As the thymus is a unique site for T cell differentiation and development  the involution process results in a dysfunction of the cellular immune system. Less naïve T cell develop that can combat infections. In addition, T cells in old persons are more prone to attack normal organ and cause autoimmune diseases like atherosclerosis (AS) and rheumatoid arthritis (RA).

Glucocorticoids (GC) are hormones produced in the adrenal glands which strongly influence immunity in both positive and negative ways. Basal levels are important for normal immune functions and increased levels, during different types of stress responses, negatively feed-back regulate excessive T cell responses. Increased GC levels also strongly influence the thymus gland by killing thymocytes through a controlled death mechanism called “apoptosis”.

We have found the GC hormones also are produced within the thymus gland itself  and that GC synthesis by thymocytes is age-related. We will further characterize the regulation of this synthesis and its significance in relation to thymic involution and the development of autoimmune diseases.

GCs may also be useful for “tolerogenic vaccination”. This type of therapeutic vaccination aims at restoring immune tolerance against tissues that are undergoing autoimmune attack. We will approach this by two ways. First, by vaccinating with a combination of GC and antigen in vivo with the aim to induce T cells that can induce tolerance, regulatory T cells (Treg). Second, by vaccination with antigen presenting cells that are treated with GCs and and antigen in vitro and therefore develop the property to induce Treg responses in vivo.

The role of GCs in the development of autoimmune diseases will be furter studied by the use of transgenic mice with an increased GC-sensitivity in thymocytes and T cells in models for AS and RA.