Editorial [Hot Topic: Immunomodulators in Medicinal Chemistry and Drug Discovery (Guest Editor: Dr. Athanasia Mouzaki)]

One of the “Holy Grails” of modern medicine (and pharmaceutical companies alike) is to be able to “persuade” the immune system to treat all pathologies, that do not result from awry Mendelian genetics, specifically, without side effects and, most importantly, avoiding bystander destruction of healthy cells and tissues. These goals have not been achieved yet, but the tremendous progress that has been made in basic science has enabled us to understand better the ways the immune and the other physiological systems work, and how they interact with each other. Importantly, empirical data from published clinical trials of drugs, successful, partially successful or failed, have helped to clarify misconceptions of past years and, in turn, define new drug targets and/or re-assess old ones. Two striking examples that come to mind are (i) the realization that T regulatory cells are a separate entity of T-cells [1] that can be destroyed by immunomodulatory drugs that target activated T-cells expressing the high affinity interleukin-2 receptor (such as anti-IL2R monoclonal antibodies used in organ transplantation), with potentially detrimental long-term consequences for the patient and (ii) the recently publicized TGN1412 trial fiasco in which an anti-CD28 antibody, inadequately tested before entering into clinical trials, sent six healthy volunteers to the intensive care unit [2]. This issue includes eight reviews on current and experimental immunotherapeutic regiments for various diseases including neoplasias, autoimmune diseases and AIDS. The first three reviews cover the current immunomodulatory therapies for hematological malignancies, cancer and autoimmune diseases (with emphasis on antibodies, but also cytokines, proteasome inhibitors and thalidomide), that are becoming the treatments of choice in the clinic. The 4th review covers the design and synthesis of artificial carriers of peptide epitopes for the construction of antigenic and immunogenic conjugates, and their application in diagnostics and vaccine development. The 5th review deals with RNA-mediated therapeutics and their potential use for gene inactivation and therapy. The 6th review is an update on T regulatory cells which - as we now know- must be taken into consideration when immunomodulatory drugs are used and when designing “intelligent“ drugs to alter the balance of the immune response to treat disease. The 7th review recapitulates what is now known on the mode of action of traditional immunosuppressive drugs and T-cell activation pathways, and how this current knowledge can be exploited to (re)assess their use as adjunct drugs to treat HIV disease in various clinical settings. Finally, the last review invites us to rethink our ideas on drug targets in polygenic diseases. I learned a lot preparing this issue, and I thank the Editor for giving me the opportunity and the motivation to go through this process. REFERENCES [1] Regulatory T-cells. Nature Immunol., 6(4):327-361 (2005). [2] Tragic drug trial spotlights potent molecule: Study reveals risks of interfering with immune system. Nature News, published on line: 17 March 2006; doi:10.1038/news060313-17.