Unraveling the Mechanisms of Cutaneous Graft-Versus-Host Disease

The skin is the most common target organ affected by graft-versus-host disease (GVHD), with severity and response to therapy representing important predictors of patient survival. Although many of the initiating events in GVHD pathogenesis have been defined, less is known about why treatment resistance occurs or why there is often a permanent failure to restore tissue homeostasis. Emerging data suggest that the unique immune microenvironment in the skin is responsible for defining location- and context-specific mechanisms of injury that are distinct from those involved in other target organs. In this review, we address recent advances in our understanding of GVHD biology in the skin and outline the new research themes that will ultimately enable design of precision therapies

Dendritic cells in tissues: in situ stimulation of immunity and immunopathology

Dendritic cells (DCs) prime and orchestrate naïve T cell immunity in lymphoid organs, but recent data also highlight the importance of DC–effector T cell interactions in tissues. These studies suggest that effector T cells require a second activating step in situ from tissue DCs to become fully competent for effector functions and/or proliferation and survival. DC stimulation of effector T cells within tissues has evolved as a mechanism to ensure that T cells are activated to their full potential only at the site of ongoing infection. Here, we propose that under conditions of uncontrolled inflammation and release of tissue antigens, the same DC-dependent checkpoint perpetuates a destructive response and immunopathology

SHIFTED LEGENDRE POLYNOMIAL BASED GALERKIN AND COLLOCATION METHODS FOR SOLVING FRACTIONAL ORDER DELAY DIFFERENTIAL EQUATIONS

In this article, effective numerical methods for the solution of fractional order delay differential equations (FODDEs) are presented. The fractional derivative (FD) is defined in Caputo sense. Shifted Legendre polynomials are used in the Collocation and Galerkin methods to convert FDDEs to the linear and/or nonlinear system in algebraic form of equations. Example problems are addressed to show the powerfulness and efficacy of the methods

Dendritic Cells Cross-Present Immunogenic Lentivector-Encoded Antigen from Transduced Cells to Prime Functional T Cell Immunity

Recombinant lentiviral vectors (LVs) are highly effective vaccination vehicles that elicit protective T cell immunity in disease models. Dendritic cells (DCs) acquire antigen at sites of vaccination and migrate to draining lymph nodes, where they prime vaccine-specific T cells. The potency with which LVs activate CD8+ T cell immunity has been attributed to the transduction of DCs at the immunization site and durable presentation of LV-encoded antigens. However, it is not known how LV-encoded antigens continue to be presented to T cells once directly transduced DCs have turned over. Here, we report that LV-encoded antigen is efficiently cross-presented by DCs in vitro. We have further exploited the temporal depletion of DCs in the murine CD11c.DTR (diphtheria toxin receptor) model to demonstrate that repopulating DCs that were absent at the time of immunization cross-present LV-encoded antigen to T cells in vivo. Indirect presentation of antigen from transduced cells by DCs is sufficient to prime functional effector T cells that control tumor growth. These data suggest that DCs cross-present immunogenic antigen from LV-transduced cells, thereby facilitating prolonged activation of T cells in the absence of circulating LV particles. These are findings that may impact on the future design of LV vaccination strategies

Expression of a dominant T-cell receptor can reduce toxicity and enhance tumor protection of allogeneic T-cell therapy

Due to the lack of specificity for tumor antigens, allogeneic T-cell therapy is associated with graft-versus-host disease. Enhancing the anti-tumor specificity while reducing the graft-versus-host disease risk of allogeneic T cells has remained a research focus. In this study, we demonstrate that the introduction of ‘dominant’ T-cell receptors into primary murine T cells can suppress the expression of endogenous T-cell receptors in a large proportion of the gene-modified T cells. Adoptive transfer of allogeneic T cells expressing a ‘dominant’ T-cell receptor significantly reduced the graft-versus-host toxicity in recipient mice. Using two bone marrow transplant models, enhanced anti-tumor activity was observed in the presence of reduced graft-versus-host disease. However, although transfer of T-cell receptor gene-modified allogeneic T cells resulted in the elimination of antigen-positive tumor cells and improved the survival of treated mice, it was associated with accumulation of T cells expressing endogenous T-cell receptors and the development of delayed graft-versus-host disease. The in vivo deletion of the engineered T cells, mediated by endogenous mouse mammary tumor virus MTV8 and MTV9, abolished graft-versus-host disease while retaining significant anti-tumor activity of adoptively transferred T cells. Together, this study shows that the in vitro selection of allogeneic T cells expressing high levels of a ‘dominant’ T-cell receptor can lower acute graft-versus-host disease and enhance anti-tumor activity of adoptive cell therapy, while the in vivo outgrowth of T cells expressing endogenous T-cell receptors remains a risk factor for the delayed onset of graft-versus-host disease

Low 25(OH) vitamin D concentrations in international UK track and field athletes

Objective. While it is recognised that vitamin D deficiency iscommon in the general population, there have been no studies inelite athletes in the UK. This observational study aimed to assessthe 25 hydroxy-vitamin D (25(OH)D) status of elite athletes onthe Great Britain track and field team.Methods. A cross-sectional observational study was performedby analysing blood results from elite athletes on the British athleticsteam (N=63; mean ± standard deviation (SD) age 24.9±4.2 years).Athletes on the elite programme were offered blood tests throughthe winter and summer of 2009 and were eligible for inclusion inthe study.Results. Nineteen per cent (n=12) of athletes in the currentstudy can be classified as 25(OH)D deficient (<20 mcg/l), while afurther 29% (n=18) can be classified as having insufficient serum25(OH)D levels (20 - 30 mcg/l). Female sex (insufficent anddeficient OH(D) prevalence 58%, n=18) and dark skin (prevalence65%, n=20) were found to be independent predictors of serum25(OH)D levels of <30 mcg/l.Conclusion. This study reveals a notable prevalence of low serum25(OH)D levels in elite athletes and subsequent management ofdeficient athletes is likely to be of importance for athlete health.The impact of these results on athletic performance remains to bedetermined, and clinical trials to assess performance, particularlymuscular performance, following correction of 25(OH)D status indeficient athletes are required

Flavor violation and extra dimensions

We analyze new sources of flavor violation in models with extra dimensions. We focus on three major classes of five dimensional models: models with universal extra dimension, models with split fermions, and models with warped extra dimension.We study the implications of these new sources on the associate CP violating asymmetries to the rare B-decays. We show that among these models only the split fermions scenario may accommodate the recent experimental deviation between the CP asymmetry of B_d -> phi K_S and sin 2 beta.Comment: 17 pages, 3 figure