Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes

IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29 are new members of the IL-10 interferon family. Monocytes are well-known sources of IL-19, IL-20, and IL-24. We demonstrated here that monocytes also expressed IL-29, and monocyte differentiation into macrophages (Mphi) or dendritic cells (DCs) strongly changed their production capacity of these cytokines. Maturation of DCs with bacterial stimuli induced high expression of IL-28/IL-29 and IL-20. Simulated T cell interaction and inflammatory cytokines induced IL-29 and IL-20 in maturing DCs, respectively. Compared with monocytes, DCs expressed only minimal IL-19 levels and no IL-24. The differentiation of monocytes into Mphi reduced their IL-19 and terminated their IL-20, IL-24, and IL-29 production capacity. Like monocytes, neither Mphi nor DCs expressed IL-22 or IL-26. The importance of maturing DCs as a source of IL-28/IL-29 was supported by the much higher mRNA levels of these mediators in maturing DCs compared with those in CMV-infected fibroblasts, and the presence of IL-28 in lymph nodes but not in liver of lipopolysaccharide-injected mice. IL-19, IL-20, IL-22, IL-24, and IL-26 do not seem to affect Mphi or DCs as deduced from the lack of corresponding receptor chains. The significance of IL-20 and IL-28/IL-29 coexpression in maturing DCs may lie in the broadly amplified innate immunity in neighboring tissue cells like keratinocytes. In fact, IL-20 induced the expression of antimicrobial proteins, whereas IL-28/IL-29 enhanced the expression of toll-like receptors (TLRs) and the response to TLR ligands. However, the strongest response to TLR2 and TLR3 activation showed keratinocytes in the simultaneous presence of IL-20 and IL-29.     

The developmental plasticity of colocalization pattern of peptide YY and glucagon-like peptide-1 in the endocrine cells of bovine rectum

Peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) are produced in endocrine cells that show distal distribution in each of small and large intestine. They are colocalized in the same endocrine cells at different ratios depending on the animal species. The present study examined the possibility of plasticity in the colocalization pattern in the bovine rectum, which is known to contain endocrine cells at a high concentration. Consecutive sections from different pre- and postnatal stages were stained immunohistochemically. The immunoreactive (IR) cells were divided into three groups: 1) cells IR for both PYY and GLP-1 (PYY/GLP-1-IR cells), 2) cells IR only for PYY (PYY-IR cells), and 3) cells IR only for GLP-1 (GLP-1-IR cells). The percentage of PYY/GLP-1-IR cells was high in the prenatal (early, mid- and late fetuses) and suckling stages, whereas it decreased in the herbivorous (weaning, weaned and adult) stages. In contrast, percentages of PYY and GLP-1-IR single cells were low in the prenatal and suckling stages and increased after the suckling stage. PYY/GLP-1 endocrine cells may adapt to the change of digestion depending on feeding habits and/or specific developmental stages of cattle. The present results suggest the developmental plasticity of the colocalization pattern of gut hormones with nutritional transition.     

Biomarkers and personalized medicine: current status and further perspectives with special focus on dermatology

Biomarkers are of increasingly high importance in medicine, particularly in the realm of ‘personalized medicine’. They are valuable for predicting prognosis and dose selection. Moreover, they may be helpful in detecting therapeutic and adverse responses and in patient stratification based on efficacy or safety prediction. Thus, biomarkers are essential tools for the selection of appropriate patients for treatment with certain drugs to and enable personalized medicine, that is ‘providing the right treatment to the right patient, at the right dose at the right time’. Currently, there are six drugs approved for dermatological indications with recommended or mandatory biomarker testing. Most of them are used to treat melanoma and human immunodeficiency virus infection. In contrast to the few fully validated biomarkers, many exploratory biomarkers and biomarker candidates have potential applications. Prognostic biomarkers are of particular significance for malignant conditions. Similarly, diagnostic biomarkers are important in autoimmune diseases. Disease severity biomarkers are helpful tools in the treatment for inflammatory skin diseases. Identification, qualification and implementation of the different kinds of biomarkers are challenging and frequently necessitate collaborative efforts. This is particularly true for stratification biomarkers that require a companion diagnostic marker that is co‐developed with a certain drug. In this article general definitions and requirements for biomarkers as well as for the impact of biomarkers in dermatology are reviewed and opportunities and challenges are discussed.     

