805 research outputs found
Applications of Nanoparticles for Treating Cutaneous Infection
Today, nanotechnology is finding applications in medicine. The unique physical and chemical properties of nanoparticles can overcome barriers and allow them to gain access to biological systems. Because of the increasing prevalence of microbial resistance to conventional therapies, the development of novel antimicrobials is imperative. Creating nanotechnology-based drug delivery systems with antibacterial and immunomodulatory activities may lead to novel treatments for cutaneous pathogens
Quantitative Comparison of Abundance Structures of Generalized Communities: From B-Cell Receptor Repertoires to Microbiomes
The \emph{community}, the assemblage of organisms co-existing in a given
space and time, has the potential to become one of the unifying concepts of
biology, especially with the advent of high-throughput sequencing experiments
that reveal genetic diversity exhaustively. In this spirit we show that a tool
from community ecology, the Rank Abundance Distribution (RAD), can be turned by
the new MaxRank normalization method into a generic, expressive descriptor for
quantitative comparison of communities in many areas of biology. To illustrate
the versatility of the method, we analyze RADs from various \emph{generalized
communities}, i.e.\ assemblages of genetically diverse cells or organisms,
including human B cells, gut microbiomes under antibiotic treatment and of
different ages and countries of origin, and other human and environmental
microbial communities. We show that normalized RADs enable novel quantitative
approaches that help to understand structures and dynamics of complex
generalize communities
Plasmodium yoelii infection of BALB/c mice results in expansion rather than induction of CD4+ Foxp3+ regulatory T cells
Recently, we demonstrated elevated numbers of CD4(+) Foxp3(+) regulatory T (Treg) cells in Plasmodium yoeliiâinfected mice contributing to the regulation of antiâmalarial immune response. However, it remains unclear whether this increase in Treg cells is due to thymusâderived Treg cell expansion or induction of Treg cells in the periphery. Here, we show that the frequency of Foxp3(+) Treg cells expressing neuropilinâ1 (Nrpâ1) decreased at early timeâpoints during P. yoelii infection, whereas percentages of Helios(+) Foxp3(+) Treg cells remained unchanged. Both Foxp3(+) Nrpâ1(+) and Foxp3(+) Nrpâ1(â) Treg cells from P. yoeliiâinfected mice exhibited a similar Tâcell receptor Vβ chain usage and methylation pattern in the Tregâspecific demethylation region within the foxp3 locus. Strikingly, we did not observe induction of Foxp3 expression in Foxp3(â) T cells adoptively transferred to P. yoeliiâinfected mice. Hence, our results suggest that P. yoelii infection triggered expansion of naturally occurring Treg cells rather than de novo induction of Foxp3(+) Treg cells
Local Induction of Immunosuppressive CD8+ T Cells in the Gut-Associated Lymphoid Tissues
Background: In contrast to intestinal CD4 + regulatory T cells (Tregs), the generation and function of immunomodulatory intestinal CD8 + T cells is less well defined. To dissect the immunologic mechanisms of CD8 + T cell function in the mucosa, reactivity against hemagglutinin (HA) expressed in intestinal epithelial cells of mice bearing a MHC class-I-restricted T-cellreceptor specific for HA was studied. Methodology and Principal Findings: HA-specific CD8 + T cells were isolated from gut-associated tissues and phenotypically and functionally characterized for the expression of Foxp3 + and their suppressive capacity. We demonstrate that intestinal HA expression led to peripheral induction of HA-specific CD8 + Foxp3 + T cells. Antigen-experienced CD8 + T cells in this transgenic mouse model suppressed the proliferation of CD8 + and CD4 + T cells in vitro. Gene expression analysis of suppressive HA-specific CD8 + T cells revealed a specific up-regulation of CD103, Nrp1, Tnfrsf9 and Pdcd1, molecules also expressed on CD4 + T reg subsets. Finally, gut-associated dendritic cells were able to induce HA-specific CD8 + Foxp3 + T cells. Conclusion and Significance: We demonstrate that gut specific antigen presentation is sufficient to induce CD8 + T regs in vivo which may maintain intestinal homeostasis by down-modulating effector functions of T cells
Gene profile analysis of osteoblast genes differentially regulated by histone deacetylase inhibitors
<p>Abstract</p> <p>Background</p> <p>Osteoblast differentiation requires the coordinated stepwise expression of multiple genes. Histone deacetylase inhibitors (HDIs) accelerate the osteoblast differentiation process by blocking the activity of histone deacetylases (HDACs), which alter gene expression by modifying chromatin structure. We previously demonstrated that HDIs and HDAC3 shRNAs accelerate matrix mineralization and the expression of osteoblast maturation genes (e.g. alkaline phosphatase, osteocalcin). Identifying other genes that are differentially regulated by HDIs might identify new pathways that contribute to osteoblast differentiation.