A 4.5 km resolution Arctic Ocean simulation with the global multi-resolution model FESOM1.4

In the framework of developing a global modeling system which can facilitate modeling studies on Arctic Ocean and high- to midlatitude linkage, we evaluate the Arctic Ocean simulated by the multi-resolution Finite Element Sea ice-Ocean Model (FESOM). To explore the value of using high horizontal resolution for Arctic Ocean modeling, we use two global meshes differing in the horizontal resolution only in the Arctic Ocean (24 km vs. 4.5 km). The high resolution significantly improves the model's representation of the Arctic Ocean. The most pronounced improvement is in the Arctic intermediate layer, in terms of both Atlantic Water (AW) mean state and variability. The deepening and thickening bias of the AW layer, a common issue found in coarse-resolution simulations, is significantly alleviated by using higher resolution. The topographic steering of the AW is stronger and the seasonal and interannual temperature variability along the ocean bottom topography is enhanced in the high-resolution simulation. The high resolution also improves the ocean surface circulation, mainly through a better representation of the narrow straits in the Canadian Arctic Archipelago (CAA). The representation of CAA throughflow not only influences the release of water masses through the other gateways but also the circulation pathways inside the Arctic Ocean. However, the mean state and variability of Arctic freshwater content and the variability of freshwater transport through the Arctic gateways appear not to be very sensitive to the increase in resolution employed here. By highlighting the issues that are independent of model resolution, we address that other efforts including the improvement of parameterizations are still required

The site of allergen expression in hematopoietic cells determines the degree and quality of tolerance induced through molecular chimerism

The transplantation of allergens (e.g. Phl p 5 or Bet v 1) expressed on BM cells as membrane-anchored full-length proteins leads to permanent tolerance at the T-cell, B-cell, and effector-cell levels. Since the exposure of complete allergens bears the risk of inducing anaphylaxis, we investigated here whether expression of Phl p 5 in the cytoplasm (rather than on the cell surface) is sufficient for tolerance induction. Transplantation of BALB/c BM retrovirally transduced to express Phl p 5 in the cytoplasm led to stable and durable molecular chimerism in syngeneic recipients (∼20% chimerism at 6 months). Chimeras showed allergen-specific T-cell hyporesponsiveness. Further, Phl p 5-specific TH1-dependent humoral responses were tolerized in several chimeras. Surprisingly, Phl p 5-specific IgE and IgG1 levels were significantly reduced but still detectable in sera of chimeric mice, indicating incomplete B-cell tolerance. No Phl p 5-specific sIgM developed in cytoplasmic chimeras, which is in marked contrast to mice transplanted with BM expressing membrane-anchored Phl p 5. Thus, the expression site of the allergen substantially influences the degree and quality of tolerance achieved with molecular chimerism in IgE-mediated allergy

Activated Human T Cells, B Cells, and Monocytes Produce Brain-derived Neurotrophic Factor In Vitro and in Inflammatory Brain Lesions: A Neuroprotective Role of Inflammation?

Brain-derived neurotrophic factor (BDNF) has potent effects on neuronal survival and plasticity during development and after injury. In the nervous system, neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro. Notably, in T helper (Th)1- and Th2-type CD4+ T cell lines specific for myelin autoantigens such as myelin basic protein or myelin oligodendrocyte glycoprotein, BDNF production is increased upon antigen stimulation. The BDNF secreted by immune cells is bioactive, as it supports neuronal survival in vitro. Using anti-BDNF monoclonal antibody and polyclonal antiserum, BDNF immunoreactivity is demonstrable in inflammatory infiltrates in the brain of patients with acute disseminated encephalitis and multiple sclerosis. The results raise the possibility that in the nervous system, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective immunotherapies

Arctic Sea Ice Decline Significantly Contributed to the Unprecedented Liquid Freshwater Accumulation in the Beaufort Gyre of the Arctic Ocean

