In rare disorders the process of translation from laboratory observation to effective drugs require particular expertises. Besides a thorough understanding of human pharmacology, investigators will need to be trained in use of preclinical model systems, the development of quantitative indices of drug mechanism and response, the use and interpretation of genomic, lipidomic and proteomic information, the physiology of evoked phenotypes, novel biomarkers, and the use of bioinformatics to harvest and integrate preclinical and clinical information relevant to drug response. In this application we propose a new educational experience to integrate elements of disciplines previously segregated within basic science and clinical medicine. The translational space imposed on the process of drug development is defined as stretching from Proof of Concept (PoC) in cells and model systems to completion of studies of drug mechanism and variability of response that afford a basis for individualized dose selection. An effective translation from bench to bedside requires not only a close networking between basic scientists and clinicians but also the need to address ethical and regulatory issues. These last include pre-clinical and early-phase clinical development, biomarker validation, study design and management, data analysis, regulatory submission and research governance. Go to Event I

It has been recently discovered that the innate immune system can recognize key molecular signatures borne by pathogens called pathogen-associated molecular patterns (PAMPs). Receptors that recognize these PAMPs, referred to as pathogen-recognition receptors (PRRs), play a key role in eliciting inflammation. More recently it has been shown that damage associated molecular pattern molecules (DAMPs) present on molecules released during cell damage can also be recognized by the macrophages and other cells of the immune system. There is now large and growing evidence that DAMPs recruit inflammatory cells and mediate signals between lymphocytes, dendritic cells and macrophages. The study of PAMPs- and DAMPs-mediated innate immunity activation represents therefore a new and very promising frontier in research related to the pathogenesis of chronic inflammation. The recognition of the role that PAMPs, DAMPs and their receptors play in inflammation could lead to the identification of drugs that can selectively target and/or modulate the activity of the innate immune system.

Many rheumatic disorders, such as rheumatoid arthritis, are considered secondary to an abnormal, Th1 skewed, response. Others, such as systemic lupus erythematosus, are characterized by an abnormal B cell response. Recently however strong evidence has emerged pointing to an important role of B cells also in the pathogenesis of other diseases such rheumatoid arthritis. Finally, a major advance in recent years has been the identification of physiological regulatory mechanisms within the cellular immune response. Several types of regulatory T cells suppressing the function of other T cells have been identified and there is growing evidence of the role that these mechanisms play in the pathogenesis of autoimmune diseases. In particular in juvenile idiopathic arthritis, there is evidence that endogenous heat shock proteins may elicit specific regulatory T cell. Moreover, there is growing evidence that mesenchymal stem cells can exert and important immunomodulatory effects. All these finding open new avenues of therapeutic possibilities that can exploit the physiologic regulatory mechanisms that operate within the immune system.

During the last years it has been discovered that a group of diseases is due to mutations of genes that are involved in the control and in the regulation of the inflammatory response. These inherited diseases, that have been called "auto-inflammatory", are characterized by recurrent fever attacks associated with other symptoms such as cutaneous, articular and intestinal manifestations. The identification of the responsible gene has led, in some of these diseases, to the discovery of effective treatments such as IL-1 inhibition in NALP3/cryopirin related diseases. The "auto-inflammatory" diseases so far identified represent the tip of an iceberg in which a large group of diseases and pathogenic mechanisms remains to be identified. Information coming from the comprehension of the molecular mechanisms leading to inflammation in these genetic disorders may shed light on the pivotal points of control of inflammation and may have important implications for other chronic inflammatory disorders of unknown etiology with a great socio-economical impact, such as rheumatoid arthritis.