Objective
The central objective of this project is to develop a technology that makes it possible to follow the immunological fate of transplanted beta islets with ultrasound. To enable this technology, we will engineer biocompatible human cell lines to sense specific biomolecular markers of immune rejection and, upon doing so, express acoustic reporter genes – proteins that produce ultrasound contrast. We will develop methods to co-encapsulate these cells with islets and demonstrate that the two cell types are functional after implantation in providing glucose control and a noninvasive readout of immune rejection.
Background Rationale
A major challenge in islet transplantation therapies for type 1 diabetes is immunological attack and graft rejection. Despite recent advances in immunoisolation technologies for allogeneic islet transplantation, immune responses remain a critical issue, and the only viable clinically proven method for islet transplantation requires chronic systemic immunosuppression, which has multiple undesirable side-effects. If we could monitor immune reactions to transplanted cells noninvasively, this would allow physicians to track the status of the transplant and adjust immunosuppression regimens in individual patients. In this project, we will develop cell-based sentinels of anti-transplant immunity that can be included with encapsulated islets, sense local immune signals and produce ultrasound contrast. Ultrasound is among the world’s most commonly used medical imaging technologies. It is inexpensive, portable and uses no ionizing radiation. Ultrasound waves penetrate multiple centimeters deep into tissues, providing access to most human organs with an imaging resolution on the order of 100 µm. Given its widespread availability and convenience, ultrasound is an ideal modality for chronic monitoring during outpatient checkups. By comparison, nuclear imaging technologies like PET or SPECT expose patients to ionizing radiation and must be performed in specialized facilities; magnetic resonance imaging is expensive and unavailable to patients who have certain types of implants; optical technologies have inherently limited tissue penetration due to light scattering and absorption, restricting access to deep organs.
Description of Project
Type 1 diabetes affects more than 1.6 million individuals in the United States and 20 million worldwide. Insulin injections are the most common treatment to manage diabetes complications, but are unable to mimic the dynamics of natural insulin secretion from beta cells, leading to undesirable fluctuations in glucose and other complications such as organ damage from hyper- and hypo-glycemia. These limitations could be overcome by islet transplantation, which can restore more natural glycemic control. However, a major challenge in transplantation therapies is immunological attack and graft rejection. Despite recent advances in immunoisolation technologies for allogeneic islet transplantation, immune responses remain a critical issue, and the only viable clinically proven method for islet transplantation requires chronic systemic immunosuppression, which has multiple undesirable side-effects. If we could monitor immune reactions to transplanted cells noninvasively, this would allow physicians to track the status of the transplant and adjust immunosuppression regimens in individual patients. In this project, we will develop cell-based sentinels of anti-transplant immunity that can be included with encapsulated islets, sense local immune signals and produce ultrasound contrast. This will allow physicians to examine the immunological environment of the transplant with a simple noninvasive imaging technique available in virtually every doctor’s office. Compared to other approaches for immune cell monitoring (such as PET or MRI), our approach will not require administering radioactive or potentially toxic chemical agents (such as radionuclides or gadolinium) or expensive imaging equipment.
Anticipated Outcome
If successful, this project will introduce the first technology for noninvasive ultrasound monitoring of transplant rejection. Because encapsulated cells are an emerging clinical technology, and because ultrasound is widely available in medicine, we believe this technology has strong potential for clinical translation.
Relevance to T1D
This project is inherently centered on type 1 diabetes because it seeks to improve the paradigm for islet transplantation as a treatment approach that can restore more natural glycemic control. Accordingly, we will conduct our experiments in an established animal model relevant to type 1 diabetes.