The Beaufort Gyre (BG) is the largest liquid freshwater reservoir of the Arctic Ocean. The liquid freshwater content (FWC) significantly increased in the BG in the 2000s during an anticyclonic wind regime and remained at a high level despite a transition to a more cyclonic state in the early 2010s. It is not well understood to what extent the rapid sea ice decline during this period has modified the trend and variability of the BG liquid FWC in the past decade. Our numerical simulations show that about 50% of the liquid freshwater accumulated in the BG in the 2000s can be explained by the sea ice decline caused by the Arctic atmospheric warming. Among this part of the FWC increase, 60% can be attributed to surface freshening associated with the reduction of the net sea ice thermodynamic growth rate, and 40% to changes in ocean circulation, which makes freshwater more accessible to the BG for storage. Thus, the rapid increase of the BG FWC in the 2000s was due to the concurrence of the anticyclonic wind regime and the high freshwater availability. We also find that if the Arctic sea ice had not declined, the liquid FWC in the BG would have shown a stronger decreasing tendency at the beginning of the 2010s owing to the cyclonic wind regime. From our results we argue that changes in sea ice conditions should be adequately taken into account when it comes to understanding and predicting variations of BG liquid FWC in a changing climate

Allograft and patient survival after sequential HSCT and kidney transplantation from the same donorA multicenter analysis

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Cell Therapy for Prophylactic Tolerance in Immunoglobulin E-mediated Allergy

AbstractBackgroundTherapeutic strategies for the prophylaxis of IgE-mediated allergy remain an unmet medical need. Cell therapy is an emerging approach with high potential for preventing and treating immunological diseases.We aimed to develop a cell-based therapy inducing permanent allergen-specific immunological tolerance for preventing IgE-mediated allergy.MethodsWild-type mice were treated with allergen-expressing bone marrow cells under a short course of tolerogenic immunosuppression (mTOR inhibition and costimulation blockade). Bone marrow was retrieved from a novel transgenic mouse ubiquitously expressing the major grass pollen allergen Phl p 5 as a membrane-anchored protein (BALB/c-Tg[Phlp5-GFP], here mPhl p 5). After transplantation recipients were IgE-sensitized at multiple time points with Phl p 5 and control allergen.ResultsMice treated with mPhl p 5 bone marrow did not develop Phl p 5-specific IgE (or other isotypes) despite repeated administration of the allergen, while mounting and maintaining a strong humoral response towards the control allergen. Notably, Phl p 5-specific T cell responses and allergic airway inflammation were also completely prevented. Interestingly allergen-specific B cell tolerance was maintained independent of Treg functions indicating deletional tolerance as underlying mechanism.ConclusionThis proof-of-concept study demonstrates that allergen-specific immunological tolerance preventing occurrence of allergy can be established through a cell-based therapy employing allergen-expressing leukocytes

Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two- photon imaging

Autoreactive encephalitogenic T cells exist in the healthy immune repertoire but need a trigger to induce CNS inflammation. The underlying mechanisms remain elusive, whereby microbiota were shown to be involved in the manifestation of CNS autoim-munity. Here, we used intravital imaging to explore how microbiota affect the T cells as trigger of CNS inflammation. Encephalitogenic CD4(+) T cells transduced with the calcium-sensing protein Twitch -2B showed calcium signaling with higher frequency than polyclonal T cells in the small intestinal lamina propria (LP) but not in Peyer's patches. Interestingly, nonencephalitogenic T cells specific for OVA and LCMV also showed calcium signaling in the LP, indicating a general stimulating effect of microbiota. The observed calcium signaling was microbiota and MHC class II dependent as it was significantly reduced in germfree animals and after administration of anti- MHC class II antibody, respectively. As a consequence of T cell stimulation in the small intestine, the encephalitogenic T cells start expressing Th17- axis genes. Finally, we show the migration of CD4(+) T cells from the small intestine into the CNS. In summary, our direct in vivo visualization revealed that microbiota induced T cell activation in the LP, which directed T cells to adopt a Th17- like phenotype as a trigger of CNS inflammation