Aurora A and B kinases are closely related kinases involved in regulating separate points in the cell cycle. This review highlights the rationale for Aurora kinases as cancer targets and examines the currently known Aurora kinase inhibitors in the patent and scientific literature. The known crystal structures of the Aurora kinases are described with relevance to bound ligand interactions and the prospect of the generation of drug-resistant mutant forms. The potential for selectivity versus primary cells will also be discussed. The status of the inhibitors in clinical development is described.
Kaposi sarcoma-associated herpesvirus (KSHV) is etiologically linked to Kaposi sarcoma (KS), a tumor genetically akin to lymphatic endothelial cells (LECs). IntroductionKaposi sarcoma (KS) lies at the interface of infection and malignancy. [1][2][3] It is a neoplasm common in para-Mediterranean populations, endemic in parts of sub-Saharan Africa, and frequently seen in patients with AIDS. 3 KS is a tumor of microvascular endothelium and gene-expression microarray (GEM) studies suggest that it belongs to the lymphatic endothelial lineage. 4 KS-associated herpesvirus (KSHV) is linked to the etiopathogenesis of KS 5,6 and certain lymphoproliferations, including primary effusion lymphoma (PEL) 7 and a plasmablastic variant of multicentric Castleman disease (MCD). 8 The risk of developing KS, PEL, and MCD is significantly higher during acquired or iatrogenic immunosuppression. 3,9 Moreover, posttransplantation KS can resolve when immunosuppressive therapy is reduced, 9 and the introduction of effective antiretroviral therapy for HIV infection has led to a decline in KS incidence. 3 These observations indicate that disruption of host-pathogen equilibrium promotes the precipitation of these neoplasms.Herpesviruses have evolved elaborate mechanisms to modulate host immune responses. 10 EBV is the prototype of a cancerinducing human herpesvirus. [11][12][13] EBV modulates cellular antiviral responses in various ways, including down-regulation of major histocompatibility complex (MHC) proteins 14 and blocking proteasomal degradation and antigen synthesis. 15,16 However, EBV also enhances antiviral immune responses by way of its latent membrane protein 1 (LMP1), which up-regulates MHC-I. 17,18 This leads to cytotoxic T-cell (CTL)-mediated elimination of EBV latency III cells, promoting the transition to latency I-infected B cells. As with KSHV, immunosuppression disturbs the host-virus equilibrium leading to an increased incidence of EBV-associated tumors. 12 Several KSHV proteins regulate host innate or adaptive immune responses. 19 Among these there are 5 viral proteins that block the innate antiviral interferon (IFN) response, including orf45, 20 viral , 21 viral interferon regulatory factors (vIRFs) 1 and 2, [22][23][24][25][26][27] and the transactivator of the lytic cycle, RTA. 28 Furthermore 2 viral modulators of immune response (vMIRs) act as E3 ubiquitin ligases and down-regulate MHC-I. 29,30 vMIR2 also down-regulates ICAM-1 and CD86 by enhancing endocytosis, lysosomal targeting, and proteasome-mediated degradation 31,32 and increases endocytosis of CD1d, leading to the escape of infected cells from NKT cells. 33 The majority of these viral mechanisms are used during the lytic viral cycle, when most of these proteins are expressed and a vigorous host response occurs to curtail viral dissemination.Immune regulation during KSHV latency remains insufficiently characterized. However, the KSHV lytic and latent gene profiles are not mutually exclusive. Some lytic proteins, such as RTA and vMIR2, are expressed during the...
Summary. Dendritic cells (DCs) are the most potent antigenpresenting cells described to date. In human peripheral blood, both myeloid and lymphoid subsets of DCs have been identified. In contrast, cord blood (CB) DCs have recently been described as being exclusively of the immature CD11c 2 lymphoid DC subset. Using an alternative method of enrichment, based on a negative selection system, both lymphoid (HLA-DR 1 CD123 111 CD11c 2 CD33 2 ) and myeloid (HLA-DR 11 CD123 1 CD11c 1 CD33 1 ) DCs were identified in CB. Although the majority of CB DCs showed a lymphoid phenotype, a significant number of CD11c 1 myeloid DCs (25´6%^14´5%, n 13) were also present.Other markers, such as CD80 and CD83, were negative in both subsets. Analyses of the allostimulatory capacity of both subsets showed that freshly isolated CB lymphoid DCs failed to induce a potent allostimulation of naive CB T cells. These features are therefore consistent with previous work reporting an immature phenotype for lymphoid DCs in adult blood. The significance of the inverted CD11c 1 /CD11c 2 ratio observed in CB DCs (1:3) with respect to adult blood DCs (3:1) remains to be explained.
