The project is to look at novel approaches to normalise immune function in old age on three complementary levels.

• The first of these is to look into the basic mechanisms of age-related changes in immune function, concentrating on how self-antigens are displayed in the thymus, the identification of auto-reactive T cells, the effect of aging on regulatory T cells (which prevent an over-reaction of the immune system), hormonal influences (particularly glucocorticoids), and the action of cytokines in aging organisms.

The process leading to the expression of heat shock, or stress, proteins starts with a stress for the cell (for example infection, chemicals, oxidation, UV light), which is registered by the cell. The cell reacts to protect itself by expressing heat shock proteins which help to keep the cell functioning normally. If too many heat shock proteins are expressed, or for too long, the body recognises this as a warning signal and mobilises further systems for protection. Several families of HSP exist, in the present context heat shock protein with a molecular weight of 60,000 Da (HSP60) is the central focus of the project. © Georg Wick

• The second part of the project will focus on two paradigmatic age related diseases, atherosclerosis and rheumatoid arthritis. The effect of aging on the autoimmune reaction to a protein induced when cells are put under stress called heat shock protein 60, which has been shown to be an important auto-antigen in both of these diseases, will be investigated in detail. In particular, attempts will be made to jointly apply knowledge gained in the first part by making the immune system tolerant (inducing tolerance) to heat shock protein 60 in mouse models of both atherosclerosis and rheumatoid arthritis, at various ages and disease stages. The knowledge gained of how the immune system ‘ages’ will then be used to focus and fine tune efforts inducing tolerance towards heat shock protein 60. 

Solid ribbon model of Hsp60 (based on Protein Database entry 1SRV) Click on image for further source information.  Source of Image: Walsh, M.A., Dementieva, I., Evans, G., Sanishvili, R., Joachimiak, A. Taking MAD to the extreme: ultrafast protein structure determination. Acta Crystallogr., Sect.D v55 pp.1168-1173 , 1999

• The ultimate goal of TOLERAGE is to lay the basis for the development of vaccines against atherosclerosis and rheumatoid arthritis in humans, to reduce the incidence and severity of these diseases, and reduce the burden they cause to society.  

The presence of large amounts of heat shock protein 60 (black colouring) are shown on a rabbit artery after treatment with a chemical isolated from bacteria. Protein expression is particularly intense around the branching point due to the changes in blood flow in this region adding an additional stress for the cells in this area.     © Marius Wick

• The third element, the identification of the mechanisms responsible for a normalisation of the immune response after appropriate intervention (e.g. nasal/oral application of fragments of HSP60 or HSP60 compoonents packed into and transferred via infection with harmless "transport viruses") on the cellular level, is an important practical component of the project. Investigations elaborating the mechanisms responsible for tolerance are to address the role of central and peripheral deletion of T cells, the action of regulatory T cells, the balance of immune regulatory cytokines, and hormonal (particularly glucocorticoids) influences during the aging process.