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