevent the reactivation of TB could lead to pathology, particularly in highly revealed populations. The importance of the cytokine IFN- in the protecting response to Mtb is definitely well established (North and Young, 2004); however, the mediator of pathological Tyclopyrazoflor reactions has not been recognized. The Koch-like pathologies explained in the previous paragraph were consistently associated with neutrophil influx and could therefore become mediated by IL-17 (Miyamoto et al., 2003; Kolls and Linden, 2004). Further, although IL-17 is definitely induced during mycobacterial illness, it does not play a significant role during the early period of illness (up to 100 d; Khader and Cooper, 2008). In addition, IFN- is able to regulate the IL-17 response during BCG illness (Cruz et al., 2006), and in Tmem1 the absence of IFN- signaling in the stroma, an increase in neutrophil involvement in the TB granuloma is seen (DesVignes and Ernst, 2009); these data reflect an important regulatory activity for IFN- in the control of pathology in TB. Consequently, we hypothesized that repeated antigen exposure would allow the IL-17 response to conquer the IFN-Cmediated rules and therefore mediate immunopathological effects, and that the Koch trend may result from an unregulated IL-17 response. To test.