From Immunosuppression to Immunomodulation: Current Principles and Future Strategies

Abstract

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.

Liver transplantation

“…In the future, a tailored ‘cocktail’ of monoclonal antibodies against specific cytokines, receptors and growth factors depending on individual patient's immunological features will form the standard of care to prevent chronic rejection and graft loss. The therapeutic paradigm will change from immunosuppression to immunomodulation [73]. With the available immunosuppressants, the best approach to prevent malignancy after liver transplantation nowadays would be to decrease the number and the dosage of the immunosuppressive drugs to the minimum, starting as soon as possible after liver transplantation.…”

What did HERA teach us about the structure of the proton?

“…However, each of these methods has difficulties. The neutrino data uses heavy isoscalar targets such that uncertain nuclear corrections [55] are necessary. The deuterium target data also needs some nuclear binding corrections [56] and extraction of the d-quark is dependent on the assumption of strong isospin invariance.…”

“…Firstly, the neutrino-F e fixed-target scattering data from CCFR and NuTeV, which is often used to help to determine the valence densities, needs corrections for nuclear effects (the 'EMC effect'). Although such nuclear corrections are made in the global PDF analyses, they are not perfectly determined and the uncertainty due to these corrections is not fully accounted [55]. More recently similar critisms have been made of the use deuterium target data (either in DIS or Drell-Yan).…”

The Role of Local and Systemic Inflammation in the Pathogenesis of Intensive Care Unit-acquired Weakness

“…The advances in anti-inflammatory therapies are promising, since more selective immunomodulatory drugs, which target a specific component of the immune system, have been developed [28].…”