Antigen-Specific Immune Tolerance through Dendritic Cell Modulation

Abstract

The immune system is a complex network of cells, tissues, and molecules that work together to protect the body against bacteria, viruses, and other pathogens. The immune system is very good at recognizing molecules on the surfaces of pathogens, called antigens. When the immune system malfunctions, however, it will not be able to distinguish pathogenic antigens and self-antigens anymore. Therefore, the immune system will start attacking your own healthy cells and tissues. This is called loss of immune tolerance, and can lead to the development of autoimmune diseases, such as rheumatoid arthritis (RA). RA is a chronic autoimmune disease that can cause painful inflammation in the joints. Current treatments focus on improving the quality of life by reducing disease symptoms. The downside to these medications is that they not only inhibit the immune response to self-antigens, but also to pathogenic ones, leaving patients more susceptible to other diseases. To circumvent this, antigen-specific immunotherapies, targeting only the self-antigen causing the autoimmune disease, could provide an excellent solution. In this thesis, novel ways for inducing antigen-specific immune tolerance are explored. The immune cells of interest are dendritic cells (DCs), which are very adept at processing and presenting antigens on their cell surface to T cells. Only T cells that recognize the antigen that is presented by the DC can interact with them. The DC and T cell “communicate” through the use of signalling molecules called cytokines. Depending on the cytokines the DC secretes, T cells can either induce an inflammatory immune response (through effector T cells), or inhibit an immune response (regulatory T cells (Tregs)). For the treatment of RA, DCs should “tell” T cells that they have to inhibit the immune response against the antigen that causes the inflammation. To help DCs do this, these cells can be modulated by immunomodulators such as retinoic acid and dexamethasone to become tolerogenic DCs (tolDCs). TolDCs are able to induce Tregs and inhibit the effector T cell response in an antigen-specific way. To induce RA-specific tolDCs, DCs need to be exposed to an immunomodulator and RA-relevant antigen at the same time. To do this, we packaged an RA-antigen and immunomodulator together in liposomes. Liposomes are nanoparticles that consists of a lipid bilayer, surrounding an aqueous core. DCs that took up liposomes that were carrying an RA-relevant antigen and an immunomodulator were able to induce antigen-specific tolDCs and Tregs in vitro and in vivo. Next, we investigated the effectiveness of these liposomes in a mouse model for RA. By injecting mice with our liposomes before the onset of RA, the development of rheumatoid arthritis could be prevented. Even in mice that had already developed RA, treatment with our liposomes significantly inhibited disease development. Furthermore, we see that mice that were treated with our liposomes have more immune inhibiting molecules in their paws, that help with the local suppression of the immune response. In conclusion, this thesis provides novel insights into the effect of dendritic cell modulation on the induction of antigen-specific immune tolerance.