D endritic cells (DCs) have a central role in the initiation and control of T cell-mediated immunity. Immature DCs residing in tissues endocytose soluble antigens, microbes, or apoptotic cells, and receive microbial or inflammatory maturation cues depending on the type of pathogen and the nature and extent of tissue damage (1-3). Maturing DCs migrate to lymph nodes via afferent lymphatics where they complete their maturation and present peptides derived from protein degradation on MHC class I and class II molecules to CD8 and CD4 T cells, respectively (2). The type and composition of maturation signals received by DCs determine whether they induce productive T cell responses or tolerance (4, 5).Because of their potent immunostimulatory capacity, there is much interest in employing DCs as tumor vaccines to induce effector and long-term memory CD4 and CD8 T cells with broad tumor antigen (TA) specificities (6-8). Early-stage trials using ex vivo TA-loaded and matured monocyte-or CD34 ϩ progenitorderived DCs have provided some evidence for clinically beneficial immunostimulatory effects (9, 10). However, many variables remain to be explored, including antigen sources and modes of DC antigen-loading. Most commonly, DCs are pulsed with synthetic TA-derived MHC-binding peptides (11,12). This approach is constrained by limited knowledge of TA, their natural and immunoselected variation within and among tumors, and by the MHC allele-specific restrictions of peptide-binding, thus producing narrow repertoires of antigen-specific T cells. Other methods include transfection of DCs with tumor-derived RNA, the use of viral vectors for expression of TA, and facilitating DC uptake of tumorderived exosomes, apoptotic tumor cells, or recombinant proteins for antigen processing and presentation (13)(14)(15)(16)(17)(18)(19). Moreover, DC expression of Ig Fc receptors (Fc␥R) can be exploited for targeting immune complexes and antibody-coated tumor cells to DCs (20,21). Exposure of DCs to anti-syndecan mAb-opsonized myeloma cells promotes efficient in vitro cross-priming of cytotoxic T lymphocytes, yielding results that are superior to cross-presentation of TA from apoptotic tumor cells (22).This immunization mode is appealing because it may operate in vivo and contribute to the beneficial effects of some antibody-based cancer therapies (23,24). Hence, antibody targeting of surface molecules that are absent from most cell types and tissues but are frequently tumor-associated could be a viable approach to inducing tumor immunity. Suitable candidate molecules are MHC class I chain-related proteins A (MICA) and B (MICB), which are distantly related to MHC class I and function as ligands of the NKG2D receptor on natural killer cells and T cell subsets (25,26). In healthy individuals, the tissue distribution of MIC is restricted to variable areas of gastrointestinal epithelium (25, 27). However, MICs are abundantly expressed in many lung, breast, kidney, ovarian, prostate, gastric, and colon carcinomas, and melanomas, as well as in certai...
One of the most striking changes in the primary lymphoid organs during human aging is the progressive involution of the thymus. As a consequence, the rate of naïve T cell output dramatically declines with age and the peripheral T cell pool shrinks. These changes lead to increased incidence of severe infections and decreased protective effect of vaccinations in the elderly. Little is, however, known of the composition and function of the residual naïve T cell repertoire in elderly persons. To evaluate the impact of aging on the naïve T cell pool, we investigated the quantity, phenotype, function, composition, and senescence status of CD45RA(+)CD28(+) human T cells--a phenotype generally considered as naïve cells--from both young and old healthy donors. We found a significant decrease in the number of CD45RA(+)CD28(+) T cells in the elderly, whereas the proliferative response of these cells is still unimpaired. In addition to their reduced number, CD45RA(+)CD28(+) T cells from old donors display significantly shorter telomeres and have a restricted TCR repertoire in nearly all 24 Vbeta families. These findings let us conclude that naïve T cells cannot be classified with conventional markers in old age.
Background: RNA interference (RNAi) is a cellular pathway of gene silencing in a sequence-specific manner at the messenger RNA level. The basic mechanism behind RNAi is the breaking of a double-stranded RNA (dsRNA) matching a specific gene sequence into short pieces called short interfering RNA, which trigger the degradation of mRNA that matches its sequence. In this study, we explored the effects of RNAi in reducing the target gene expression in human myeloid leukemia cell lines. Methods: Four myeloid leukemia cell lines (HL-60, U937, THP-1, and K562) were transfected with dsRNA duplexes corresponding to the endogenous c-raf and bcl-2 genes and the gene expression inhibition was assessed. The effect of RNAi on cell differentiation was studied; the apoptosis induction and the sensitization of the leukemia cell lines to etoposide and daunorubicin were quantified by flowcytometric methods. Results: Transfection of the myeloid leukemia cell lines with dsRNA corresponding to c-raf and bcl-2 genes decreased the expression of Raf-1 and Bcl-2 proteins. RNAi for c-raf gene blocked the appearance of the monocytic differentiation induced by treatment with TPA. Combined RNAi for c-raf and bcl-2 induced apoptosis in HL-60, U937, and THP-1 cells and increased chemosensitivity to etoposide and daunorubicin. Conclusions: RNAi is a functional pathway in human myeloid leukemia cell lines and combined RNAi of c-raf and bcl-2 genes may represent a novel approach to leukemia, providing a means to overcome the resistance to chemotherapeutic agents and ultimately to augment the efficacy of chemotherapy in myeloid leukemia.
BACKGROUND Ligand activation of peroxisome proliferator‐activated receptor γ (PPARγ) results in the inhibition of proliferation of various cancer cells. The aim of this study is to investigate the mechanisms of cell growth inhibition of hepatocellular carcinoma (HCC) cell lines by the PPARγ ligand, troglitazone. METHODS Six HCC cell lines were used to study the effects of troglitazone on cell growth by 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT) assay, on cell cycle by flow cytometry, and on the cell cycle‐regulating factors of late G1 phase by Western blotting. Apoptosis assays were performed by flow cytometry using membrane, nuclear, cytoplasmic, and mitochondrial markers. Caspase inhibitors were used to analyze the mechanisms of apoptosis induced by troglitazone. RESULTS Troglitazone showed a potent dose‐dependent effect on the growth inhibition of all six HCC cell lines, which were suppressed to under 50% of control at the concentration of 10 μmol/L. The growth inhibition was linked to the G1 phase cell cycle arrest through the up‐expression of the cyclin‐dependent kinase inhibitors, p21 and p27 proteins, and the hypophosphorylation of retinoblastoma protein. Troglitazone induced apoptosis by caspase‐dependent (mitchondrial transmembrane potential decrease, cleavage of poly [adenosine diphosphate ribose] polymerase, 7A6 antigen exposure, Bcl‐2 decrease, and activation of caspase 3) and caspase‐independent (phosphatidylserine externalization) mechanisms. CONCLUSIONS Our data suggest that ligand activation of PPARγ by troglitazone or modified analogs of the thiazolidinedione class of drugs is a novel target for effective therapy against HCC, because of the significant antiproliferative and programmed cell death induction capabilities demonstrated by troglitazone. Cancer 2002;95:2243–51. © 2002 American Cancer Society. DOI 10.1002/cncr.10906
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