TOLERAGE · Normalisation of immune reactivity in old age – from basic mechanisms to clinical application

When restoration of the immune response in older age is the target of basic and clinical research, boosting innate and adaptive immunity, e.g. by more efficient vaccination strategies, is the general approach. However, TOLERAGE has a fundamentally different focus, i.e. restoring the age-dependent decline of auto-tolerance that underlies the development of the paradigmatic age-associated diseases atherosclerosis (AS) and rheumatoid arthritis (RA). These diseases represent the major medical and socioeconomic burden in aging societies. They start earlier in life but become clinically manifest with increasing age. To reach this aim a consortium of ten partner groups was formed that have an outstanding track record in areas of immunology pertinent for this task. The work of TOLERAGE will focus on three major issues, viz. 1. Investigating basic principles of the induction of central and peripheral tolerance in mice against autoantigens, including heat shock protein 60 (HSP60) that has been shown to play a major role in the development of AS and RA. 2. Determination of the mediators of central and peripheral tolerance that are responsible for the T effector/T regulatory cell dysbalance in older age in general and in AS and RA in particular. 3. Translation of the results obtained in (a) and (b) into practical application for the prevention and treatment of AS and RA by appropriate vaccines. For all partners, important technical platforms will be available, including unique transgenic and knockout mouse strains, sophisticated models for in vitro and in vivo transfection of dendritic cells (DCs) and a well established Functional Genomics Facility.