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Immune mechanisms are known to control the pathogenesis of atherosclerosis. However, the exact role of DCs, which are essential for priming of immune responses, remains elusive. We have shown here [...]

Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/ or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-[beta] production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs. allergy | cellular therapy | immunomodulation | mesenchymal stem cell www.pnas.org/cgi/doi/10.1073/pnas.0910720107

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs--also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-[alpha]) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups., Sepsis, a serious medical condition that affects 18 million people per year worldwide, is characterized by a generalized inflammatory state caused by infection. Widespread activation of inflammation and coagulation pathways [...]

In this study we investigated the role of histamine on the extramedullary hematopoiesis. Male histidine decarboxylase knockout (HDC−/−) mice and wild-type mice were used ( n = 5/group). Groups of mice received sublethal total-body gamma irradiation at a single dose of 4 Gy. Spleen cells were studied at different time points post-irradiation by flow cytometry, colony forming unit (CFU) assay, and real-time PCR. For statistical analysis Student’s t test, ANOVA, and Holm-Sidak post-hoc test were used. By day 14 after irradiation, spleen cell counts increased almost eightfold in wild-type and not even fourfold in HDC−/− mice ( P < 0.01). The proliferative capacity and interleukin-3 signaling of stem cells were impaired in HDC−/− mice. STAT5 mRNA expression was decreased in granulocyte-myeloid colonies by 72.9 ± 8.6% ( P < 0.001), compared to the wild-type. The absence of histamine adversely affects splenic hematopoiesis via direct and indirect mechanisms. [ABSTRACT FROM AUTHOR]

Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs—also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups. [ABSTRACT FROM AUTHOR]

In recent years, medicine has taken some important first steps toward a major paradigm shift that could result in a landslide for personalized therapies. Indeed, evidence-based medicine seems to yield to personalized medicine in multiple areas, including both the thinking patterns of healthcare workers and everyday medical practice. Nevertheless, although a steadily increasing number of personalized treatment modalities have recently become available for patients, so far, no breakthrough can be seen in the paradigm shift from evidence-based medicine to personalized therapy. We believe that a more efficient identification and utilisation of future and already known biomarkers, respectively, might be the key to speed up this progress. In line with this, biomarkers are becoming increasingly important tools in late stage research, drug development and in clinical practice, as well. Correct classification of biomarkers becomes especially important, as different types of biomarkers provide markedly different information to drug developers and health care professionals.