PubMed · 9442947
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M Scherk-Nixon. 1998. Using the fentanyl patch.. https://pubmed.ncbi.nlm.nih.gov/9442947/
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Dendritic cells (DC) bring Ags into lymphoid organs via lymphatic vessels. In this study, we investigated the possibility that the sympathetic neurotransmitter norepinephrine (NE) influences DC migration. Murine epidermal Langerhans cells mobilization is enhanced by systemic treatment with the alpha(2)-adrenergic antagonist yohimbine and inhibited by local treatment with the specific alpha(1)-adrenergic antagonist prazosin (PRA). Consistently, NE enhances spontaneous emigration of DC from ear skin explants, and PRA inhibits this effect. In addition, local treatment with PRA during sensitization with FITC inhibits the contact hypersensitivity response 6 days later. In vitro, bone marrow-derived immature, but not CD40-stimulated mature DC migrate in response to NE, and this effect is neutralized by PRA. NE seems to exert both a chemotactic and chemokinetic activity on immature DC. Coherently, immature, but not mature DC, express mRNA coding for the alpha(1b)-adrenergic receptor subtype. Inactivation of this adrenergic receptor by the specific and irreversible antagonist chloroethylclonidine hinders the migration of injected DC from the footpad to regional lymph nodes. Thus, besides regulating lymph flow, the sympathetic innervation of lymphatic vessels may participate in directing DC migration from the site of inflammation to regional lymph nodes. Alternatively, the chemokinetic activity of NE may enhance the ability of DC to sample local Ags, and hence increase the number of DC migrating to the draining lymph nodes. This finding might improve our understanding of the biological basis of skin diseases and allergic reactions, and opens new pharmacological possibilities to modulate the immune response.
The role of CD4(+) vs CD8(+) T cells in contact hypersensitivity (CHS) remains controversial. In this study, we used gene knockout (KO) mice deficient in CD4(+) or CD8(+) T cells to directly address this issue. Mice lacking either CD4(+) or CD8(+) T cells demonstrated depressed CHS responses to dinitrofluorobenzene and oxazolone compared with wild-type C57BL/6 mice. The depression of CHS was more significant in CD8 KO mice than in CD4 KO mice. Furthermore, in vivo depletion of either CD8(+) T cells from CD4 KO mice or CD4(+) T cells from CD8 KO mice virtually abolished CHS responses. Lymph node cells (LNCs) from hapten-sensitized CD4 and CD8 KO mice showed a decreased capacity for transferring CHS. In vitro depletion of either CD4(+) T cells from CD8 KO LNCs or CD8(+) T cells from CD4 KO LNCs resulted in a complete loss of CHS transfer. LNCs from CD4 and CD8 KO mice produced significant amounts of IFN-gamma, indicating that both CD4(+) and CD8(+) T cells are able to secrete IFN-gamma. LNCs from CD8, but not CD4, KO mice were able to produce IL-4 and IL-10, suggesting that IL-4 and IL-10 are mainly derived from CD4(+) T cells. Intracellular cytokine staining of LNCs confirmed that IFN-gamma-positive cells consisted of CD4(+) (Th1) and CD8(+) (type 1 cytotoxic T) T cells, whereas IL-10-positive cells were exclusively CD4(+) (Th2) T cells. Collectively, these results suggest that both CD4(+) Th1 and CD8(+) type 1 cytotoxic T cells are crucial effector cells in CHS responses to dinitrofluorobenzene and oxazolone in C57BL/6 mice.
Transdermal drug delivery experiments are often tedious and time consuming in terms of sampling, labor, etc. In this way, the automation of such experiments has increased in the last few years. A protocol suitable to validate an automated diffusion equipment with seven in-line flow-through cells is described. The proposed protocol was divided into two parts. First, validation of each component which makes up the whole equipment, including the study of the statistical variability of the internal volumes between the cells, the temperature into the different chambers, the time and sample volumes, etc. In the second part, a series of permeation studies were carried out comparing the performance of the system against a classical Franz-type diffusion cell. Ketoprofen was used as a model drug. It was proved the low variability of the replicates obtained with the automated flow-through diffusion cells. The best work conditions as flow rate into the receptor chamber, temperature, etc., as well as the best mathematical approach for the diffusion data, were determined. The advantages in terms of time saved and easiness of validation of the flow-through cell design in comparison to the Franz-type cell were evidenced.