RNA Aptamers Recognizing Murine CCL17 Inhibit T Cell Chemotaxis and Reduce Contact Hypersensitivity In Vivo.

The chemokine CCL17, mainly produced by dendritic cells (DCs) in the immune system, is involved in the pathogenesis of various inflammatory diseases. As a ligand of CCR4, CCL17 induces chemotaxis and facilitates T cell-DC interactions. We report the identification of two novel RNA aptamers, which were validated in vitro and in vivo for their capability to neutralize CCL17. Both aptamers efficiently inhibited the directed migration of the CCR4+ lymphoma line BW5147.3 toward CCL17 in a dose-dependent manner. To study the effect of these aptamers in vivo, we used a murine model of contact hypersensitivity. Systemic application of the aptamers significantly prevented ear swelling and T cell infiltration into the ears of sensitized mice after challenge with the contact sensitizer. The results of this proof-of-principle study establish aptamers as potent inhibitors of CCL17-mediated chemotaxis. Potentially, CCL17-specific aptamers may be used therapeutically in humans to treat or prevent allergic and inflammatory diseases.

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4.

The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8(+) T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.

Cytokine-dependent regulation of dendritic cell differentiation in the splenic microenvironment.

The DC-derived chemokine CCL17, a ligand of CCR4, has been shown to promote various inflammatory diseases such as atopic dermatitis, atherosclerosis, and inflammatory bowel disease. Under steady-state conditions, and even after systemic stimulation with LPS, CCL17 is not expressed in resident splenic DCs as opposed to CD8α⁻CD11b⁺ LN DCs, which produce large amounts of CCL17 in particular after maturation. Upon systemic NKT cell activation through α-galactosylceramide stimulation however, CCL17 can be upregulated in both CD8α⁻ and CD8α⁺ splenic DC subsets and enhances cross-presentation of exogenous antigens. Based on genome-wide expression profiling, we now show that splenic CD11b⁺ DCs are susceptible to IFN-γ-mediated suppression of CCL17, whereas LN CD11b⁺CCL17⁺ DCs downregulate the IFN-γR and are much less responsive to IFN-γ. Under inflammatory conditions, particularly in the absence of IFN-γ signaling in IFN-γRKO mice, CCL17 expression is strongly induced in a major proportion of splenic DCs by the action of GM-CSF in concert with IL-4. Our findings demonstrate that the local cytokine milieu and differential cytokine responsiveness of DC subsets regulate lymphoid organ specific immune responses at the level of chemokine expression.

[The KomMent study: a pilot project on structured interprofessional communication in uro-oncology]. / Die KomMent-Studie: ein Pilotprojekt zur strukturierten interprofessionellen Kommunikation in der Uroonkologie.

BACKGROUND: Communication and interprofessional collaboration with patients diagnosed with cancer is challenging. Structured communication training has not yet been integrated into postgraduate medical education. The aim of this study was to evaluate the feasibility of an 80-teaching unit interprofessional communication training (ICT), as recommended in the National Cancer Plan, at a clinic with a uro-oncological focus. METHODS: A needs assessment was conducted using focus groups and individual interviews. Learning objectives were aligned with (inter)national learning objective catalogs. The ICT was developed using the six-step approach according to Kern and design-based research. Utilization and acceptance were evaluated. The ICT comprised six face-to-face workshops (50 teaching units) and team supervision sessions (10 teaching units). Six defined settings were identified for the individual workplace-based training (20 teaching units): Ward rounds, handover, reporting of medical findings, admission and discharge interviews, and a freely choosable setting. RESULTS: Physician participation rates in the workshops were 83.0% and nursing participation rates were 58.3%. Utilization of the workplace-based training was 97%. The physicians evaluated the ICT very positively. All participants felt better prepared for discussions with patients and relatives. For continuity, physicians were trained as mentors. CONCLUSION: The implementation of an ICT with 80 teaching units is successfully feasible in a urological clinic and leads to a sustainable improvement of the communication culture, among other things through mentor training.

A Systematic Review: The Effect of Cancer on the Divorce Rate.

Introduction: Research on the impact of cancer on close relationships brings up conflicting results. This systematic review collects empirical evidence on the research questions whether a cancer diagnosis in general or the type of cancer affects the divorce rate. Materials and Methods: This systematic review was conducted according to the guidelines of the Cochrane Collaboration and the PRISMA statement. The following electronic databases were searched: Web of Science, Ovid SP MEDLINE, PsycINFO, PsyINDEX, CINAHL, ERIC. Risk of bias assessment was performed with the preliminary risk of bias for exposures tool template (ROBINS-E tool). The grading of methodological quality was assessed with the Newcastle-Ottawa Scale. Results: Of 13,929 identified records, 15 were included in the qualitative synthesis. In 263,616 cancer patients and 3.4 million healthy individuals, we found that cancer is associated with a slightly decreased divorce rate, except for cervical cancer, which seems to be associated with an increased divorce rate. Discussion: According to this systematic review, cancer is associated with a tendency to a slightly decreased divorce rate. However, most of the included studies have methodologic weaknesses and an increased risk of bias. Further studies are needed.

Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation.

Data from preclinical and clinical studies have demonstrated that granulocyte macrophage colony-stimulating factor (GM-CSF) can function as a key proinflammatory cytokine. However, therapies that directly target GM-CSF function could lead to undesirable side effects, creating a need to delineate downstream pathways and mediators. In this work, we provide evidence that GM-CSF drives CCL17 production by acting through an IFN regulatory factor 4-dependent (IRF4-dependent) pathway in human monocytes, murine macrophages, and mice in vivo. In murine models of arthritis and pain, IRF4 regulated the formation of CCL17, which mediated the proinflammatory and algesic actions of GM-CSF. Mechanistically, GM-CSF upregulated IRF4 expression by enhancing JMJD3 demethylase activity. We also determined that CCL17 has chemokine-independent functions in inflammatory arthritis and pain. These findings indicate that GM-CSF can mediate inflammation and pain by regulating IRF4-induced CCL17 production, providing insights into a pathway with potential therapeutic avenues for the treatment of inflammatory diseases and their associated pain.