Objective-Thrombotic events and immunoinflammatory processes take place next to each other during vascular remodeling in atherosclerotic lesions. In this study we investigated the interaction of platelets with dendritic cells (DCs). Methods and Results-The rolling of DCs on platelets was mediated by PSGL-1. Firm adhesion of DCs was mediated through integrin ␣ M ␤ 2 (Mac-1). In vivo, adhesion of DCs to injured carotid arteries in mice was mediated by platelets. Pretreatment with soluble GPVI, which inhibits platelet adhesion to collagen, substantially reduced recruitment of DCs to the injured vessel wall. In addition, preincubation of DCs with sJAM-C significantly reduced their adhesion to platelets. Coincubation of DCs with platelets induced maturation of DCs, as shown by enhanced expression of CD83. In the presence of platelets, DC-induced lymphocyte proliferation was significantly enhanced. Moreover, coincubation of DCs with platelets resulted in platelet phagocytosis by DCs, as verified by different cell phagocytosis assays. Finally, platelet/DC interaction resulted in apoptosis of DCs mediated by a JAM-Cdependent mechanism. Conclusions-Recruitment of DCs by platelets, which is mediated via CD11b/CD18 (Mac-1) and platelet JAM-C, leads to DC activation and platelet phagocytosis. This process may be of importance for progression of atherosclerotic lesions. 3 In atherosclerotic plaques, the number of DCs is substantially enhanced and DCs preferentially accumulate at rupture-prone regions. 4,5 Recently, DCs were shown to accumulate in the intima of atherosclerosis-predisposed regions of the aorta of C57BL/6 mice. 6 However, the mechanisms involved in the recruitment of circulating DCs at site of vascular lesions are poorly understood so far.It is well recognized that platelets rapidly adhere to the extracellular matrix of the subendothelium at sites of vascular lesions. If this process is controlled, platelets passivate vascular injury and initiate the healing process. 1 However, uncontrolled platelet-mediated thrombus formation leads to acute thrombotic occlusion or plaque progression resulting in, eg, acute coronary syndrome. 7 Platelet-mediated cell recruitment to the atherosclerotic plaque plays a central role for vascular repair mechanisms. DCs participate both in the innate and adaptive immune system and represent highly specialized antigen-presenting cells. 8 Thereby, they are capable of stimulating naive, memory, and effector T-cells, as well as activating natural killer cells. 8 Proteins are internalized by phagocytosis, degraded into short peptides, and presented via the MHC II receptors. 9 During maturation, DCs express various adhesion receptors, which enable DCs to interact with other cell types and mediate homing of DCs to target tissues. 4,8 Original The present study evaluates the role of platelets for DC adhesion to vascular lesions and shows that platelets play a critical role for the recruitment and function of DCs. Materials and MethodsDCs were generated from buffy coats derived fr...

This review analysis consists of the antitumor activity and toxic deaths reported in single agent Phase I clinical trials using cytotoxic compounds published from 1972 to 1987. A total of 6639 patients with a variety of solid tumors and hematological malignancies were accrued in 211 trials studying 87 compounds. The median number of patients per trial was 28 (range: 7-111) and the median of the median ages reported in the individual trial was 56 (range of individual age: 2 to 93 years). Ten percent of the trials enrolled pediatric patients (less than 18 years), but the exact numbers of children were not always given or separated from the adult patients. Nine percent of the patients had received no prior treatment, 75% were pretreated either with chemotherapy alone (50%) or radio- plus chemotherapy (25%). Radiotherapy alone was administered to 11% of the patients and the remaining 5% of the patients received prior treatments which was not specified. The most frequent tumor types were those of the gastrointestinal tract (22%) and the respiratory tract (19%). The frequency of the remaining malignancies was less than 10% of all patients. There were 23 (0.3%) complete responders and 279 (4.2%) partial responders for an overall response rate of 4.5% among all entries. Toxic deaths were rare and reported in only 31 patients (0.5% of the entire population). Responses were usually observed in chemosensitive tumor types. Despite a low response rate reported during the first phase of cytotoxic drug development, the present analysis shows that some therapeutic benefit can be achieved.

The cytotoxic mechanisms of thionins from Viscum album L., the viscotoxins, were investigated in human granulocytes and lymphocytes. The time course of viscotoxin effects indicate accidental cell death, i.e. membrane permeabilization, degradation of cytoplasm and chromatin, swelling of mitochondria with loss of their cristae, and generation of reactive oxygen intermediates within 1±2 h, followed by secondary apoptosis-associated events. The viscotoxin homologue purothionin from whole-wheat flour and viscotoxin B, however, did not induce cell death in cultured lymphocytes. Cytotoxicity of cationic and amphipathic viscotoxin was prevented only by cleavage of its disulphide bridges.Keywords: thionins; viscotoxins; reactive oxygen intermediates; apoptosis.The viscotoxins are toxic proteins from Viscum album L., isolated first by Winterfeld and co-workers [1] and by Samuelsson and co-workers [2,3]. They are related to the family of a-and b-thionins, a group of highly basic cysteine-rich polypeptides found in the endosperms of several Gramineae, which consist of 45±47 amino acids, and have three or four disulfide bridges (reviewed in [4]). Several thionins have been sequenced and they appear to be highly homologous at the amino-acid level [4,5]. The cysteine residues, which form three disulfide bridges, the thyrosine residue at position 13, and in addition, the distribution of hydrophobic and hydrophilic residues are highly conserved [4±7]. Because of their positive charge, thionins interact with the negatively charged phospholipids making up the membranes, resulting in either pore formation or a specific interaction with a specific lipid domain [4]. The positively charged viscotoxins were found to form complexes with the negatively charged DNA, resulting in protection of the double helix against thermal denaturation [8], but, leaving the DNA conformation unaffected.Thionins are toxic to laboratory animals, insect larvae, bacteria, yeasts and mammalian cells (reviewed in [4,9]). However, there are only few reports concerning the cytotoxicity of viscotoxin to cultured cell lines. Konopa et al. [10] reported that the isolated polypeptides exhibited cytotoxic activity against the human tumour cell lines KB and HeLa in a concentration range (ED 50 ) of 0.2±1.7 mg´mL 21 . Surprisingly, Yoshida sarcoma cells were found to be more sensitive to viscotoxin than the leukaemia cell line . However, the mechanisms of viscotoxin-mediated cytotoxicity are unclear.To analyse their cytotoxic properties, we cultured peripheral blood cells with thionins from mistletoe (viscotoxin) and from whole-wheat flour (purothionin), and apoptosis-inducing proteins [12] such as mistletoe lectin (ML I) and the RNA synthesis-inhibiting Streptomyces toxin actinomycin D. The galactose-binding ML I belongs to the family of ribosomeinhibiting proteins with a lectin B chain linked by hydrophobic bonds and disulfide bridges to the catalytic A chain, which is a highly specific N-glycosidase and cleaves the N-glycosidic bond of at least one particular adenin...

. Additionally, we observed an activation of caspase 3, caspase 8 and caspase 9 upon apoptotic Fas triggering. In summary, we demonstrate that IFN-␥ and TNF-␣ sensitize primarily apoptosis-resistant ESCs to Fas-mediated cell death. This might be due to an upregulation of Fas expression, and apoptosis seems to be mediated by active caspase 3, caspase 8 and caspase 9. The observed pro-apoptotic effect of IFN-␥ and TNF-␣ on ESCs could play an important role in the modulation of early implantation.

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