1,720,969 research outputs found
Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplantation
No full textOBJECTIVE—In type 1 diabetes, allogeneic pancreatic islet
transplant restores insulin production, but life-threatening immunosuppression
is required to avoid graft rejection. Induction of
antigen (Ag)–specific tolerance by cell therapy with regulatory
T-cells (Tregs) represents an attractive alternative approach but
its therapeutic efficacy in islet transplant remains to be determined.
Among the different subsets of CD4 Tregs, the T
inducible regulatory type 1 (Tr1) cells can be generated from
naive T-cells in the presence of interleukin-10 (IL-10) and represent
one promising therapeutic choice. This study was designed
to define the efficacy of Tr1-cell therapy in preclinical models of
islet transplant.
RESEARCH DESIGN AND METHODS—Non–Ag-specific
polyclonal Tr1 cells and donor Ag-specific Tr1 cells were transferred,
in the absence of any pharmacological treatment, in two
distinct mouse models of islet transplant. The two models
differed in their therapeutic stringency, based on the mean
rejection time of untreated mice that underwent a transplant.
RESULTS—Transfer of polyclonal Tr1 cells engendered graft
tolerance only in the nonstringent mouse model. Conversely, cell
therapy with Ag-specific Tr1 cells induced an IL-10–dependent
tolerance in the stringent mouse model of islet transplant. The
therapeutic advantage of Ag-specific Tr1 cells over polyclonal
Tr1 cells was due to their donor Ag specificity.
CONCLUSIONS—These results demonstrate that Tr1-cell therapy
leads to tolerance in settings of islet transplant and that its
therapeutic efficacy is highly dependent on the antigen specificity
of these cells
Rapamycin prevents and breaks the anti-CD3-induced tolerance in NOD mice
No full textOBJECTIVE—Non–Fc-binding anti-CD3–specific antibodies
represent a promising therapy for preserving C-peptide production
in subjects with recent-onset type 1 diabetes. However, the
mechanisms by which anti-CD3 exerts its beneficial effect are
still poorly understood, and it is questionable whether this
therapeutic approach will prove durable with regard to its ability
to impart metabolic preservation without additional actions
designed to maintain immunological tolerance. We used the NOD
mouse model to test whether rapamycin, a compound wellknown
for its immunomodulatory activity in mice and humans,
could increase the therapeutic effectiveness of anti-CD3 treatment
in type 1 diabetes.
RESEARCH DESIGN AND METHODS—Rapamycin was administered
to diabetic NOD mice simultaneously with anti-CD3
or to NOD mice cured by anti-CD3 therapy. The ability of this
combined therapy to revert type 1 diabetes and maintain a state
of long-term tolerance was monitored and compared with that of
anti-CD3 therapy alone.
RESULTS—Rapamycin inhibited the ability of anti-CD3 to revert
disease without affecting the frequency/phenotype of T-cells.
Rapamycin also reinstated diabetes in mice whose disease was
previously reversed by anti-CD3. Withdrawal of rapamycin in
these latter animals promptly restored a normoglycemic state.
CONCLUSIONS—Our findings indicate that, when combined
with anti-CD3, rapamycin exerts a detrimental effect on the
disease outcome in NOD mice for as long as it is administered.
These results suggest strong caution with regard to combining
these treatments in type 1 diabetic patient
Key role of macrophages in tolerance induction via T regulatory type 1 (Tr1) cells
No full textT regulatory type 1 (Tr1) cells are a class of regulatory T cells (Tregs) participating in peripheral tolerance, hence the rationale behind their testing in clinical trials in different disease settings. One of their applications is tolerance induction to allogeneic islets for long-term diabetes-free survival. Currently the cellular and molecular mechanisms that promote Tr1-cell induction in vivo remain poorly understood. We employed a mouse model of transplant tolerance where treatment with granulocyte colony-stimulating factor (G-CSF)/rapamycin induces permanent engraftment of allogeneic pancreatic islets in C57BL/6 mice via Tr1 cells. The innate composition of graft and spleen cells in tolerant mice was analyzed by flow cytometry. Graft phagocytic cells were co-cultured with CD4+ T cells in vitro to test their ability to induce Tr1-cell induction. Graft phagocytic cells were depleted in vivo at different time-points during G-CSF/rapamycin treatment, to identify their role in Tr1-cell induction and consequently in graft survival. In the spleen, the site of Tr1-cell induction, no differences in the frequencies of macrophages or dendritic cells (DC) were observed. In the graft, the site of antigen uptake, a high proportion of macrophages and not DC was detected in tolerant but not in rejecting mice. Graft-infiltrating macrophages of G-CSF/rapamycin-treated mice had an M2 phenotype, characterized by higher CD206 expression and interleukin (IL)-10 production, whereas splenic macrophages only had an increased CD206 expression. Graft-infiltrating cells from G-CSF/rapamycin-treated mice-induced Tr1-cell expansion in vitro. Furthermore, Tr1-cell induction was perturbed upon in-vivo depletion of phagocytic cells, early and not late during treatment, leading to graft loss suggesting that macrophages play a key role in tolerance induction mediated by Tr1 cells. Taken together, in this mouse model of Tr1-cell induced tolerance to allogeneic islets, M2 macrophages infiltrating the graft upon G-CSF/rapamycin treatment are key for Tr1-cell induction. This work provides mechanistic insight into pharmacologically induced Tr1-cell expansion in vivo in this stringent model of allogeneic transplantation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Enforced IL-10 Expression Confers Type 1 Regulatory T Cell (Tr1) Phenotype and Function to Human CD4(+) T Cells
No full text"Type 1 regulatory T (Tr1) cells are an inducible subset of CD4(+) Tr cells characterized by high levels of interleukin (IL)-10 production and regulatory properties. Several protocols to generate human Tr1 cells have been developed in vitro. However, the resulting population includes a significant fraction of contaminating non-Tr1 cells, representing a major bottleneck for clinical application of Tr1 cell therapy. We generated an homogeneous IL-10-producing Tr1 cell population by transducing human CD4(+) T cells with a bidirectional lentiviral vector (LV) encoding for human IL-10 and the marker gene, green fluorescent protein (GFP), which are independently coexpressed. The resulting GFP(+) LV-IL-10-transduced human CD4(+) T (CD4(LV-IL-10)) cells expressed, upon T-cell receptor (TCR) activation, high levels of IL-10 and concomitant low levels of IL-4, and markers associated with IL-10. Moreover, CD4(LV-IL-10) T cells displayed typical Tr1 features: the anergic phenotype, the IL-10, and transforming growth factor (TGF)-β dependent suppression of allogeneic T-cell responses, and the ability to suppress in a cell-to-cell contact independent manner in vitro. CD4(LV-IL-10) T cells were able to control xeno graft-versus-host disease (GvHD), demonstrating their suppressive function in vivo. These results show that constitutive over-expression of IL-10 in human CD4(+) T cells leads to a stable cell population that recapitulates the phenotype and function of Tr1 cells.
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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