Targeting T regulatory cells combined with temporary immune suppression: a double edged sword for the treatment of autoimmune arthritis

Juvenile Idiopathic Arthritis (JIA) is one of the most common autoimmune diseases in childhood and a major cause of chronic disease with serious disability and loss of quality of life. The current treatment of human arthritis consists of general immune suppression, e.g. through agents that block the TNF-alfa pathway. Despite the efficacy of these immune suppressive strategies in controlling disease symptoms, three major problems still remain: 1. The treatment is non-specific and therefore has considerable side effects, in particular an increased vulnerability for infections. 2. Some patients do not respond to these new forms of therapy, and even more patients become unresponsive over time. 3. The treatment fails to induce a real cure of the disease: a lasting remission of the symptoms after withdrawal of the treatment. So far, the only treatment that is capable of inducing such a lasting, medication-and symptoms free remission in JIA is autologous Bone Marrow (or Stem Cell) Transplantation (aBMT). aBMT, a “last resort” for patients who are refractory to any type of therapy, leads to a (temporary) cure of the disease in a majority of patients. Data from patients with JIA suggest a role for so-called regulatory T cells (Treg) in this renewed state of immune tolerance after aBMT (de Kleer et al, Blood 2005). It would be a major breakthrough if we can understand the mechanisms underlying this success and apply it to develop alternative strategies, aiming at specific immune modulation to restore long-term immune tolerance. One of the most promising approaches to achieve this goal is mucosal induction of antigen specific regulatory T cells (Treg). The mucosal immune system is highly efficient in inducing tolerance and, consequently, mucosal administration of self-antigens involved in autoimmune inflammation can lead to a restoration of immune tolerance (van Eden & Prakken, Nature Rev Immunology 2005). The proof of principle for translation of this technology into human arthritis was established in a first Phase I/II clinical trial in Rheumatoid Arthritis (Prakken, PNAS 2004). This approach is highly efficacious in preventive protocols (before disease induction), but less effective in treating ongoing disease. Assumedly, the induction of antigen-specific tolerance is hampered by mediators of chronic inflammation, such as pro-inflammatory cytokines. Therefore – in line with the success of aBMT - combination therapies that target both a-specific and specific elements of autoimmune inflammation may be more successful. In fact, we have shown that combined therapy of anti-TNF-alfa and mucosal peptide therapy improves efficacy of treatment of experimental arthritis through the induction of Treg (Roord et al, PlosOne 2006). In this project we will take the next step by exploring the therapeutic potential and underlying mechanisms of aBMT and combination therapies in the mouse model of proteoglycan (PG) induced arthritis. Proteoglycan induced arthritis (PGIA) has close clinical, immunological and histopathological resemblance to human arthritis. Also, other than most experimental mouse models, it has a chronic relapsing remitting course, which allows exploring therapeutic interventions during ongoing disease. Recently, we have shown that aBMT in the same model leads to restoration of the immune balance and the induction of Treg (Roord et al, Blood 2008). We here propose to study firstly: what determines the success and failure of aBMT, and, secondly: how this knowledge can be translated to design combination therapy that yields similar effects but without the toxicity of aBMT.