Novel strategies for immune therapy of arthritis - Towards sustained disease remission

Abstract

The current treatment of Juvenile Idiopathic Arthritis and Rheumatoid Arthritis consists of a generalized suppression of the immune system. Despite improvement in disease outcome, there are some major disadvantages. The drugs need to be administered continuously in order to remain effective, do not lead to a cure, and may lead to damaging side effects. In addition, some patients remain unresponsive to the currently available treatment methods. For those severely ill children, autologous Bone Marrow Transplantation (aBMT) has been a promising last resource. It leads to drug free disease remission in a majority of patients for a long period of time. However, some patients have been shown to get a disease relapse in due time after all. In this thesis, we describe and characterize several ways to improve disease outcome of experimental arthritis with subsequent implications for translational therapy. Our principal aim was to identify methods to more specifically obtain long lasting disease remission with fewer side effects. We particularly focused on the underlying immunological mechanisms induced. The first part of the thesis focuses on characterizing and improving antigen specific therapy. Nasal administration of an antigen present at the site of inflammation has previously been shown to induce antigen specific immune tolerance. We were able to improve this mucosal tolerance induction in two ways: 1) by nasal administration of an altered peptide ligand, in which one amino acid has been replaced at a critical binding site, leading to the induction of regulatory T cells that produce IL-10 and TGF-beta at the site of tolerance induction as well as the site of inflammation; 2) by preceding mucosal tolerance induction by the administration of anti TNF-alpha, which shuts down the dominant pro-inflammatory milieu and is able to induce a more tolerogenic environment. This resulted in active immune regulation through the induction of CD4+CD25+Foxp3+ regulatory T cells producing IL-10. These studies have provided a significant step forward in the process of antigen specific immunomodulation by improving the clinical outcome and unraveling the immunological mechanisms involved. They are now ready to be translated to the human situation. In the second part of the thesis we focused on unraveling the working mechanism of aBMT in the Proteogylcan Induced Arthritis model. We show that irradiation followed by aBMT induced a rapid decrease of arthritis followed by stabilization of disease at a level below its severity before aBMT. In the first phase, suppression of the pro-inflammatory Th17 auto-antigen specific response occurred, which may have created the ideal window for the next phase, in which stabilization of the disease took place. In this second phase, we found an important role for CD4+CD25+ Foxp3+ Tregs in inducing a long-term restoration of the immune balance post aBMT. By unravelling the underlying processes induced by aBMT, future therapies may be devised in which a similar immunological mechanism can be induced, without the unwanted side effects of severe conditioning that precedes aBMT.