Immunomodulation by interleukin-10 therapy decreases the incidence of relapse and prolongs the relapse-free interval in Psoriasis

The ability of interleukin-10 therapy to reduce the severity of exacerbated psoriasis has been demonstrated recently. Considering the immunobiologic properties of this cytokine we investigated the effects of long-term interleukin-10 application on the immune system and duration of psoriasis remission. We performed a placebo-controlled, double-blind, phase II trial using interleukin-10 in patients with chronic plaque psoriasis in remission. Patients received subcutaneous injections with either interleukin-10 (10 microg per kg body weight; n = 7) or placebo (n = 10) three times per week until relapse or study termination after 4 months. The treatment was well tolerated. In the placebo group almost all patients (90%) showed a relapse during the observation period. In contrast to this, only two of seven patients (28.6%) relapsed in the interleukin-10-treated group. Kaplan-Meier analysis revealed a significantly lower relapse incidence in the interleukin-10 than in the placebo group (p = 0.02). The mean relapse-free interval time was 101.6 +/- 12.6 d in the interleukin-10 group in comparison with 66.4 +/- 10.4 d in the placebo group. Immunologic activity of interleukin-10 application was indicated by an increase in soluble interleukin-2 receptor plasma levels and higher ex vivo interleukin-4 secretion capacities. Remarkably, a significant negative correlation was demonstrated between the interleukin-4 secretion capacity and Psoriasis Area and Severity Index score (r = -0.36, p < 0.01). Our data suggest that interleukin-10 therapy is immunologic effective, decreases the incidence of relapse and prolongs the disease-free interval in psoriasis. Its value should be further determined in larger trials and for the prevention of re-exacerbation of other inflammatory disorders with a similar immunologic profile.     

Techniques: species' finest blend--humanized mouse models in inflammatory skin disease research

Differences between humans and mice often hamper the transfer of promising results from the bench to the clinic. For ethical reasons, research that involves patients is limited, and so there is an urgent need for models that mimic the human situation as closely as possible. In recent years, there has been considerable progress in generating humanized mouse models, and their application to drug discovery has proved fruitful. So, how can mice be humanized, and how can humanized mice be employed in immunology research and drug discovery? In this article, we answer these questions, focusing on T-cell-mediated skin diseases as an example.     

IL-7 mRNA is not overexpressed in mycosis fungoides and pleomorphic T-cell lymphoma and is unlikely to be an autocrine growth factor in vivo

Interleukin-7 (IL-7) is thought to be a growth factor for cutaneous T-cell lymphoma (CTCL) since it has been shown that IL-7 transgenic mice develop a cutaneous disorder characterized by enhanced T-cell proliferation with progression to malignancy and that in vitro growth of Sézary cell lines is IL-7 dependent. However, no direct in vivo evidence exists for the involvement of IL-7 in the pathogenesis of CTCL. Therefore, we examined IL-7 mRNA expression in skin biopsies from patients with mycosis fungoides (MF) ( n = 20) and pleomorphic T-cell lymphoma ( n = 5). By semiquantitative RT-PCR, IL-7 mRNA was not detectable in any of the CTCL samples, or in normal human skin ( n = 8) or in skin from patients with psoriasis ( n = 7) or atopic dermatitis ( n = 5). In contrast, IL-7 mRNA was detected in a biopsy from a kidney allograft transplant, in normal keratinocytes under various culture conditions and in several cell lines. Interestingly, using a highly sensitive nested PCR, IL-7 mRNA was detectable in all specimens tested, but there was no indication of IL-7 overexpression in MF when analysing lesions of patch, plaque or tumour stages. In contrast, increasing CD3 expression was found, which was most likely a consequence of the enhanced density of malignant T cells in advanced tumour stages. In summary, by the use of semiquantitative RT-PCR we were not able to detect IL-7 overexpression in MF or pleomorphic T-cell lymphoma. This indicates that IL-7 is probably not an autocrine growth factor in these CTCLs. Received: 22 March 1996     

