Towards cell therapies to treat Type I Diabetes

“Can we walk around the lab while we talk?” asks UW Carbone Cancer Center researcher, Rahul Das, PhD, with a big grin. He grabs an ice bucket with test tubes and heads from the cell culture room towards his lab’s chemical room, where on the bench opposite the chemicals is a computer connected to the lab’s workhorse instrument.

Das is a new postdoctoral fellow in the laboratory of Jacques Galipeau, MD. Galipeau himself started as faculty in UW’s Department of Medicine the fall of 2016, bringing to this campus expertise in translational immunology. The lab’s focus is in using cell therapy to treat auto-immune diseases and cancer.

The immune system deals with the invasion of bacteria, viruses, other microorganisms, and even cancer cells by mounting an inflammatory response with a dedicated set of specialized cells and proteins. B cells and T cells work together to recognize invading foreign entities from the other cells of the body. B cells produce antibodies that bind to specific regions on the intruding cells, or antigens. A protein called HLA then binds to the antigen, and the antigen-HLA complex serves as a signal for activated T cells to target these antigen-presenting cells for destruction.

The study of the immune system has led to life-saving treatments for patients. For example, one type of cancer immunotherapy, CAR-T cell therapy, focuses on better directing T cells towards killing cancer cells. The treatment involves isolating T cells from the patient’s blood and engineering the patient’s T-cells to display chimeric antigen receptors (CAR) on their cell surface which combine the antigen-recognition capabilities of B cell receptor proteins with the signaling portion of T cell receptor proteins.

Rather than studying the T cells, the Galipeau lab has focused on B cells. In a healthy immune system, some B cells release small proteins called cytokines that in this case signal to T cells to stop the inflammatory response. On the other hand, people with chronic inflammatory diseases are thought to have deficiencies in the number and activity of these suppressor or regulatory B cells (Bregs).

 “Bregs hold tremendous therapeutic potential since they selectively affect activated T cells,” says Das, still setting up for his experiment by testing different acquisition parameters on the instrument.

Finding the right environment to promote Breg development has been a major area of research within the Galipeau lab. Initially, the lab was interested in studying signaling events between cells triggered by cytokines, and their work uncovered how the fusion of different cytokines into one bioactive molecule can dramatically affect the immune response. In bringing together two different types cell surface receptors, these GIFT fusokines (granulocyte-macrophage colony-stimulating factor [GM-CSF] interleukin fusion transgenes) change the way proteins within the cell interact with each other after the receptors are activated. These changes in cellular signaling events are responsible for changes in the immune response. Surprisingly, one of the early GIFT fusokines developed had the unexpected property of being able to convert B cells into Bregs. Bregs made using this approach have been used successfully in mouse models of the autoimmune disease multiple sclerosis.

This research made Das excited to join the Galipeau lab with more ideas for applications of these cell therapy approaches. Bridging his background studying insulin signaling and the genetic factors underlying Type 2 diabetes with the lab’s interests in autoimmune diseases, Das’s central research focus is now Type 1 diabetes (T1D).

T1D, also known as juvenile diabetes, is an autoimmune disease in which immune cells attack the insulin-producing beta cells of the pancreas, resulting in the body being unable to properly regulate blood sugar levels. Because they are not able to naturally produce insulin, Type I diabetics rely on synthetic insulin administered via injection or pump, and these patients need to constantly check their blood sugar levels to avoid dangerously low or high levels. Insulin therapy helps T1D patients survive, but it does not cure them of the disease. Even with diligent monitoring of blood sugar levels, patients still have difficulties striking a balance between diet, exercise, and their insulin dosage.

“There is a huge need for cell therapeutic approaches in the prevention and treatment of T1D,” says Das, who is has now started acquiring data from his samples and is explaining to what all the different plots on the computer screen mean.

Currently, he is currently using cell culture and mouse models of T1D to test the efficacy of Bregs in suppressing the immune response. Having only been in the lab six months, his project is in its early stages, but he hopes that his work could form the foundation for future studies in human patients. The overarching goal of this research would be that in the future Bregs prepared from a patient’s own blood could be used to prevent the infiltration of pancreatic beta cells by immune cells.

For the time being, though, Das is happy to spend his days in “a productive and encouraging environment,” where he can continue doing research he finds fulfilling and pursuing his dream to come a professor.