Melanoma, despite its aggressive growth characteristics, is an antigenic tumor expressing several characterized neo‐ and differentiation antigens. Dendritic cells (DC) when pulsed with definedpeptides have been shown to effectively induce melanoma‐specific T cell responses in humans and mice. These protect animals from challenge with melanoma, but so far have failed to induce significant tumor regressions. To study the efficacy of DC‐based anti‐tumor vaccinations, we set up a therapeutic model using C57BL/6J mice with established pulmonary and subcutaneous metastases induced by the B16‐melanoma cell line B78‐D14. Mice were vaccinated twice with 20,000 antigen‐presenting cells, either bone marrow‐derived DC or epidermal Langerhans cells (LC), which were loaded with the tyrosinase‐related protein 2 (TRP2) peptide. Generally, DC cultured with fetal calf serum (FCS) induced a dominant unspecific response. This was not seen using LC cultured without serum; however, vaccination with TRP2‐loaded FCS‐free LC alone failed to influence the growth of established B16 tumors. A reproducible reduction of tumor size and weight was only obtained if LC vaccinations with TRP2 were followedby a 5‐day treatment of mice with 200,000 IU IL‐2 intraperitoneally twice/daily. Omitting the TRP2 peptide abolished the efficacy of this combined treatment, demonstrating the crucial role of priming a melanoma‐specific T cell response. Microcytotoxic assays performed with spleen‐derived T cells and melanoma as well as congenic fibroblast lines as targets confirmed the TRP2‐dependent specificity of LC‐induced immune responses. Thus, despite the fact that tumor‐specific T cells were primed, an additional IL‐2‐dependent stimulus was needed to translate this immune response into a therapeutic effect against established tumors.
A fter out-of-hospital resuscitation, a 65-year-old hyperlipidemic patient with a history of smoking was brought to our hospital for early revascularization of an ST-segmentelevation myocardial infarction. Left ventricular function was found to be severely impaired with anterolateral akinesia by transthoracic echocardiography. Coronary angiography showed heavily calcified subtotal stenosis of the proximal left anterior descending and the left circumflex arteries. Immediate percutaneous coronary intervention was performed with stent placement in both affected vessels. Coronary blood flow was fully resorted, and the patient was referred to our intensive care unit. Experiencing severe brain damage despite early hypothermia treatment, the patient died 48 hours after percutaneous coronary intervention. Autopsy revealed a large acute anterolateral myocardial infarction including both papillary muscles. On histopathologic examination, cross-sections through the corresponding coronary arteries showed a large atheroma with negative remodeling, formation of mature lamellar bone including fatty bone marrow, and capillary neovascularization within the media of the vessel wall. Bone formation per se was not the main cause of lumen narrowing; however, it directly reflects late atheroma progression and plaque burden. No acute plaque rupture was found in the available cross-sections. The definite mechanism for the large myocardial infarction remains uncertain. Intimal Calcific Atherosclerosis With Enchondral OssificationVascular calcification has long been thought to represent a passive precipitation of calcium phosphate crystals within the vessel wall and is now recognized as an organized pathobiological process sharing many similarities with bone development and metabolism. Accumulation of oxidation-specific epitopes, such as minimally oxidized low-density lipoprotein and oxidized phospholipids, and cytokines, such as tumor necrosis factor-α and interleukin-6, in the subendothelial space of arteries, as well as mechanical and proinflammatory metabolic factors found in atheromatous plaques, represent the initiating process. Subpopulations of endothelial, mesenchymal, and hematopoietic cells become attracted to the lesion and deposit calcium in an attempt to resolve the inflammation in the vascular wall.1 Activation of osteogenic regulatory genes eventually promotes ectopic ossification and matrix calcification. The origin of vascular calcifying cells remains controversial and may be of both resident cells in the vasculature, as well as of osteogenic progenitors recruited from the circulation. Bone marrow-derived cells infiltrate the plaque via vasa vasorum from the adventitia or directly from the circulation on the luminal side. Circulating vascular smooth muscle cells reprogram their lineage toward osteochondrogenesis and contribute to intimal calcification. Once osteochondrogenic cells are established, mineralization proceeds within the extracellular matrix as a result of a complex and tightly regulated process orchestrated ...
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