Novel nanoparticulate systems for lung cancer therapy: an updated review

Lung cancer is the leading cause of cancer-related deaths in the world. Conventional therapy for lung cancer is associated with lack of specificity and access to the normal cells resulting in cytotoxicity, reduced cellular uptake, drug resistance and rapid drug clearance from the body. The emergence of nanotechnology has revolutionized the treatment of lung cancer. The focus of nanotechnology is to target tumor cells with improved bioavailability and reduced toxicity. In the recent years, nanoparticulate systems have extensively been exploited in order to overcome the obstacles in treatment of lung cancer. Nanoparticulate systems have shown much potential for lung cancer therapy by gaining selective access to the tumor cells due to surface modifiability and smaller size. In this review, various novel nanoparticles (NPs) based formulations have been discussed in the treatment of lung cancer. Nanotechnology is expected to grow fast in future, and it will provide new avenues for the improved treatment of lung cancer. This review article also highlights the characteristics, recent advances in the designing of NPs and therapeutic outcomes.     

Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects

Glucocorticoids (GCs) are the most commonly used antiinflammatory and immunosuppressive drugs. Their outstanding therapeutic effects, however, are often accompanied by severe and sometimes irreversible side effects. For this reason, one goal of research in the GC field is the development of new drugs, which show a reduced side-effect profile while maintaining the antiinflammatory and immunosuppressive properties of classical GCs. GCs affect gene expression by both transactivation and transrepression mechanisms. The antiinflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. Our aim has been to identify ligands of the GC receptor (GR), which preferentially induce transrepression with little or no transactivating activity. Here we describe a nonsteroidal selective GR-agonist, ZK 216348, which shows a significant dissociation between transrepression and transactivation both in vitro and in vivo. In a murine model of skin inflammation, ZK 216348 showed antiinflammatory activity comparable to prednisolone for both systemic and topical application. A markedly superior side-effect profile was found with regard to increases in blood glucose, spleen involution, and, to a lesser extent, skin atrophy; however, adrenocorticotropic hormone suppression was similar for both compounds. Based on these findings, ZK 216348 should have a lower risk, e.g., for induction of diabetes mellitus. The selective GR agonists therefore represent a promising previously undescribed class of drug candidates with an improved therapeutic index compared to classical GCs. Moreover, they are useful tool compounds for further investigating the mechanisms of GR-mediated effects.     

Comparison of the Quality of Life after Skeletonized versus Pedicled Grafts in Coronary Artery Bypass Graft Surgery

It remains a controversial issue whether internal thoracic artery (ITA) should be dissected in skeletonized or pedicled manner during coronary artery bypass graft (CABG) surgery. The main objective of this cohort study was to compare skeletonized versus pedicled grafts on the basis of patients'' perceptions of their physical and mental well-being. Isolated nonemergent CABG patients were divided into two groups according to the type of graft used; skeletonized or pedicled. The quality of life (QOL) was measured preoperatively, 6 months postoperatively, and 12 months postoperatively for each patient using the 36-Item Short Form Health Survey tool. The main outcome variables were physical component summary (PCS) score and mental component summary (MCS) score. A total of 140 patients were included in the study with 70 patients in each group. The PCS (p-value = 0.235) and MCS (p-value = 0.239) scores of patients were similar in both the groups before CABG. The PCS and MCS scores were significantly (p-values < 0.0001) improved after CABG at 6 months in both the groups. However, the PCS and MCS scores in the skeletonized group were significantly higher (p-values < 0.0001) than the scores in the pedicled group at 6 and 12 months post-CABG. Both the harvesting techniques improve QOL significantly after CABG. However, skeletonization results in significantly better PCS and MCS scores compared with pedicled harvesting technique.