Antigen Specific Immunotherapy to Treat Autoimmune Disease
Treatment for autoimmune diseases has improved over the past several decades, but the optimal treatment for these conditions remains a work in progress. Type 1 diabetes (T1D), caused by autoimmune destruction of pancreatic β-cells, has been increasing in prevalence in recent years and can lead to many complications. Although intensive insulin therapy reduces the risks of complications from T1D, these risks are not eliminated. The current treatment options for rheumatoid arthritis (RA), systemic lupus erythematosis (SLE), and multiple sclerosis (MS), which include physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroids, disease-modifying anti-inflammatory drugs, anti-cytokine therapies, monoclonal antibodies, biological inhibitors of T-cell function, and B-cell inhibition, have had a significant impact on the quality of life of millions of patients but may have considerable drawbacks. Current treatment options are generally nonspecific immunosuppressants, and medications ranging from cyclophosphamide, glucocorticoids, and azathioprine to biologic therapies have been associated with an increased risk for infection, as well as several other adverse effects including hepatotoxicity, gastrointestinal perforation, nausea, diarrhea, and fatigue. Autoimmune diseases typically require lifelong therapy, as current drugs do not induce the restoration of immune tolerance to self-antigens. The ideal treatment would target disease-associated antigens rather than act as a global immunosuppressant, thereby limiting side effects as well as focusing on the underlying cause of the disease.
Autoimmune disorders are caused by physiologic immune responses to autoantigens. In diseases where the pathophysiology is understood and the culprit autoantigens are recognized, these pathways can theoretically be manipulated to induce immune tolerance to self-antigens. There have been considerable efforts to use autoantigen-based immunotherapy to modify the immune response, and studies in several animal models that simulate chronic inflammatory conditions have found that controlled administration of autoantigens can provide protection from autoimmune disease. Antigen-specific immunotherapy (ASI) for autoimmune disease has the potential to control the disease much like allergen-specific immunotherapy has been used to treat allergic diseases. However, there are fundamental differences between allergen-specific immunotherapy and ASI, including that allergic diseases consist of Th2 dominant responses whereas autoimmune diseases consist of Th1 and Th17 dominant responses. While the promising animal studies of ASI have not yet been translated into clinical efficacy, there have been encouraging advances.
Immunological changes induced by immunotherapy
ASI for autoimmune disease is conceptually similar to allergen-specific immunotherapy, which has been used with good (and potentially curative) effect for >100 years. ASI is thought to work through repeatedly exposing the immune system to increasing amounts of an allergen, which results in immune deviation (alteration in cytokine production) upon exposure to allergens from a Th2 response to a Th1 response as well as the induction of FOXP3+CD4+CD25+ regulatory T-cells (Tregs) that secrete interleukin (IL)-10 and transforming growth factor (TGF)-β. Antigen-specific therapy for autoimmune disease similarly aims to take advantage of immune deviation and the induction of Tregs in order to promote autoantigen-specific tolerance. The long-term disease modification and safety profile that is seen with allergen immunotherapy provides hope that a similar therapeutic modality could be effective for autoimmune diseases with known autoantigens.
In contrast to allergic diseases that are typically dominated by Th2 responses, autoimmune disorders are usually associated with Th1 and Th17 responses targeted against self-antigens. However, Th1, Th2, Th9, and Th17 cells all secrete IL-10 in response to chronic exposure to an antigen. Autoimmune diseases could potentially be treated by eliminating pathogenic Th1 and Th17 cells that are specific for autoantigens or by blocking the immune response directed by autoantigen-specific T-cells. Through repeated exposure to antigens, both allergen immunotherapy and autoantigen specific-immunotherapy aim to manipulate this phenomenon to promote tolerance.
Studies in animals have demonstrated the induction of Tregs and immune deviation with increased production of IL-4, IL-10, and TGF-β after administration of autoantigenic peptides. In humans, some studies have shown immune deviation consistent with Treg generation, peptide-specific IL-10, and increased levels of IFNγ, IL-5, IL-13, IL-17, IL-6, tumor necrosis factor-α (TNFα), and FoxP3 after administration of autoantigens. Yet, other studies demonstrated no clear biological effects after ASI.
Another method to induce immunological changes is via manipulation of dendritic cells (DCs). DCs are essential to the induction phase of the immune response and are therefore critically important in determining whether a response toward an antigen will be inflammation or tolerance. DCs can influence if naïve T-cells will undergo deletion, anergy, or differentiation. Deletion and anergy of T-cells can occur when DCs present the antigen without costimulation. DC responses to a specific antigen are influenced by the tissue environment and innate stimuli associated with that antigen. Emerging therapies are beginning to target DCs to induce tolerance.