Identifying chemokines as therapeutic targets in renal disease: Lessons from antagonist studies and knockout mice

Chemokines, in concert with cytokines and adhesion molecules, play multiple roles in local and systemic immune responses. In the kidney, the temporal and spatial expression of chemokines correlates with local renal damage and accumulation of chemokine receptor-bearing leukocytes. Chemokines play important roles in leukocyte trafficking and blocking chemokines can effectively reduce renal leukocyte recruitment and subsequent renal damage. However, recent data indicate that blocking chemokine or chemokine receptor activity in renal disease may also exacerbate renal inflammation under certain conditions. An increasing amount of data indicates additional roles of chemokines in the regulation of innate and adaptive immune responses, which may adversively affect the outcome of interventional studies. This review summarizes available in vivo studies on the blockade of chemokines and chemokine receptors in kidney diseases, with a special focus on the therapeutic potential of anti-chemokine strategies, including potential side effects, in renal disease. Copyright (C) 2004 S. Karger AG, Basel

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable "steady state" after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions

Host specificity and species colouration mediate the regional decline of nocturnal moths in central European forests

The high diversity of insects has limited the volume of long-term community data with a high taxonomic resolution and considerable geographic replications, especially in forests. Therefore, trends and causes of changes are poorly understood. Here we analyse trends in species richness, abundance and biomass of nocturnal macro moths in three quantitative data sets collected over four decades in forests in southern Germany. Two local data sets, one from coppiced oak forests and one from high oak forests included 125K and 48K specimens from 559 and 532 species, respectively. A third regional data set, representing all forest types in the temperate zone of central Europe comprised 735K specimens from 848 species. Generalized additive mixed models revealed temporal declines in species richness (−38%), abundance (−53%) and biomass (−57%) at the regional scale. These were more pronounced in plant host specialists and in dark coloured species. In contrast, the local coppiced oak forests showed an increase, in species richness (+62%), while the high oak forests showed no clear trends. Left and right censoring as well as cross validation confirmed the robustness of the analyses, which led to four conclusions. First, the decline in insects appears in hyper diverse insect groups in forests and affects species richness, abundance and biomass. Second, the pronounced decline in host specialists suggests habitat loss as an important driver of the observed decline. Third, the more severe decline in dark species might be an indication of global warming as a potential driver. Fourth, the trends in coppiced oak forests indicate that maintaining complex and diverse forest ecosystems through active management may be a promising conservation strategy in order to counteract negative trends in biodiversity, alongside rewilding approaches

Immune enhancement by novel vaccine adjuvants in autoimmune-prone NZB/W F1 mice: relative efficacy and safety

<p>Abstract</p> <p>Background</p> <p>Vaccines have profoundly impacted global health although concerns persist about their potential role in autoimmune or other adverse reactions. To address these concerns, vaccine components like immunogens and adjuvants require critical evaluation not only in healthy subjects but also in those genetically averse to vaccine constituents. Evaluation in autoimmune-prone animal models of adjuvants is therefore important in vaccine development. The objective here was to assess the effectiveness of experimental adjuvants: two phytol-derived immunostimulants PHIS-01 (phytanol) and PHIS-03 (phytanyl mannose), and a new commercial adjuvant from porcine small intestinal submucosa (SIS-H), relative to a standard adjuvant alum. Phytol derivatives are hydrophobic, oil-in water diterpenoids, while alum is hydrophilic, and SIS is essentially a biodegradable and collagenous protein cocktail derived from extracellular matrices.</p> <p>Results</p> <p>We studied phthalate -specific and cross-reactive anti-DNA antibody responses, and parameters associated with the onset of autoimmune disorders. We determined antibody isotype and cytokine/chemokine milieu induced by the above experimental adjuvants relative to alum. Our results indicated that the phytol-derived adjuvant PHIS-01 exceeded alum in enhancing anti-phthalate antibody without much cross reactivity with ds-DNA. Relatively, SIS and PHIS-03 proved less robust, but they were also less inflammatory. Interestingly, these adjuvants facilitated isotype switching of anti-hapten, but not of anti-DNA response. The current study reaffirms our earlier reports on adjuvanticity of phytol compounds and SIS-H in non autoimmune-prone BALB/c and C57BL/6 mice. These adjuvants are as effective as alum also in autoimmune-prone NZB/WF1 mice, and they have little deleterious effects.</p> <p>Conclusion</p> <p>Although all adjuvants tested impacted cytokine/chemokine milieu in favor of Th1/Th2 balance, the phytol compounds fared better in reducing the onset of autoimmune syndromes. However, SIS is least inflammatory among the adjuvants evaluated.</p

The Swiss Kidney Stone Cohort (SKSC), a longitudinal, multi-centric, observational cohort to study course and causes of kidney stone disease in Switzerland

Kidney stone disease has a high prevalence worldwide of approximately 10 % of the population and is characterized by a high recurrence rate Kidney stone disease results from a combination of genetic, environmental, and life-style risk factors, and the dissection of these factors is complex. The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multi-centric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data up to 10 years. SKSC comprises 782 adult patients (age &gt; 18 yrs) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT-scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24 hr urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits were collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. SKSC provides an unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogenous collective of patients throughout the whole Swiss population

The Swiss Kidney Stone Cohort (SKSC), a longitudinal, multi-centric, observational cohort to study course and causes of kidney stone disease in Switzerland.

