Characterization of Rheumatoid Arthritis-Specific Immune Responses and Evaluation of a Novel Peptide Immunotherapy in the Collagen Induced Arthritis Mouse Model
Rheumatoid arthritis (RA) is an incurable autoimmune disease that predominately affects the joints. RA is characterized by a breakdown of immunological tolerance against citrullinated and homocitrullinated proteins/peptides (CitP and HomoCitP). To study RA, mice with collagen induced arthritis (CIA) are commonly used; however, it remains unclear whether this pre-clinical model adequately represents disease-specific autoimmune responses. Therefore, this thesis first evaluated the suitability of CIA mice for studying RA-specific immune responses and then investigated the efficacy of a novel transdermal immunotherapy (TI) in this model. We hypothesized that CIA mice would develop immune responses to CitP and HomoCitP, and that the proposed TI would reduce arthritis and RA-specific immune responses. We found that the adjuvant concentration used to induce CIA influenced joint histopathology, with the 1.0 mg/mL concentration promoting the greatest joint damage. Furthermore, CIA mice exhibited joint pain (measured by von Frey behavioural testing), and osteopenia (measured by micro-computed tomography imaging and bone mineral density analysis). Arthritic mice developed elevated splenic T cell proliferative responses to HomoCitP, but not CitP, which strongly correlated with joint swelling, pain, and histopathological damage. IgG antibodies against HomoCitP and CitP were rare in CIA. These findings supported the use of this model in studying novel RA-specific treatments. Thus, we next tested a CitP and HomoCitP TI, which is hypothesized to restore immune tolerance when applied to the skin. Compared to a mock treatment, TI reduced arthritis scores and pain-like behaviours in CIA mice. Furthermore, mitogen-induced splenic T cell proliferation was reduced in the TI vs. mock treatment groups, suggesting that bystander tolerance occurred. However, no differences were seen in joint histopathology or bone mineral density. Overall, CIA mice developed immune responses to HomoCitP which correlated with increased arthritis severity, indicating that HomoCitP-specific T cells may be potential contributors to RA pathogenesis. However, T cell responses to CitP did not develop in CIA mice, highlighting some differences between the animal model and human disease. Furthermore, our findings indicate that TI may reduce disease symptoms by modulating immune responses, underscoring the potential of this novel approach for RA treatment.
Animal Models, Autoantibodies, Autoimmunity, Citrulline, Collagen Induced Arthritis, Homocitrulline, Immune Tolerance, Rheumatoid Arthritis, T Cells, Transdermal Immunotherapy
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