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Inflammation is a physiological response that may go uncontrolled and thereby develop in a chronic way. This seems to happen in many common diseases of autoimmune, degenerative, or allergic character. Rheumatoid arthritis (RA) is by definition a chronic disease with an autoimmune inflammatory attack on diarthrodial cartilaginous joints. The development of new treatment neutralizing cytokines involved in the inflammatory attack has given relief and gives the promise of more effective treatment of already established disease. It is now time to set our eyes on a new vision to develop preventive and curative treatment based on knowledge of the unique and causative pathogenic mechanisms. To do this we believe it is important to identify the natural-selected polymorphisms that are associated with disease. These have proven to be extremely difficult to identify in complex diseases such as RA, but using animal models, this work is closer to reality. Animal models have recently been developed mimicking various aspects of the human disease. We will present an example in which a genetic polymorphism associated with the development of arthritis has been identified. On the basis of this finding, a new pathway involving control of immune tolerance by reactive oxidative species has been identified and a new class of antiinflammatory agents activating the induced oxidative burst protein complex is suggested.

Current therapeutic options that are based on immunosuppression do not provide a cure for the treatment of chronic inflammation. Though more efficient immunosuppression and the introduction of biologicals such as antibodies targeting cytokines have improved clinical outcomes, immunosuppressive therapy has to be continued to be efficient, thus enhancing the risk of adverse events and undesired side effects. Why can immunosuppression ameliorate, even stop, but not cure chronic inflammation? Is chronic inflammation perpetuated beyond suppression by mechanisms independent of the immune system, or is it perpetuated by components of the immune system which are resistant to a block of ongoing immune reactions? One such component of the immune system is immunological memory. This article will review the role of immunological memory in chronic inflammation, as far as we understand it today, and discuss implications for the development of novel therapeutic strategies aiming at a cure for diseases involving chronic inflammation.

The biosynthesis of inflammatory mediators relies on controlling the biogenesis and utilization of their corresponding messenger RNAs (mRNAs). These latter “utilization steps” encompass post-transcriptional mechanisms that gradually and variably impose a series of flexible-rate limiting controls to modify the abundance of an mRNA and the rate of its translation to protein in response to environmental signals. Mechanistically, post-transcriptional machines comprise networks of RNA binding proteins (RBPs), which recognize, passively or inducibly, secondary or tertiary ribonucleotide structures located on their target RNAs. The outcome of these interactions is the stringent control of mRNA maturation, localization, turnover and translation. It is conceivable that if these post-transcriptional interactions fail, they may perturb cellular responses to provide the impetus for chronic disease. Such is the case of the signal-responsive mechanisms affecting inflammatory mRNAs containing the AU-rich family of elements (AREs), which are recognized by a specific subset of RBPs. Intense research in this area has yielded important insight on the specific signals and mechanisms affecting the utilization of ARE-containing mRNAs. Here, we indicate briefly the inflammatory relevance of ARE-related mechanisms to highlight their importance in pathophysiology and their potential in the development of future biological therapies.

“Individualized therapy strategies” involve strategies that allow treatment to be guided by patient-specific conditions. For this, robust biomarkers are needed. Examples of biomarker-guided therapies already in use are the treatment of insulin-dependent diabetes (biomarker: blood glucose level) or the treatment of hypertension (biomarker: blood pressure). By contrast, most immunomodulatory therapies are given according to the patient's body weight or the patient's drug blood level rather than according to biomarkers indicating the patient's state of the immune system. Herein we report on new biomarker-guided studies in the immunosuppressive treatment of transplant patients and patients with autoimmune disease and we discuss its benefits and pitfalls.

T cell therapies are increasingly used for the treatment of malignancies and viral-associated diseases. Initial studies focused on the use of unmanipulated T cell populations after allogeneic stem cell transplantation. More recently, the use of antigen-specific T cells has been explored. This chapter reviews the clinical experience with polyclonal Epstein-Barr virus (EBV)-specific cytotoxic T cells (CTL) for the treatment of EBV-associated malignancies. Strategies on how to improve the antitumor activity of EBV-specific CTL are being discussed. If effective, these strategies will have broad implications for T cell therapies for a range of human tumors with defined antigens.

Antibodies have been used successfully as therapeutics for over 100 years. The successful development of therapeutic human(ized) monoclonal antibodies (mAbs) in the last 20 years has demonstrated the potency of mAbs but also revealed some of their limitations. Studies in animals and humans demonstrated that it is possible to overcome some of these limitations using mixtures of mAbs or polyclonal antibody (pAb) preparations. pAbs from human and animal plasma are efficacious and safe therapeutics for the treatment of many diseases. Novel technologies are being developed for the production of human pAbs in genetically engineered animals. Immunization of such animals should allow the production of effective and safe high-titer antibody preparations for the treatment of infectious diseases, cancer, and autoimmunity.