SummaryImmunohistochemical analysis of challenge sites such as skin and the peritoneal cavity has identified neutrophils as virtually the sole cellular participants in acute bacterial inflammation, peak influx occurring 24-48 h in advance of mononuclear cell populations associated with adaptive immunity This study challenges the general applicability of this paradigm. We demonstrate here that the earliest detectable cellular response after inhalation ofMoraxdla catarrhalis organisms is the recruitment of putative class II major histocompatibflity complex-bearing dendritic cell (DC) precursors into the airway epithelium, the initial wave arriving in advance of the neutrophil influx. Unlike the neutrophils which rapidly transit into the airway lumen, the DC precursors remain within the epithelium during the acute inflammatory response where they differentiate, and develop the dendriform morphology typical of resident DC found in the normal epithelium. During the ensuing 48-h period, these cells then migrate to the regional lymph nodes. No comparable DC response was observed after epidermal or intraperitoneal challenge, and it may be that mucosal surfaces are unique in their requirement for rapid DC responses during acute inflammation. We hypothesize that the role of the DC influx during acute inflammation may be surveiUance for opportunistic viruses, and that this covert protective mechanism is operative at a restricted number of mucosal tissue sites. p revious reports from this laboratory have established the importance of dendritic cells (DC) as APC within normal lung tissue (1, 2), and have additionally shown that a functionally and morphologically identical DC population exists within the epithelial lining of the conducting airways of both humans (3) and rodents (4, 5), where they form a contiguous network analogous to the Langerhans cell (LC) population in the epidermis.We have also recently presented evidence that the density, distribution, and surface phenotype of airway DC populations reflects the level of stimulation provided by inhalation of airborne irritant stimuli (5). Moreover, brief exposure to aerosolized bacterial LPS was demonstrated to induce a transient increase (,o50%) in the density of airway intraepithelial DC during the 24-48-h period after exposure, suggesting active participation of DC in the acute inflammatory response (5). The present study sought to further elucidate the role of DC in acute inflammation in the airways, employing a much more potent inhaled stimulus in the form of whole bacteria. Materiah and MethodsAnimals. Specific pathogen-free (SPF) adult PVG rats were used in these experiments. They were barrier housed under dust-free conditions, as detailed previously (5).Aerosol Exposure The animals were exposed for 60 rain to an aerosol of heat-killed MoraxeUa catarrhalis organisms (clinical hospital isohte) suspended in normal saline at '~109 CFU/ml.Antibodies and Iraraunostaining. The mAbs Ox6 (Ia), Ox19 (CDS; pan T cell), Ox12 (r light chains; pan B cell) (6), and Ox 42 (~ cha...
A key rate-limiting step in the adaptive immune response at peripheral challenge sites is the transmission of antigen signals to T cells in regional lymph nodes. Recent evidence suggests that specialized dendritic cells (DC) fulfill this surveillance function in the resting state, but their relatively slow turnover in most peripheral tissues brings into question their effectiveness in signaling the arrival of highly pathogenic sources of antigen which require immediate mobilization of the full range of host defenses for maintenance of homeostasis. However, the present report demonstrates that recruitment of a wave of DC into the respiratory tract mucosa is a universal feature of the acute cellular response to local challenge with bacterial, viral, and soluble protein antigens. Consistent with this finding, we also demonstrate that freshly isolated respiratory mucosal DC respond in vitro to a variety of CC chemokines as well as complementary cleavage products and N-formyl-methionyl-leucine-phenylalanine. This suggests that rapid amplification of specific antigen surveillance at peripheral challenge sites is an integral feature of the innate immune response at mucosal surfaces, and serves as an “early warning system” to alert the adaptive immune system to incoming pathogens.
Therapeutic use of IL-2 can generate antitumor immunity; however, a variety of different mechanisms have been reported. We injected IL-2 intratumorally (i.t.) at different stages of growth, using our unique murine model of mesothelioma (AE17; and AE17 transfected with secretory OVA (AE17-sOVA)), and systematically analyzed real-time events as they occurred in vivo. The majority of mice with small tumors when treatment commenced displayed complete tumor regression, remained tumor free for >2 mo, and survived rechallenge with AE17 tumor cells. However, mice with large tumors at the start of treatment failed to respond. Timing experiments showed that IL-2-mediated responses were dependent upon tumor size, not on the duration of disease. Although i.t. IL-2 did not alter tumor Ag presentation in draining lymph nodes, it did enhance a previously primed, endogenous, tumor-specific in vivo CTL response that coincided with regressing tumors. Both CD4+ and CD8+ cells were required for IL-2-mediated tumor eradication, because IL-2 therapy failed in CD4+-depleted, CD8+-depleted, and both CD4+- and CD8+-depleted C57BL/6J animals. Tumor-infiltrating CD8+ T cells, but not CD4+ T cells, increased in association with a marked reduction in tumor-associated vascularity. Destruction of blood vessels required CD8+ T cells, because this did not occur in nude mice or in CD8+-depleted C57BL/6J mice. These results show that repeated doses of i.t. (but not systemic) IL-2 mediates tumor regression via an enhanced endogenous tumor-specific CTL response concomitant with reduced vasculature, thereby demonstrating a novel mechanism for IL-2 activity.
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