The acquisition of self-perpetuating, immunological tolerance specific for graft alloantigens has long been described as the “holy grail” of clinical transplantation. By removing the need for life-long immunosuppression following engraftment, the adverse consequences of immunosuppressive regimens, including chronic infections and malignancy, may be avoided. Furthermore, autoimmune diseases and allergy are, by definition, driven by aberrant immunological responses to ordinarily innocuous antigens. The re-establishment of permanent tolerance towards instigating antigens may, therefore, provide a cure to these common diseases. Whilst various cell types exhibiting a tolerogenic phenotype have been proposed for such a task, tolerogenic dendritic cells (tol-DCs) are exquisitely adapted for antigen presentation and interact with many facets of the immune system: as such, they are attractive candidates for use in strategies for immune intervention. We review here our current understanding of tol-DC mediated induction and maintenance of immunological tolerance. Additionally, we discuss recent in vitro findings from animal models and clinical trials of tol-DC immunotherapy in the setting of transplantation, autoimmunity and allergy which highlight their promising therapeutic potential, and speculate how tol-DC therapy may be developed in the future.

The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir-saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.

Toll-like receptors (TLRs) are important innate immune receptors for the identification and clearance of invading pathogens. Twelve TLRs that recognize various conserved components of microorganisms are currently known. Among these, the endosomal TLRs 3, 7/8, and 9 recognize dsRNA, ssRNA, and CpG DNA, respectively. Nucleic acid-sensing TLRs, TLR 7 in particular, have been implicated in systemic lupus erythematosus (SLE) and are thought to exacerbate disease pathology. Activation of these TLRs results in the production of inflammatory cytokines and type I interferon. Genome-wide association studies, single nucleotide polymorphism analyses as well as experimental mouse models have provided evidence of TLR signaling involvement in SLE and other autoimmune diseases. Since activation of these receptor pathways promotes autoimmune phenotypes, inhibitory drugs that target these pathways constitute important new therapeutic strategies for the treatment of systemic autoimmunity.

Cell types differentiated from induced pluripotent stem cells (iPSCs) are frequently arrested in their development program, more closely resembling a fetal rather than an adult phenotype, potentially limiting their utility for downstream clinical applications. The fetal phenotype of iPSC-derived dendritic cells (ipDCs) is evidenced by their low expression of MHC class II and costimulatory molecules, impaired secretion of IL-12, and poor responsiveness to conventional maturation stimuli, undermining their use for applications such as immune-oncology. Given that iPSCs display an epigenetic memory of the cell type from which they were originally derived, we investigated the feasibility of reprogramming adult DCs to pluripotency to determine the impact on the phenotype and function of ipDCs differentiated from them. Using murine bone marrow-derived DCs (bmDCs) as proof of principle, we show here that immature DCs are tractable candidates for reprogramming using non-integrating Sendai virus for the delivery of Oct4, Sox2, Klf4, and c-Myc transcription factors. Reprogramming efficiency of DCs was lower than mouse embryonic fibroblasts (MEFs) and highly dependent on their maturation status. Although control iPSCs derived from conventional MEFs yielded DCs that displayed a predictable fetal phenotype and impaired immunostimulatory capacity in vitro and in vivo, DCs differentiated from DC-derived iPSCs exhibited a surface phenotype, immunostimulatory capacity, and responsiveness to maturation stimuli indistinguishable from the source DCs, a phenotype that was retained for 15 passages of the parent iPSCs. Our results suggest that the epigenetic memory of iPSCs may be productively exploited for the generation of potently immunogenic DCs for immunotherapeutic applications. K E Y W O R D S dendritic cell, epigenetic memory, immunostimulation, immunotherapy, induced pluripotent stem cell, maturation