Kidney stone disease has a high prevalence worldwide of approximately 10 % of the population and is characterized by a high recurrence rate Kidney stone disease results from a combination of genetic, environmental, and life-style risk factors, and the dissection of these factors is complex. The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multi-centric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data up to 10 years. SKSC comprises 782 adult patients (age &gt; 18 yrs) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT-scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24 hr urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits were collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. SKSC provides an unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogenous collective of patients throughout the whole Swiss population

Differences in the food consumption between kidney stone formers and non-formers in the Swiss Kidney Stone Cohort.

OBJECTIVE Diet has a major influence on the formation and management of kidney stones. However, kidney stone formers' diet is difficult to capture in a large population. Our objective was to describe the dietary intake of kidney stone formers in Switzerland and to compare it to non-stone formers. METHODS We used data from the Swiss Kidney Stone Cohort (n=261), a multicentric cohort of recurrent or incident kidney stone formers with additional risk factors, and a control group of CT-scan proven non-stone formers (n=197). Dieticians conducted two consecutive 24-h dietary recalls, using structured interviews and validated software (GloboDiet). We took the mean consumption per participant of the two 24-h dietary recalls to describe the dietary intake and used two-part models to compare the two groups. RESULTS The dietary intake was overall similar between stone and non-stone formers. However, we identified that kidney stone formers had a higher probability of consuming cakes and biscuits (odds ratio, OR[95% CI] =1.56[1.03; 2.37]) and soft drinks (OR=1.66[1.08; 2.55]). Kidney stone formers had a lower probability of consuming nuts and seeds (OR =0.53[0.35; 0.82]), fresh cheese (OR=0.54[0.30; 0.96]), teas (OR=0.50[0.3; 0.84]), and alcoholic beverages (OR=0.35[0.23; 0.54]), especially wine (OR=0.42[0.27; 0.65]). Furthermore, among consumers, stone formers reported smaller quantities of vegetables (β coeff[95% CI]= - 0.23[- 0.41; - 0.06]), coffee (β coeff= - 0.21[- 0.37; - 0.05]), teas (β coeff= - 0.52[- 0.92; - 0.11]) and alcoholic beverages (β coeff= - 0.34[- 0.63; - 0.06]). CONCLUSION Stone formers reported lower intakes of vegetables, tea, coffee, and alcoholic beverages, more specifically wine, but reported drinking more frequently soft drinks than non-stone formers. For the other food groups, stone formers and non-formers reported similar dietary intakes. Further research is needed to better understand the links between diet and kidney stone formation and develop dietary recommendations adapted to the local settings and cultural habits

Maternal Serum Macrophage Inhibitory Cytokine-1 as a Biomarker for Ectopic Pregnancy in Women with a Pregnancy of Unknown Location

Ectopic pregnancy (EP) occurs in 1-2% of pregnancies, but is over-represented as a leading cause of maternal death in early pregnancy. It remains a challenge to diagnose early and accurately. Women often present in early pregnancy with a 'pregnancy of unknown location' (PUL) and the diagnosis and exclusion of EP is difficult due to a lack of reliable biomarkers. A serum biomarker able to clearly distinguish between EP and other pregnancy outcomes would greatly assist clinicians in diagnosing and safely managing PULs. This study evaluates the ability of maternal serum macrophage inhibitory cytokine-1 (MIC-1) levels to differentiate between EP and other pregnancy outcomes in women with a PUL.Sera were collected from 120 women with a PUL at first clinical presentation and assayed for MIC-1 by ELISA. Results were classified according to ultimate pregnancy outcome and the discriminatory ability of MIC-1 to diagnose EP was assessed.Serum MIC-1 levels were lower in women with histologically confirmed (definite) EP (dEP) (median 552 ng/mL; interquartile range (IQR) 414-693 ng/mL) compared to women with definite viable intra-uterine pregnancies (dVIUPs) (722 ng/mL; IQR 412-1122 ng/mL), and higher when compared to women with definite non-viable intra-uterine pregnancies (dNVIUPs) (465 ng/mL; IQR 341-675 ng/mL). MIC-1 levels were significantly higher in women with dEP compared to women whose PULs resolved without medical intervention (srPUL) (401 ng/mL; IQR 315-475 ng/mL) (p<0.003). There were no women with an ectopic pregnancy where serum MIC-1>1000 ng/mL.Serum MIC-1 levels in PUL were not able to categorically diagnose EP, however, MIC-1 could distinguish women with an EP that required medical intervention and those women whose PULs spontaneously resolved. A single serum MIC-1 measurement also excluded EP at levels above 1000 ng/mL. MIC-1 may play a role in the development of a combined assay of biomarkers for the diagnosis of EP