ISS immune modulation, vaccination and the regulation of arthritis

Abstract

Bacterial DNA contains unique unmethylated CpG motifs. The cytosine-phosphate-guanisine (CpG) sequence of this motif has an unmethylated cytosine which is suppressed or methylated in mammalian DNA. Synthetic oligodeoxynucleotides containing these CpG (CpG-ODN) motifs are called Immunostimulatory DNA Sequences (ISS). Our goal is to gain a better understanding of how ISS, a TLR9 agonist, modulates the immune response and how this response may influence chronic inflammation in those with Juvenile idiopathic arthritis (JIA). JIA is the most common rheumatic disease in children with an incidence of 1 in 1,000. It is defined as chronic arthritic conditions lasting for a minimum of three months affecting children under the age of 16 years. JIA is often characterized by a waxing and waning course, with flares separated by periods of time during which no symptoms of active synovitis are noted (remission). This is especially the case in the Oligoarticular subtype (OA-JIA) that is characterized by prolonged periods of medication-free remission of the disease. However, the polyarticular subtype (PA-JIA) is more severe and has a worse prognosis. The first part of this thesis demonstrates the potential candidacy of ISS as a future vaccine adjuvant with its Th1 promoting properties when administered systemically as well as at mucosal sites. Furthermore, ISS was shown to be arthritogenic in an experimental arthritis model such as adjuvant arthritis (AA). This led us to explore the safety and efficacy of a human vaccine with a bacterial component such as the MenC vaccine in the JIA population addressing the issue of whether an immune response to a bacterial antigen may harbor the risk of exacerbating autoimmunity in susceptible individuals. The MenC vaccine proved to be safe and effective in the JIA population, despite administration of immune suppressive medication. Moreover, we also investigated the quality and quantity of the immune response elicited by the OA-JIA as well as PA-JIA after vaccination towards vaccine and arthritis associated antigens including their regulatory mechanisms. When compared to the OA-JIA group or healthy individuals, the poly-articular subgroup’s greater T cell proliferation to an environmental trigger (the MenC vaccine) corresponds to a dysfunction of their CD4+CD25+ Tregs (despite their greater numbers), the suppressors of the immune response. This suggests that the hyperproliferation seen in the PA-JIA may be the result of the lack of function of the CD4+CD25+ Tregs potentially due to their higher levels of TNF-alpha. In summary, vaccinations and, by extension, infections may break tolerance in those predisposed to autoimmunity potentially leading to aggravation or even induction of the disease. It is conceivable that subunit vaccinations do not evoke a pro-inflammatory response that is strong enough to induce or exacerbate chronic inflammation. However, the risk may still exist, especially for live-attenuated vaccines known to induce more vigorous immune response. Therefore, it is important to evaluate the effects of every new vaccine in those predisposed to chronic inflammatory diseases both clinically as well as immunologically.