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The absorption of drugs with narrow absorption windows in the upper small intestine can be improved with a mucoadhesive drug delivery system such as enteric films. To predict the mucoadhesive behaviour in vivo, suitable in vitro or ex vivo methods can be performed. In this study, the influence of tissue storage and sampling site on the mucoadhesion of polyvinyl alcohol film to human small intestinal mucosa was investigated. Tissue from twelve human subjects was used to determine adhesion using a tensile strength method. Thawing of tissue frozen at −20 °C resulted in a significantly higher work of adhesion (p = 0.0005) when a low contact force was applied for one minute, whereas the maximum detachment force was not affected. When the contact force and time were increased, no differences were found for thawed tissue compared to fresh tissue. No change in adhesion was observed depending on the sampling location. Initial results from a comparison of adhesion to porcine and human mucosa suggest that the tissues are equivalent.
Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells
(B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The
function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and
peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed
in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to
S1P was studied in vitro. The role of S1P signalling was further explored in a s1p4
−/− mouse
strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4
(S1P1 and S1P4, respectively). S1P1 showed differential expression between the distinct peritoneal B
cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration
response to S1P. s1p4
−/− mice displayed significant alterations in the composition of peritoneal
B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA) in the
gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P4 deficiency alters the
composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest
that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies.
Background: Gram-negative infections of the peritoneal cavity result in profound modifications of peritoneal B cell populations and induce the migration of peritoneal B cells to distant
secondary lymphoid organs. However, mechanisms controlling the egress of peritoneal B cells from
the peritoneal cavity and their subsequent trafficking remain incompletely understood. Sphingosine1-phosphate (S1P)-mediated signaling controls migratory processes in numerous immune cells. The
present work investigates the role of S1P-mediated signaling in peritoneal B cell trafficking under
inflammatory conditions. Methods: Differential S1P receptor expression after peritoneal B cell activation was assessed semi-quantitatively using RT-PCR in vitro. The functional implications of
differential S1P1 and S1P4 expression were assessed by transwell migration in vitro, by adoptive
peritoneal B cell transfer in a model of sterile lipopolysaccharide (LPS)-induced peritonitis and in
the polymicrobial colon ascendens stent peritonitis (CASP) model. Results: The two sphingosine-1-
phosphate receptors (S1PRs) expressed in peritoneal B cell subsets S1P1 and S1P4 are differentially
regulated upon stimulation with the TLR4 agonist LPS, but not upon PMA/ionomycin or B cell receptor (BCR) crosslinking. S1P4 deficiency affects both the trafficking of activated peritoneal B cells
to secondary lymphoid organs and the positioning of these cells within the functional compartments of the targeted organ. S1P4 deficiency in LPS-activated peritoneal B cells results in significantly reduced numbers of splenic innate response activator B cells. Conclusions: The S1P-S1PR system is implicated in the trafficking of LPS-activated peritoneal B cells. Given the protective role of peritoneal B1a B cells in peritoneal sepsis, further experiments to investigate the impact of S1P4 mediated signaling on the severity and mortality of peritoneal sepsis are warranted.
Abstract
(1) Background: Surgery is the most important element of multimodal treatment concepts in oncological patients, especially in the early stages of pancreatic tumours. While the influence of primary tumour resection on the immune status was analysed in several studies, the impact of tumour-unrelated visceral surgery on the tumour-bearing organism and on the primary tumour itself is not yet fully understood. (2) Methods: We combined a murine model of orthotopically implanted adenocarcinoma of the pancreas with the model of surgically-induced immune dysfunction (SID). Mortality and general condition including body weight were observed over a period of 28 days. Tumour growth was analysed by MRI scans on days 8 and 27 following tumour implantation. On day 28, the immune cell populations in the blood and spleen as well as the serum cytokines were quantified. (3) Results: SID results in a significant deterioration of the general condition and a reduced increase in the body weight of tumour-bearing mice compared to the control groups, while mortality and tumour growth rate were not influenced. The numbers of spleen macrophages and neutrophils were increased in tumour-bearing animals following SID. Furthermore, both macrophage and neutrophil levels were increased in the peripheral blood. (4) Conclusions: The presented results might contribute to the basic understanding of the interaction of tumour and immune system and could contribute to new approaches to immunotherapeutic strategies.