Reprogramming autoimmune diseases

A new therapy in clinical trials is modifying a type of immune cell to re-programme the underlying responses at play in rheumatoid arthritis and other autoimmune diseases.

Ranjeny Thomas and her team at The University of Queensland’s Diamantina Institute developed the immunotherapy, which comprises liposome nanoparticles encapsulating an immune-modulating drug and a joint-specific self-antigen (something that the body should see as ‘self’ and therefore should not cause an immune reaction). The technology is being commercialized by UniQuest, The University of Queensland’s technology transfer company.

Rheumatoid arthritis is triggered by immune responses that attack the lining of the joints, causing inflammation and pain. “Currently, patients with rheumatoid arthritis receive drugs that block inflammation to improve their symptoms, but it’s very difficult to withdraw patients from these treatments, because the drugs don’t restore immune regulation or tolerance,” explains Thomas. The possibilities of adverse events, incomplete responses and eventual loss of efficacy also plague these existing options. Thomas’s findings could have important implications for those living with the chronic and debilitating disease — a group making up about 1% of the global population.

Thomas’s research focuses on the function of dendritic cells, which are fundamental factors in autoimmune diseases. She describes these cells as “chief conductors” that orchestrate the immune system’s response as they process and present antigens on their surface to other cells. T cells play a leading part, responding to the dendritic cells’ signals by driving antibody production or attacking foreign (non-self) antigens or infected cells.

In autoimmune diseases, aberrant dendritic cell activation or function is associated with a loss of regulation in the process of T cell activation, resulting in an expansion of immune cells programmed to attack the host’s own cells. Inflammation driven by this mechanism is linked to symptoms associated with autoimmune diseases, such as rheumatoid arthritis, Sjögren's syndrome, vasculitis, type 1 diabetes and celiac disease.

Almost 20 years ago, Thomas began examining the dendritic cells of mice that lacked RelB, a sub-unit of the transcription factor NF-κB, which regulates the function (and development) of dendritic cells. “When we exposed these dendritic cells to antigen, we found that the responding T cells were regulatory rather than activated or primed to fight infection, and this suppressed an immune response,” explains Thomas.

As a clinical researcher, Thomas says she knew immediately that the finding was significant. “The identification of a molecular switch in dendritic cells that turns specific T cells in the immune system from activation to regulation could be extremely powerful therapeutically,” she points out.

Thomas and her team then developed a method to treat human dendritic cells, looking to achieve the same outcome as seen in the dendritic cells in RelB-deficient mice.

Outside of the body, the dendritic cells of rheumatoid arthritis patients were enriched and exposed simultaneously to rheumatoid arthritis antigen and a drug that blocks NF-κB signaling. These cells were then returned to the patients. After this treatment, the researchers measured signals that suggested that the immune responses of T cells reacting to rheumatoid arthritis antigen were suppressed, and inflammation was reduced. “This was the first proof of concept that the immune system of rheumatoid arthritis patients can be modified with their own dendritic cells,” says Thomas.

There are several other ongoing trials in which dendritic cells from patients with autoimmune diseases have been extracted, modified by exposure to their self-antigens, and reintroduced to the patient. Although this approach is proving to be safe and may reset the immune response, it’s difficult to move beyond proof-of-concept trials due to the manufacturing, regulatory, and financial challenges of large-scale, patient-specific dendritic cell therapy.

To address this, Thomas’s team developed the clinically and commercially practical solution of modifying dendritic cells within the body. This involves liposome nanoparticles that co-encapsulate an NF-κB inhibitor and an antigen commonly found in rheumatoid arthritis. These liposomes are readily engulfed by dendritic cells, which then stimulate the generation of regulatory T cells, and suppress the activity of inflammatory T cells, allowing the desired immune resetting in the body without the need for a patient-specific cell therapy.

In mouse models of rheumatoid arthritis, administering these therapeutic liposomes suppressed pre-existing immune responses in an antigen-specific manner and reduced clinical signs of the disease. Importantly, the effect was fast; dendritic cell uptake occurred within minutes, immune tolerance was observed within days, and T cell regulation was sustained by the presence of the self-antigen.

While initial clinical trials of products such as liposomes or dendritic cell therapy focus on safety and immune responses, future clinical trials will help to determine whether this approach can be used to treat existing rheumatoid arthritis or to prevent disease in genetically at-risk individuals soon after the first symptoms develop.

If clinically effective, says Thomas, such precision medicines could herald a new era for the treatment of other autoimmune diseases, such as type 1 diabetes and vasculitis.