DC-based therapeutic approaches designed to stimulate immune responses to tumours have been employed in patients with advanced cancers for nearly 15 years, with one of the earliest reports appearing in 1996 [10]. Such studies utilize DCs Z-VAD-FMK clinical trial pulsed with tumour antigens [10], tumour antigen-derived peptides

[6,7,11,12,15] or tumour lysates [9], or DCs transfected with tumour antigen cDNA (e.g. Muc1) [13], total tumour RNA [14] or RNA encoding tumour antigens (e.g. prostate-specific antigen) [8]. As reviewed, such therapies are safe, and tumour regression has been observed in some patients [22]. Multiple studies have revealed that mature DCs are optimal for stimulation of anti-tumour immune responses [7,11]. In contrast, and of clear relevance for type 1

diabetes therapeutics, when immature DCs pulsed with an influenza matrix peptide were administered to healthy controls [49,116] the outcome was inhibition of the function of peptide-specific effector CD8+ T cells and the appearance of peptide-specific IL-10-producing CD8+ T cells [116], as well as regulatory CD8+ T cells that required cell–cell contact to exert their suppressive effects [49]. At this time, the use of DCs in humans is being extended slowly beyond cancer immunotherapy to treatment of Temozolomide nmr infectious diseases [117] and autoimmune diseases including type 1 diabetes [118] and rheumatoid arthritis [119]. As discussed in an earlier section of this review, the administration of DCs rendered phenotypically immature by treatment with anti-sense oligonucleotides for CD80, CD86

and CD40 can prevent diabetes development in NOD mice [50,63]. The safety of this strategy is currently being evaluated in a Phase I clinical trial of long-standing adult type 1 diabetes patients in which autologous DCs are being generated from blood precursors after leukapheresis and treated with anti-sense oligonucleotides in vitro[118]. In this study, which began in 2007, the selleck products DCs are injected intradermally at a site proximal to the pancreas where they are expected to migrate to the nearest lymph nodes, including those of the pancreas. This same group reported that in vivo administration of microspheres incorporating the anti-sense oligonucleotides is capable of preventing and reversing type 1 diabetes development in NOD mice [111], and they anticipate human trials in the near future [118]. If approved, this strategy would greatly simplify the therapeutic protocol, as it would eliminate the need for leukapheresis and in vitro DC generation and treatment with oligonucleotides. Despite the DC defects that have been reported in NOD mice [120–123], a variety of DC-based immunotherapeutic strategies have shown great promise in this model, as we have summarized here (Fig. 2). Now the challenge will be to translate these approaches to patients. The ongoing investigation of the safety of phenotypically immature autologous DCs administered to type 1 diabetes patients represents a giant step forward in this regard [118].