Exposure to urban particulate matter (UPM) exacerbates asthmatic lung inflammation. Lung dendritic cells (DCs) are critical for stimulating T cell immunity and in maintaining airway tolerance, but they also react to airway UPM. The adjuvant role of UPM in enhancing primary immune responses by naive cells to allergen has been reported, but the direct effects of UPM-activated DCs on the functionality of human memory CD4 T cells (Tms), which constitute the majority of T cells in the lung, has not been investigated. Blood CD1c 1 DCs were purified and activated with UPM in the presence or absence of house dust mite or tetanus toxoid control antigen. 5-(and -6)-Carboxyfluorescein diacetate succinimidyl ester-labeled blood Tms were cocultured with autologous DCs, T cell proliferation and effector function were assessed using flow cytometry, and secreted cytokines were measured by combined bead array. UPM-DCs elicited IFN-g and IL-13 secretion and induced proliferation in Tms isolated from both allergic patients with asthma and healthy control subjects, whereas only IL-13 was produced by Tms from patients with atopic asthma stimulated by house dust mite-loaded DCs. UPM-DCs drove the expansion and differentiation of a mixed population of Th1, Th2, and Th17 cell effectors through a mechanism that was dependent on major histocompatibility class II but not on cytokine-driven expansion. The data suggest that UPM not only has adjuvant properties but is also a source of antigen that stimulates the generation of Th2, Th1, and Th17 effector phenotypes, which have been implicated in both exacerbations of asthma and chronic inflammatory diseases.
Recent data suggests that graft-versus-host disease (GVHD) is initiated by host APCs. Blockade of CD40:CD154 interactions between APCs and T cells in vivo induces T cell tolerance to host alloantigen and dramatically reduces GVHD. Because allogeneic cord blood (CB) transplantation results in a lower incidence and severity of acute GVHD compared with bone marrow transplantation, we have investigated whether CB T cells can express CD154 in response to stimulation by allogeneic monocyte-derived dendritic cells (MDDC) and have used 5- (and 6-)carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling in combination with intracellular cytokine analysis to assess the proliferation and cytokine profiles of alloantigen-responsive cells. CB T cells stimulated with allogeneic MDDC showed stronger proliferation than adult blood T cells. Surface CD154 expression was detected in the actively dividing CFSElow populations of both the CD4+ and CD4− subsets and was brightest in cells that had divided the most. Assessment of supernatants from MDDC-stimulated CB and adult blood T cells showed no significant difference in the levels of either IFN-γ or TNF-α, but CB T cell supernatants did show a significant lack of detectable IL-2. Intracellular cytokine analysis revealed that dividing CB T cells had been primed to produce IFN-γ, TNF-α, and IL-2 on restimulation. Further phenotype analysis showed that 75% of CB T cells producing IFN-γ were CD8+. These data suggest that MDDC-stimulated CB T cells express functional CD154 and provide enough costimulation for dendritic cells to prime naive CD8+ CB T cells and induce type 1 cytokine production.
The aim of this study was to determine whether active systemic lupus erythematosus (SLE) is associated with recruitment of resting CD45RA+ T cells or reactivation of CD45RO+ memory T cells. Three-colour immunofluorescence was used to determine CD45 isoform expression by CD4+ T cells from 28 patients with SLE. Newly recruited and highly differentiated primed T cells were distinguished by their CD45RB expression. The pattern of CD45 isoform expression varied directly with time since the onset of symptoms in patients with active SLE. Shortly after symptoms appeared, most cells were CD45RA+ resting cells or CD45RO(dull)RB(bright) early primed cells. However, over the course of active disease, patients accumulated CD45RO(bright)RB(dull) cells which represent an advanced state of differentiation. The switch from an early to late primed phenotype correlated significantly with time since the onset of symptoms. The recruitment of resting T cells in active SLE, rather than the simple reactivation of existing memory clones, has implications for understanding the pathology of this disease and for treating it.
Kaposi's sarcoma-associated herpesvirus (KSHV) is causally related to Kaposi's sarcoma (KS), the most common malignancy in untreated individuals with HIV/AIDS. The adaptive T-cell immune response against KSHV has not been fully characterized. To achieve a better understanding of the antigenic repertoire of the CD8 and CD4 T-cell responses against KSHV, we constructed a library of lentiviral expression vectors each coding for one of 31 individual KSHV open reading frames (ORFs). We used these to transduce monocyte-derived dendritic cells (moDCs) isolated from 14 KSHV-seropositive (12 HIV-positive) and 7 KSHV-seronegative (4 HIV-positive) individuals. moDCs were transduced with up to 3 KSHV ORFs simultaneously (ORFs grouped according to their expression during the viral life cycle). Transduced moDCs naturally process the KSHV genes and present the resulting antigens in the context of MHC class I and II. Transduced moDCs were cultured with purified autologous T cells and the CD8 and CD4 T-cell proliferative responses to each KSHV ORF (or group) was assessed using a CFSE dye-based assay. Two pools of early lytic KSHV genes ([ORF8/ORF49/ORF61] and [ORF59/ORF65/K4.1]) were frequently-recognized targets of both CD8 and CD4 T cells from KSHV seropositive individuals. One pool of late lytic KSHV genes ([ORF28/ORF36/ORF37]) was a frequently-recognized CD8 target and another pool of late genes ([ORF33/K1/K8.1]) was a frequently-recognized CD4 target. We report that both the CD8 and CD4 T-cell responses against KSHV are skewed towards genes expressed in the early and late phases of the viral lytic cycle, and identify some previously unknown targets of these responses. This knowledge will be important to future immunological investigations into KSHV and may eventually lead to the development of better immunotherapies for KSHV-related diseases.
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