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

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

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

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

Oppositional defiant disorder

Oppositional defiant disorder (ODD) is a disruptive behaviour disorder involving an ongoing pattern of angry/irritable mood, argumentative/defiant behaviour and vindictiveness. Onset is typically before 8 years of age, although ODD can be diagnosed in both children and adults. This disorder is associated with substantial social and economic burden, and childhood ODD is one of the most common precursors of other mental health problems that can arise across the lifespan. The population prevalence of ODD is ~3 to 5%. A higher prevalence in males than females has been reported, particularly before adolescence. No single risk factor accounts for ODD. The development of this disorder seems to arise from the interaction of genetic and environmental factors, and mechanisms embedded in social relationships are understood to contribute to its maintenance. The treatment of ODD is often successful, and relatively brief parenting interventions produce large sized treatment effects in early childhood. Accordingly, ODD represents an important focus for research, practice and policy concerning early intervention and prevention in mental health.</p

Oppositional defiant disorder

Oppositional defiant disorder (ODD) is a disruptive behaviour disorder involving an ongoing pattern of angry/irritable mood, argumentative/defiant behaviour and vindictiveness. Onset is typically before 8 years of age, although ODD can be diagnosed in both children and adults. This disorder is associated with substantial social and economic burden, and childhood ODD is one of the most common precursors of other mental health problems that can arise across the lifespan. The population prevalence of ODD is ~3 to 5%. A higher prevalence in males than females has been reported, particularly before adolescence. No single risk factor accounts for ODD. The development of this disorder seems to arise from the interaction of genetic and environmental factors, and mechanisms embedded in social relationships are understood to contribute to its maintenance. The treatment of ODD is often successful, and relatively brief parenting interventions produce large sized treatment effects in early childhood. Accordingly, ODD represents an important focus for research, practice and policy concerning early intervention and prevention in mental health.</p

Implementing changing behaviour towards aerobic and strength exercise: results of a randomised, phase I study determining the safety, feasibility, and consumer-evaluation of an online exercise program in persons with multiple sclerosis

Background: Many people with MS do not meet the recommended exercise regime to elicit health benefits. This study aimed to determine the feasibility, safety, acceptability, and appropriateness of an exercise intervention delivered online to persons with MS that meets current exercise recommendations and behaviour change principles. Methods: Seventy-two participants (age: 43.3 ± 13.3 years) with mild to moderate MS were stratified according to previous exercise behaviour and block-randomised into one of three groups: Control (CON; n = 24), General Exercise (GE; n = 24) who at screening did not meet current exercise recommendations, and Advanced Exercise, (AE; n = 24) who at screening met the current exercise recommendations. GE and AE groups received a four-month online-supervised, behaviour change theory-based exercise program and were assessed at baseline, four-months, five-months, and eleven-months for physical activity participation. The feasibility of process, resources, management, and scientific outcomes was assessed. Results: Of 198 potential participants, 143 met the eligibility criteria (72 %), and 72 were randomised. Fifty-three participants completed the intervention (74 % immediate retention), and 44 were retained at the six-month follow-up (61 %). Personnel time was 369 h, and total per-participant cost was Au$1036.20. Adherence rate to ≥70 % of exercise sessions was 73 % (GE) and 38 % (AE). The GE group observed a small magnitude of improvement in physical activity (d = −0.23). Conclusions: An online exercise program embedded with behaviour interventions for either GE or AE appears feasible, acceptable, appropriate and safe and may show long-term efficacy in increased exercise behaviours for persons with mild to moderate MS. Trial registration: ANZCRT number ACTRN12619000228189p.</p

Separation of the Ribbon From Globally Distributed Energetic Neutral Atom Flux Using the First Five Years of \u3ci\u3e IBEX \u3c/i\u3e Observations

The Interstellar Boundary Explorer (IBEX) observes the IBEX ribbon, which stretches across much of the sky observed in energetic neutral atoms (ENAs). The ribbon covers a narrow (∼20◦–50◦) region that is believed to be roughly perpendicular to the interstellar magnetic field. Superimposed on the IBEX ribbon is the globally distributed flux that is controlled by the processes and properties of the heliosheath. This is a second study that utilizes a previously developed technique to separate ENA emissions in the ribbon from the globally distributed flux. A transparency mask is applied over the ribbon and regions of high emissions. We then solve for the globally distributed flux using an interpolation scheme. Previously, ribbon separation techniques were applied to the first year of IBEX-Hi data at and above 0.71 keV. Here we extend the separation analysis down to 0.2 keV and to five years of IBEX data enabling first maps of the ribbon and the globally distributed flux across the full sky of ENA emissions. Our analysis shows the broadening of the ribbon peak at energies below 0.71 keV and demonstrates the apparent deformation of the ribbon in the nose and heliotail. We show global asymmetries of the heliosheath, including both deflection of the heliotail and differing widths of the lobes, in context of the direction, draping, and compression of the heliospheric magnetic field. We discuss implications of the ribbon maps for the wide array of concepts that attempt to explain the ribbon’s origin. Thus, we present the five-year separation of the IBEX ribbon from the globally distributed flux in preparation for a formal IBEX data release of ribbon and globally distributed flux maps to the heliophysics community