Objective
Our work to date has primarily focused on understanding the immunomodulatory potential of Bregs in mouse models. Our key findings are that Bregs engage multiple mechanisms to effectively prevent immune rejection and that these cells are most effective when they are endowed with specificity for the target donor islets. This was clearly observed in our mouse models in which we showed that Bregs generated from mice carrying a clonotypic B cell receptor for the model antigen OVA, which was expressed on the islet graft, were more potent than those from mice with a diverse receptor repertoire. This led us to explore the generation of Bregs carrying highly-specific Chimeric Antigen Receptors (CARs) to augment the regulatory activity of these cells. The objective of the current proposal is to develop this technology to facilitate islet cell replacement for patients with type 1 diabetes. To this end, we will capitalize on recent developments in lymphocyte-based cell therapies, such as CAR-T cells that permit exquisite targeting and immunomodulation. We will first use mouse models to develop CAR-Bregs that are able to protect transplanted islets. Then we will extend our studies from mouse Bregs to human Bregs. Finally, we will explore additional opportunities to improve the efficacy of these cells through more advanced Breg-augmenting engineering approaches.
Background Rationale
Our lab initially focused on the regulatory potential of Tregs to prevent allograft rejection; however, our studies unexpectedly demonstrated that B cells were more potent at preventing graft rejection than Tregs and also promoted the expansion of Tregs, perhaps adding to the immunosuppressive milieu. This surprising finding prompted us to focus our efforts on investigating the regulatory properties of this underappreciated adaptive immune cell type, regulatory B cells. Based on our observation that Bregs are most effective at preventing rejection when the cells have specificity for the target donor islets, we have recently extended our studies to generate human CAR-Bregs to function as a groundbreaking cellular therapy to protect islets after transplantation.
Description of Project
Pancreatic islet cell transplantation has provided proof of concept that diabetes can be effectively cured. The problem that remains, however, is the requirement for immunosuppression to prevent rejection of the foreign cells as these medications are associated with serious side effects. For this reason, we are pursuing novel approaches that permit transplantation without the need for perpetual toxic immunosuppressive drug therapy. Our approach relies on the use of a unique lymphocyte population, B lymphocytes, that when activated exert immunoregulatory properties that may prevent transplant rejection. We term these “immunoregulatory B cells” or Bregs for short.
Anticipated Outcome
Our preliminary observations support the development of a novel Breg cellular therapeutic to facilitate islet cell replacement and enable sustained survival without intense immunosuppression. We hypothesize that CAR-Bregs directed towards both allogeneic- and auto-antigens carried by transplanted islets will provide potent protection. We envision coordinated delivery of stem cell derived islets with CAR-Bregs directed to minor and/or major histocompatibility antigens expressed on these cells. For example, the Vertex stem cell product in their current clinical trial is known to carry a class I molecules that is an attractive target for future CAR-Bregs.
Relevance to T1D
The development of highly-functional islets derived from stem cells offers a potentially limitless supply of donor islets for use in islet cell replacement therapy, bringing the reality of a cure for T1D within reach. Tolerance-inducing therapies would address a major clinical challenge related to widespread use of islet cell replacement by securing the long-term survival of stem cell derived islets without the use of toxic immunosuppressive regimens. We believe that the Breg technology developed by our group has the potential to support sustained graft survival, replacing conventional immunosuppression. We look forward to working with BT1D to develop new and improved therapies for patients with type 1 diabetes.