The human lung T cell compartment contains many CD8 + T cells specific for respiratory viruses, suggesting that the lung is protected from recurring respiratory infections by a resident T cell pool. The entry site for respiratory viruses is the epithelium, in which a subset of lung CD8 + T cells expressing CD103 (αE integrin) resides. Here, we determined the specificity and function of CD103 + CD8 + T cells in protecting human lung against viral infection. Mononuclear cells were isolated from human blood and lung resection samples. Variable numbers of CD103 + CD8 + T cells were retrieved from the lung tissue. Interestingly, expression of CD103 was seen only in lung CD8 + T cells specific for influenza but not in those specific for EBV or CMV. CD103 + and influenza-reactive cells preferentially expressed NKG2A, an inhibitor of CD8 + T cell cytotoxic function. In contrast to CD103 -CD8 + T cells, most CD103 + CD8 + cells did not contain perforin or granzyme B. However, they could quickly upregulate these cytotoxic mediators when exposed to a type I IFN milieu or via contact with their specific antigen. This mechanism may provide a rapid and efficient response to influenza infection, without inducing cytotoxic damage to the delicate epithelial barrier.
Human bronchoalveolar lavage (BAL) has been described to contain, besides a large number of alveolar macrophages (AM) (approximately 95%), small numbers of monocyte-like cells (approximately 2%) and dendritic cells (DC) (approximately 0.4%). To separate AM (high autofluorescence) from DC, we used a fluorescence activated cell sorter (FACS) to separate BAL cells into a low autofluorescent (LAF) fraction and a high autofluorescent (HAF) fraction. Immunocytologic and functional properties of these fractions were investigated. The LAF fraction was composed of acid phosphatase (APh)- and RFD9-negative cells, which were strongly positive for HLA-DR, L25, RFD1, and CD68. A portion of these cells expressed CD1a (22%) and My4 (60%). The marker pattern of these cells is reminiscent to that of intraepithelial bronchial DC and to that of blood DC. The majority of the LAF cells had a monocyte-like morphology, but after overnight culture the percentage of LAF cells with long cytoplasmic extensions (DC morphology) was strongly augmented (from 18 to 51%). The HAF fraction contained 100% AM, strongly positive for APh, HLA-DR, CD68, RFD7, and RFD9. In culture, the LAF cells formed clusters with T cells and vigorously stimulated the proliferation of allogeneic T cells and naive (CD45RO-negative) T cells. BAL and LAF cells produced higher responses in nonsmokers than in smokers. In contrast, HAF cells did not form clusters with T cells and did not stimulate allogeneic T cell proliferation. HAF cells even suppressed mitogen-driven T cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)
Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. Method: Gemcitabine 1250 mg m 72 was administered on day 1 and day 8 and cisplatin 80 mg m 72 was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1 -31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5 -7 months) with a median survival from registration of 9.6 months (95% CI 8 -12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule.
Mononuclear phagocytes and dendritic cells (DC) play an important role in the immune response in the lung. DC act in the afferent phase of the immune response by presenting antigen to T cells, while macrophages play a role in the efferent phase by exerting phagocytic/cytotoxic functions. We investigated the localization and the marker pattern of these cells in the human lung. Macrophages, identified as large, rounded, acid phosphatase-positive cells, were mainly detected in the alveolar spaces, in the lumen of the bronch(iol)us, and in the bronchoalveolar lavage (BAL). They were positive for major histocompatibility complex (MHC) class II antigens (DR, DQ), CD68, RFD7, RFD9, and partly positive for RFD1. Irregularly shaped cells with a marker pattern comparable to that of blood-derived DC (positive for DR, DQ, L25, RFD1, and CD68) were predominantly observed in the epithelium and subepithelial tissue of the bronch(iol)us and in the bronchus-associated lymphoid tissue. In the epithelium, approximately 30% of these cells were positive for CD1a (OKT6). In the subepithelial tissue, these DC formed characteristic small clusters with T cells. The BAL, the alveolar spaces, and the alveolar walls contained only a small number of DC. These immunohistologic data suggest that the bronch(iol)us is well equipped to initiate immune responses. The high number of macrophages in the alveolar compartment, which have been described to suppress T cell proliferation, together with low numbers of DC, makes the alveolar compartment less suited for mounting an immune response.
Our data suggest that dendritic cells are involved in asthmatic inflammation and that corticosteroids may downregulate the number of dendritic.
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