From immunosuppression to immunomodulation: current principles and future strategies.

Over the last few decades, tremendous progress has been made in understanding the mechanisms of immune responses. This progress has also led to a more detailed knowledge of the processes leading to the loss of self-tolerance and the destruction of self-tissue in the case of autoimmune diseases, the effector mechanism involved in transplant allograft rejection as well as the driving factors in exacerbated inflammatory disorders. Despite this progress, the challenge still remains to selectively interfere with immune responses responsible for autoimmunity or transplant rejection while keeping an intact response to infectious agents. To date, such a selective interference is still difficult to achieve, as highlighted by the fact that an overall increased risk for infections and malignancy continues to be the most frequent side effect of the currently used immunosuppressive principles. Nevertheless, although discovered several decades ago, many of the 'first-generation' immunosuppressive principles such as steroids, methotrexate and cyclosporin A are still in clinical use, demonstrating the therapeutic value of these drugs for the patients that are in need. In this review, the author describes the mode of action of the currently most used immunosuppressive agents (not attempting to cover all principles that are available) and expands on recent activities in the discovery and development of novel immunomodulatory principles.