</p> <p>Results</p> <p>To identify other osteoblast genes that are altered early by HDIs, we incubated MC3T3-E1 preosteoblasts with HDIs (trichostatin A, MS-275, or valproic acid) for 18 hours in osteogenic conditions. The promotion of osteoblast differentiation by HDIs in this experiment was confirmed by osteogenic assays. Gene expression profiles relative to vehicle-treated cells were assessed by microarray analysis with Affymetrix GeneChip 430 2.0 arrays. The regulation of several genes by HDIs in MC3T3-E1 cells and primary osteoblasts was verified by quantitative real-time PCR. Nine genes were differentially regulated by at least two-fold after exposure to each of the three HDIs and six were verified by PCR in osteoblasts. Four of the verified genes (solute carrier family 9 isoform 3 regulator 1 (Slc9a3r1), sorbitol dehydrogenase 1, a kinase anchor protein, and glutathione S-transferase alpha 4) were induced. Two genes (proteasome subunit, beta type 10 and adaptor-related protein complex AP-4 sigma 1) were suppressed. We also identified eight growth factors and growth factor receptor genes that are significantly altered by each of the HDIs, including Frizzled related proteins 1 and 4, which modulate the Wnt signaling pathway.</p> <p>Conclusion</p> <p>This study identifies osteoblast genes that are regulated early by HDIs and indicates pathways that might promote osteoblast maturation following HDI exposure. One gene whose upregulation following HDI treatment is consistent with this notion is Slc9a3r1. Also known as NHERF1, Slc9a3r1 is required for optimal bone density. Similarly, the regulation of Wnt receptor genes indicates that this crucial pathway in osteoblast development is also affected by HDIs. These data support the hypothesis that HDIs regulate the expression of genes that promote osteoblast differentiation and maturation.</p
IL10-Deficiency in CD4+ T Cells Exacerbates the IFNÎł and IL17 Response During Bacteria Induced Colitis
Background/Aims: IL10 is a key inhibitor of effector T cell activation and a
mediator of intestinal homeostasis. In addition, IL10 has emerged as a key
immunoregulator during infection with various pathogens, ameliorating the
excessive T-cell responses that are responsible for much of the
immunopathology associated with the infection. Because IL10 plays an important
role in both intestinal homeostasis and infection, we studied the function of
IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice
and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10
were infected with the enteric pathogen Citrobacter (C.) rodentium and
analyzed for the specific immune response and pathogloy in the colon. Results:
We found that IL10 expression is upregulated in colonic tissue after infection
with C. rodentium, especially in CD4+ T cells, macrophages and dendritic
cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C.
rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived
IL10 exhibited faster clearance of the bacterial burden but worse colitis,
crypt hyperplasia, and pathology than did WT mice. In addition, the depletion
of CD4+ T cell-derived IL10 in infected animals was accompanied by an
accelerated IFNÎł and IL17 response in the colon. Conclusion: Thus, we conclude
that CD4+ T cell-derived IL10 is strongly involved in the control of C.
rodentium-induced colitis. Interference with this network could have
implications for the treatment of infection-associated intestinal
inflammation
OA07.03. Randomized, double-blind, double-dummy trial of myrrh, chamomile, coffee charcoal compared to mesalazine in maintaining remission in ulcerative colitis
Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease
BACKGROUND: Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions.
METHODS: Murine models of allergic airway diseases, and murine and human in vitro models were used.
RESULTS: In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naĂŻve autologous T cells, replicating key observations made in vivo.
CONCLUSION: H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease
Signatures of human regulatory T cells: an encounter with old friends and new players
BACKGROUND: Naturally occurring CD4(+)CD25(+ )regulatory T cells (T(Reg)) are involved in the control of autoimmune diseases, transplantation tolerance, and anti-tumor immunity. Thus far, genomic studies on T(Reg )cells were restricted to murine systems, and requirements for their development, maintenance, and mode of action in humans are poorly defined. RESULTS: To improve characterization of human T(Reg )cells, we compiled a unique microarray consisting of 350 T(Reg )cell associated genes (Human T(Reg )Chip) based on whole genome transcription data from human and mouse T(Reg )cells. T(Reg )cell specific gene signatures were created from 11 individual healthy donors. Statistical analysis identified 62 genes differentially expressed in T(Reg )cells, emphasizing some cross-species differences between mice and humans. Among them, several 'old friends' (including FOXP3, CTLA4, and CCR7) that are known to be involved in T(Reg )cell function were recovered. Strikingly, the vast majority of genes identified had not previously been associated with human T(Reg )cells (including LGALS3, TIAF1, and TRAF1). Most of these 'new players' however, have been described in the pathogenesis of autoimmunity. Real-time RT-PCR of selected genes validated our microarray results. Pathway analysis was applied to extract signaling modules underlying human T(Reg )cell function. CONCLUSION: The comprehensive set of genes reported here provides a defined starting point to unravel the unique characteristics of human T(Reg )cells. The Human T(Reg )Chip constructed and validated here is available to the scientific community and is a useful tool with which to study the molecular mechanisms that orchestrate T(Reg )cells under physiologic and diseased conditions
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