, 1999; Decker et al., 2000; Weeratna et al., 2000; Near et al., 2002). The efficacy of BCG vaccination varies widely in human beings, leading to renewed efforts to develop

novel tuberculosis vaccines that induce protection at a more reliable level. Many candidate tuberculosis vaccines, including recombinant BCG strains, attenuated tuberculosis auxotrophs, various subunit preparations and DNA vaccines, have been developed and are currently VX-770 solubility dmso being tested actively in animals. Several of these immunogenic preparations have been shown to elicit protective responses that approach the protective efficacy of BCG when tested in primary infection models (Dhillon & Mitchison, 1994; Baldwin et al., 1998; Delogu et al., 2002). However, the therapeutic effectiveness of these new tuberculosis vaccines in postexposure models is still uncertain. In some studies, these vaccines even result in disease exacerbation (Turner et al., 2000; Taylor Selleck Ceritinib et al., 2003). The key point in identifying components for postexposure vaccines is to understand the dynamic transition of the bacteria from active multiplication to dormancy to reactivation. Recently, research was performed

on antigen characteristics of dormant bacteria such as those expressed by the DosR regulon or the rpf genes (Yeremeev et al., 2003; Leyten et al., 2006). Memory T cells specific for early antigens can survive the initial stage of infection and might not substantially contribute to the containment of bacteria during dormancy when

Mtb expresses different antigen signatures. T cells directed to late-stage antigens could bypass some of the regulatory mechanisms www.selleck.co.jp/products/Vorinostat-saha.html in the chronically infected host if they are primed outside the existing network of effector and regulatory T cells that are involved in antigen recognition in the initial stage of infection. From this perspective, developing a postexposure vaccine containing a late-stage antigen is rational and feasible. In this study, we created a vaccine containing the late-stage antigen HspX (Rv2031), which was coadministered with the early antigen Ag85b(Rv 1886c) and C/E. CpG and aluminum adjuvants were added to the mixture of antigens, but this resulted in little reduction of disease progression in Mtb-challenged guinea pigs as determined by lesion scores and bacterial loads. The goal of the coadministration is to make this vaccine also available as a prophylactic vaccine and to obtain the maximum impact on all stages of Mtb infection, which still need to be verified through test series. Another study using the vaccine as a booster to the BCG prime vaccination is being carried out by our team. The animal model used in this study still requires optimization to mimic the natural infection and status of postexposure, although Wang et al.

The latter event facilitated the dissociation of Bim from Bcl-2 without affecting Bim abundance in IL-15-treated CD8αα+ iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl-2 or removal

of Bim from CD8αα+ iIELs promoted their survival in Il15ra−/− mice. Taken together, IL-15 promotes CD8αα+ iIEL survival by both increasing Bcl-2 levels and dissociating Bim from see more Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt-ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal. Intestinal intraepithelial lymphocytes (iIELs) are T cells located between the epithelial cells lining the intestinal lumen. In the small intestine of C57BL/6J (B6J) mice, approximately half the iIELs are conventional T cells, while the other half are CD4−CD8β−CD8α+ (CD8αα+) cells that consist of 30% TCRαβ+ (αβ) cells and 70% TCRγδ+ LY2606368 in vivo (γδ) cells. CD8αα+ iIELs are developmentally and functionally distinct from conventional T cells. Most CD8αα+ iIEL precursors go through a thymic stage of development, and complete maturation in the intestine [1-4]. Functionally, CD8αα+ iIELs

appear to assume an immune regulatory role in the gut mucosa, as implied by their production of immune suppressive cytokines, such as TGF-β and IL-10, and by their ability to inhibit colitis [5, 6]. IL-15 is a pleiotropic cytokine widely expressed with its exclusive high affinity receptor IL-15Rα, while IL-15Rβγ chains are the intermediate affinity receptors for both IL-15 and IL-2 and expressed mainly by hematopoietic cells [7-9]. IL-15 and IL-15Rα form a complex during synthesis

in the ER and exist as transmembrane and soluble forms [10]. Cyclin-dependent kinase 3 The transmembrane IL-15–IL-15Rα complex is “in trans presented” to the IL-15Rβγ on neighboring cells for usage [11]. This mode of IL-15 usage has been implied to control the homeostasis of several lymphoid lineages, including CD8αα+ iIELs [1, 12-14]. More than 90% of CD8αα+ iIELs are missing in Il15−/− [15], Il15ra−/− [16], and Il15rb−/− [17] mice. Bone marrow chimera studies indicate that parenchymal IL-15Rα is essential for the development and maintenance of CD8αα+ αβ and γδ iIELs in the intestine [2, 14]. IL-15 also sustains the survival of primary CD8αα+ αβ and γδ iIELs in vitro [2, 18, 19]. As specific expression of IL-15Rα in the intestinal epithelial cell (IEC) of Il15ra−/− mice restores CD8αα+ iIELs and their Bcl-2 level [1], Bcl-2 has been implicated in the prosurvival effect of the IL-15 system. However, overexpression of Bcl-2 only moderately restored CD8αα+ γδ iIELs in Il15−/− mice [20], suggesting that the increase in the level of Bcl-2 alone is not sufficient to account for the prosurvival effect of IL-15.