It is generally thought that tolerogenic treatments, including tolDC therapy, will have the greatest chance of success if they are applied early on in the disease process [101]. However, for safety reasons, new experimental therapies are being tested in patients with established disease who have failed other treatments and have a poor prognosis. Whether tolerogenic strategies can be successful under these conditions remains to be seen, and an obvious risk is

that further development of tolDC therapy may not take place if initial trials show no or little efficacy. A related concern, therefore, is how to measure efficacy. The goal of tolDC therapy is to induce immune tolerance, but this may take time to develop Selleckchem Caspase inhibitor and may not necessarily result in an immediate reduction of inflammation or other chronic disease symptoms. It has been observed that some immunomodulatory therapies that were ineffective in the short term appeared to provide benefits to RA patients in the longer term [102]. Therefore, the timing of the end-points as well CT99021 as what outcomes are being measured need careful consideration; current outcome measures for clinical trials in RA measure the consequences of inflammation, but this is unlikely to be an appropriate marker for the short-term ‘success’ of tolDC therapy. What is badly needed

is the development of appropriate biomarkers of tolerance induction, which could then be used to monitor and guide tolerogenic therapies such as tolDC. Collecting data on expression of tolerance-related genes and the function of relevant immune subsets pre- and post-treatment will be essential for the design of a robust and quantifiable biomarker set. Such a set would

enable us to measure the short-term therapeutic response in future tolerogenic therapy trials and, if standardized, would enable comparisons between different trials. Over the last decade a variety of methods have been developed to generate tolDC in the laboratory. The characteristics of these tolDC have Thymidylate synthase been defined extensively in in-vitro studies and their therapeutic potential has been demonstrated in experimental animal models of autoimmune disease. The field has now moved into a new era, translating these findings towards clinical application of tolDC. The first clinical trials have indicated that tolDC administration is tolerated and appears safe, and further studies now need to be conducted to establish their efficacy in treating autoimmune disorders, including RA, type 1 diabetes and MS. A major drawback of tolDC therapy is that it is a highly customized ‘bespoke’ therapy, which not only makes it expensive but also limits its application to centres that have appropriate facilities and are specialized in cellular therapies.