CHOP nephrologist Ulf Beier, MD, is involved in a series of NIH-funded studies. They examine whether modifying a subset of cells found in the immune system could lead to better treatment options for recipients of solid organ transplants and for those fighting autoimmune disease.
Traditional post-transplant treatment regimens call for powerful immunosuppressants that protect the new organ from rejection. While these drugs are effective at reducing rejection rates in the first year post-transplant, they also attack the immune system in a very non-specific way and have dangerous side effects, such as infections and cancers.
Beier’s work aims to improve upon current immunosuppressants by approaching the immune system in a new, selective way. The target: regulatory T-cells (Tregs) which keep the immune system from overreacting or attacking itself. Rather than eliminating this subset of T-cells, which typical immunosupressants would do, Beier and his colleagues are investigating how to make Tregs stronger.
Modifying Tregs to improve their suppressant power
Most Tregs contain a protein called forkhead box P3 (Foxp3) which plays a central role in this cell’s function. Properties of proteins like Foxp3 can be altered by enzymes that are also within the cell; these enzymes are called histone deacetylases (HDACs). An HDAC called Sirtuin-1 (Sirt1) deacetylates Foxp3 protein, which makes Foxp3 more susceptible to breakdown and diminishes its ability to bind to DNA to suppress inflammatory genes.
If Sirt1 is deleted genetically or inhibited using drugs, it is possible to strengthen the suppressive function of Tregs. This might be a new way to approach treatment of transplant recipients who are at risk of rejection. In fact, Beier and colleagues published results of a study in March 2011 which showed that when mice’s Treg lack Sirt1, or when they are treated with Sirt1 inhibitors, had prolonged allograft survival in an immunological heart transplant model. This study is the basis for follow up work happening now.
New immunology research for transplantation and autoimmune therapies
There are three focus points for the current research into Sirt1 targeted Treg therapy:
- Translate Sirt1 findings from an immunological into a functional model
To test if the findings of prolonged allograft survival translate into improved biological function, future experiments will assess whether deleting or inhibiting Sirt1 will have the same desired effect when the mice depend on their transplanted tissue or organs to perform a biologic function. This will be achieved using diabetes and kidney transplant models. In these mice, organ failure will be induced by either destroying the insulin-producing cells (causing diabetes), or by removing both kidneys (causing renal failure). Subsequent transplantation of antigen-mismatched organs (islet cells and kidney allografts) will therefore have a measureable biological outcome, i.e. glycemic control or renal function. Since the organ transplant is mismatched, it will be recognized as foreign by the host, and induce an immune rejection. This allows comparison of organ recipients lacking Sirt1 (either through Treg specific deletion, or through pharmacologic inhibition) against those who have functional Sirt1.
- Inhibition of Sirt1 to treat autoimmune disease
Tregs play a role not only in transplantation, but also in autoimmune disease. Beier and his research team believe that enhancing Tregs by deleting or inhibiting Sirt1 might make these cells more effective at controlling the immune system so it won’t attack healthy tissues. They’ll test this theory in autoimmune inflammatory bowel disease models and assess whether Treg strengthened through Sirt1 inhibition or deletion are capable of improving the burden of autoimmune mediated disease in vivo.
- Understanding the molecular mechanisms involved in Sirt1 inhibition
It’s crucial that researchers understand precisely how the process of Sirt1 inhibition works. The effect of Sirt1 on Foxp3 is understood – Sirt1 deactylases Foxp3, making it more vulnerable to destruction within the cell and less potent in binding to DNA. But there are also more mechanisms involved. Sirt1 also binds together with other transcription factors that are important for Treg function. So if you remove or inhibit it, then these processes are also altered and that must be studied further. Beier and his colleagues will also examine the role that other HDACs play in Treg function, and look for potential synergies that could make Tregs even stronger through combining several isotype specific HDAC inhibitors.
The future of transplant and autoimmune therapy
The ultimate goal of Beier’s work is to find alternative drugs for immune suppression. The hope is that eventually, these drugs could improve long-term allograft survival in every organ system, and offer better treatment options for autoimmune diseases. This research is still at the very early stages and is far from a clinical trial, but shows promise that important advances in immunotherapy are in our future.