The way in which we learn anatomy has changed exponentially over the decades and students now have access to lecture notes, textbooks, computer-assisted programmes, and a wide variety of internet based information. This study explored which resources were the most (and least) useful for a group of first year, undergraduate, medical students, with minimal prior content exposure (aged 18 and 19 years old, n = 76), over an 18 month period. Anatomy websites were found to be the most useful (30%), followed by tutorials (20%) and lectures (19%). A total of 13% found the university computer-assisted learning (CAL) platform least useful. We subsequently enhanced our ‘urogenital’ CAL anatomy module, with inclusion of new and updated images, videos and tutorials, as well as, digital and printed 3D-models. A post-intervention survey (n = 81) showed an increase from 12% to 27% for CAL as being most useful, and a decrease from 13% to 3% as being least useful. Our results provided a snapshot of students’ preferences in studying anatomy, and highlighted the importance of digital platforms and the need for evaluating our own learning resources. We must be mindful that there is an increasing tendency for students to rely on the Internet for information, which may expose them to unfiltered and unreliable content. We conclude that educators must be aware of the spectrum of learning resources used by students, to ensure that our own Institutional eLearning platforms are optimised to meet the diverse needs of learners.

Few topics in regenerative medicine have inspired such impassioned debate as the immunogenicity of cell types and tissues differentiated from pluripotent stem cells. While early predictions suggested that tissues derived from allogeneic sources may evade immune surveillance altogether, the pendulum has since swung to the opposite extreme, with reports that the ectopic expression of a few developmental antigens may prompt rejection, even of tissues differentiated from autologous cell lines. Here we review the evidence on which these contradictory claims are based in order to reach an objective assessment of the likely magnitude of the immunological challenges ahead. Furthermore, we discuss how the inherent properties of pluripotent stem cells may inform strategies for reducing the impact of immunogenicity on the future ambitions of regenerative medicine.

Objective The aim of this study was to assess disease features in Sle1.Yaa mice with genetic deficiency of IL-6. Methods Sera and tissues were collected from B6, Sle1.Yaa and Sle1.Yaa.IL-6−/− mice and analyzed for various features of disease. Serum samples were used to determine autoantibody specificities by ELISA and indirect immunofluorescence, cytokine production by Luminex and ELISA and levels of blood urea nitrogen by ELISA. Renal, lung and salivary gland tissue sections were evaluated for pathologic changes. Lymphocyte phenotypes, including CD4+ T cell cytokine production, and those of follicular and extrafollicular T helper subsets, germinal center B cells and plasma cells, were determined using flow cytometry. Results IL-6 deficiency not only ameliorated autoantibody production and renal disease in this model, but also effectively reduced inflammation of lungs and salivary glands. Furthermore, IL-6 deficiency abrogated differentiation of Th1 and extrafollicular T helper cells, germinal center B cells and plasma cells in spleen and eliminated renal T cells with IL-17, IFN-γ and IL-21 production potential. Conclusions This study highlights IL-6-mediated T cell aberrations in Yaa-driven autoimmunity and supports the concept of therapeutic IL-6/IL-6R blockade in SLE and Sjogren’s Syndrome by impairing the production of autoantibodies and lymphocytic infiltration of kidney, lung and salivary gland.

The advent of induced pluripotency has raised the prospect of personalized therapies based on the derivation of induced pluripotent stem cells (iPSC) derived from a patient's own somatic cells. Such bespoke cell products may successfully circumvent issues of rejection by the recipient's immune system but raise questions of affordability, the costs of generating patient-specific cell lines and their subsequent differentiation under cGMP conditions, proving a challenging business model. However, principles that have guided the decision between autologous and allogeneic cell products in the past may prove less reliable when considering the therapeutic use of dendritic cells (DC) differentiated from iPSC, whose role in the immune system would be adversely compromised in a fully allogeneic setting. Here, we review the immunological concepts that inform the debate between autologous and allogeneic cell therapies and discuss whether recent breakthroughs might provide a novel solution to this long-standing issue, paving the way for the widespread adoption of DC-based immunotherapy and increasing its reach from immune oncology (IO) to the induction of immunological tolerance.