Developing New Therapies for Rheumatoid Arthritis Using Antigen-Targeting to Plasmacytoid Dendritic Cells
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease in which the body s immune system mistakenly attacks the joints. This creates inflammation in the lining of the joints (the synovium), causing swelling, pain, and, over time, cartilage and bone destruction. In some cases, RA can affect other organs of the body such as the skin, eyes, lungs, and blood vessels. RA is the most common autoimmune diseases, affecting nearly 1.5 million Americans or ~ 1% of the adult US population. Without adequate treatment, RA can cause permanent disability, decreased quality of life, and increased risk of death. To date, treatments for RA have been aimed at decreasing inflammation and pain, and slowing down the disease progression. Most people with RA have only a partial response to available drugs, or respond to treatment for a limited period of time. Prolonged treatment with antirheumatic drugs also increases the chances of developing infections. Thus, instead of suppressing, an ultimate therapeutic approach for RA is to stop the autoimmune attack and to reinstate immunological tolerance. In recent years, significant progress has been made in understanding the underlying disease processes in RA and in identifying parts of the immune system that aren t functioning correctly. For example, infiltration of T cells, a type of white blood cells, within the synovium is a consistent finding in RA patients, suggesting that these cells play a central role in disease pathogenesis. In addition, activation of B cells and the production of autoantibodies (auto-Abs), molecules that can bind the body s own proteins and cause inflammation, have been associated with the development of RA. Some studies suggest that patients with RA have also reduced numbers of regulatory T cells (another type of T cell), which can function to suppress pathogenic T cells and limit auto-Ab production. Plasmacytoid dendritic cells (pDCs), a subset of immune cells, specialized in antiviral immune responses, have been also detected in the synovium of RA patients, but their role in RA is more controversial. On one hand, pDCs can produce large amounts of type I interferons (type-I IFNs), blood factors that cause widespread immune cell activation and inflammation. On the other hand, studies have suggested that pDCs may act to inhibit the activation of autoreactive T and B cells. These properties of pDCs render them as a potential immunotherapeutic target in RA. Recent findings have identified a unique molecule, expressed on the surface of human pDCs, called BDCA2 (blood dendritic cell antigen 2), which, upon engagement with anti-BDCA2 antibodies (anti-BDCA2 Abs), can inhibit the production of type I IFNs. In addition, delivering antigens (typically proteins or parts of protein that evoke immune responses) directly to the pDCs through BDCA2 can suppress immune responses against these proteins. We hypothesize that BDCA2-targeting could be an efficient new therapy to suppress the autoimmune attack in RA. We propose to (1) develop new anti-BDCA2 Abs, which can be used to target BDCA2 and deliver joint-specific antigens, such as type II collagen to the pDCs and (2) test for the first time their efficacy in suppressing RA in vivo. We will use genetically engineered mice, which express human BDCA2 specifically on their pDCs, in which we will induce RA-like disease before or after administrating anti-BDCA2 Abs, conjugated to collagen peptides. This will allow us to test if targeting Ags to BDCA2 can "immunize" mice from developing RA, or reverse symptoms in already established disease. We will also examine the effects of anti-BDCA2 Abs in suppressing T and B cells. Our prediction is that administration of anti-BDCA2 Abs will not only suppress disease progression, but also result in long-term disease remission with fewer side effects. RA and its complications can significantly affect the performance of military personnel and impair the well-being of Veterans, the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610578
Entities
People
- Natalia Giltiay
Organizations
- United States Army
- University of Washington