1,349 research outputs found

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    Co-receptor and co-stimulation blockade for mixed chimerism and tolerance without myelosuppressive conditioning

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    BACKGROUND: A major challenge in the application of marrow transplantation as a route to immunological tolerance of a transplanted organ is to achieve hematopoietic stem cell (HSC) engraftment with minimal myelosuppressive treatments. RESULTS: We here describe a combined antibody protocol which can achieve long-term engraftment with clinically relevant doses of MHC-mismatched bone marrow, without the need for myelosuppressive drugs. Although not universally applicable in all strains, we achieved reliable engraftment in permissive strains with a two-stage strategy: involving first, treatment with anti-CD8 and anti-CD4 in advance of transplantation; and second, treatment with antibodies targeting CD4, CD8 and CD40L (CD154) at the time of marrow transplantation. Long-term mixed chimerism through co-receptor and co-stimulation blockade facilitated tolerance to donor-type skin grafts, without any evidence of donor-antigen driven regulatory T cells. CONCLUSION: We conclude that antibodies targeting co-receptor and co-stimulatory molecules synergise to enable mixed hematopoietic chimerism and central tolerance, showing that neither cytoreductive conditioning nor 'megadoses' of donor bone marrow are required for donor HSC to engraft in permissive strains

    Rapamycin Conditioning of Dendritic Cells Differentiated from Human ES Cells Promotes a Tolerogenic Phenotype

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    While human embryonic stem cells (hESCs) may one day facilitate the treatment of degenerative diseases requiring cell replacement therapy, the success of regenerative medicine is predicated on overcoming the rejection of replacement tissues. Given the role played by dendritic cells (DCs) in the establishment of immunological tolerance, we have proposed that DC, rendered tolerogenic during their differentiation from hESC, might predispose recipients to accept replacement tissues. As a first step towards this goal, we demonstrate that DC differentiated from H1 hESCs (H1-DCs) are particularly responsive to the immunosuppressive agent rapamycin compared to monocyte-derived DC (moDC). While rapamycin had only modest impact on the phenotype and function of moDC, H1-DC failed to upregulate CD40 upon maturation and displayed reduced immunostimulatory capacity. Furthermore, coculture of naïve allogeneic T cells with rapamycin-treated H1-DC promoted an increased appearance of CD25hi Foxp3+ regulatory T cells, compared to moDC. Our findings suggest that conditioning of hESC-derived DC with rapamycin favours a tolerogenic phenotype

    IL-10-conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals

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    Dendritic cells (DCs) are the professional APCs of the immune system, enabling T cells to perceive and respond appropriately to potentially dangerous microbes, while also being able to maintain T cell tolerance toward self. In part, such tolerance can be determined by IL-10 released from certain types of regulatory T cells. IL-10 has previously been shown to render DCs unable to activate T cells and it has been assumed that this process represents a general block in maturation. Using serial analysis of gene expression, we show that IL-10 pretreatment of murine bone marrow-derived DCs alone causes significant changes in gene expression. Furthermore, these cells retain the ability to respond to Toll-like receptor agonists, but in a manner skewed toward the selective induction of mediators known to enhance local inflammation and innate immunity, among which we highlight a novel CXCR2 ligand, DC inflammatory protein-1. These data suggest that, while the presence of a protolerogenic and purportedly anti-inflammatory agent such as IL-10 precludes DCs from acquiring their potential as initiators of adaptive immunity, their ability to act as initiators of innate immunity in response to Toll-like receptor signaling is enhanced

    The ACS Virgo Cluster Survey IV: Data Reduction Procedures for Surface Brightness Fluctuation Measurements with the Advanced Camera for Surveys

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    The Advanced Camera for Surveys (ACS) Virgo Cluster Survey is a large program to image 100 early-type Virgo galaxies using the F475W and F850LP bandpasses of the Wide Field Channel of the ACS instrument on the Hubble Space Telescope (HST). The scientific goals of this survey include an exploration of the three-dimensional structure of the Virgo Cluster and a critical examination of the usefulness of the globular cluster luminosity function as a distance indicator. Both of these issues require accurate distances for the full sample of 100 program galaxies. In this paper, we describe our data reduction procedures and examine the feasibility of accurate distance measurements using the method of surface brightness fluctuations (SBF) applied to the ACS Virgo Cluster Survey F850LP imaging. The ACS exhibits significant geometrical distortions due to its off-axis location in the HST focal plane; correcting for these distortions by resampling the pixel values onto an undistorted frame results in pixel correlations that depend on the nature of the interpolation kernel used for the resampling. This poses a major challenge for the SBF technique, which normally assumes a flat power spectrum for the noise. We investigate a number of different interpolation kernels and show through an analysis of simulated galaxy images having realistic noise properties that it is possible, depending on the kernel, to measure SBF distances using distortion-corrected ACS images without introducing significant additional error from the resampling. We conclude by showing examples of real image power spectra from our survey.Comment: ApJS, in press, complete version of the paper at the link: http://www.physics.rutgers.edu/~pcote/acs/publications.htm

    Factors Affecting Clergy-Psychologist Referral Patterns

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    Recent research on clergy-psychologist collaboration has resulted in helpful principles for clergy and psychologists working together, but very little is known about what specific characteristics in clergy are appealing to psychologists and vice versa. Two experimental survey studies are reported, both exploring characteristics that enhance or hinder collaboration. In Study 1, Southern Baptist pastors rated the likelihood of referring to a counselor who was identified as either a Biblical Counselor or a Christian Psychologist, and was identified as either being excellent in interpersonal skills or as using scripture and prayer in counseling. Pastors demonstrated a preference for counselors using scripture and prayer in counseling over those described as having excellent interpersonal skills. In Study 2, psychologist respondents rated the likelihood of referring to a clergyperson who was identified either as a Baptist or a Unitarian universalist, and was identified either as seminary trained or as having a doctoral degree from a prestigious divinity school. Psychologists demonstrated a preference for those with a doctoral degree. The weak effect sizes and comments offered on the surveys suggest that the individual relationship between clergy and psychologist is much more salient than particular demographic characteristics when considering the possibility of collaboration
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