Objective
Although clinical islet transplantation can improve Type 1 Diabetes management, the requirement for lifelong immunosuppression in transplant recipients is treatment limiting. Current clinical protocol entails daily immunosuppressants, which weakens the body’s immune system. Due to whole-body immunosuppression, transplant recipients experience significant adverse side effects, which are sometimes life-threatening, and have increased susceptibility to infections and some types of cancer. Moreover, immunosuppressants can impair the function of transplanted insulin-producing cells, affecting treatment outcome.
To this end, our objective is to study novel local immunosuppressive strategies that are safe and effective when confined only at the transplant site, protecting the rest of the body from their harmful side effects. To achieve this, we will leverage our NICHE transplantation platform, which releases immunosuppressants directly into a vascularized transplant site, creating a locally immune protected environment for islets to engraft. The NICHE is ideal platform to study the immune microenvironment of transplanted cells with locally controlled release of immunosuppressants. This will provide scientific insights that are applicable to the NICHE, and to spectrum of new opportunities for local immunosuppressive strategies.
In the proposed study, our objectives are to: 1) identify immunosuppressants that do not affect islet viability and function; 2) evaluate the mechanism of action of immunosuppressants when delivered directly within the transplant site in a targeted and controlled manner; 3) assess the impact of local immunosuppression on overall well-being and health; and 4) determine whether immunosuppressants when delivered locally can be confined to the transplant site without harmfully distributing to other organs.
Addressing the aforementioned objectives is a critical step towards evaluating effective and safer immune approaches with potential for clinical innovation. Also, if successful, these results can immediately be applied in the conjunction with the NICHE platform as a breakthrough for patients with type 1 diabetes.
Background Rationale
Islet transplantation is a promising strategy to manage type 1 diabetes (T1D) without relying on administration of synthetic insulin, which is costly and requires lifelong strict adherence to repeated dosing regimen. However, transplant recipients require lifelong whole-body immunosuppression to prevent graft rejection. Chronic immunosuppressant exposure to the body affects the quality of life of transplant recipients, and is associated with adverse side effects, which are sometimes fatal. Further, continuous suppression of the immune system increases the susceptibility to infectious diseases and cancer.
As an alternative approach, cell transplantation technologies have emerged to confine islets in a protective barrier, termed encapsulation. The principle of cell encapsulation is to create optimal architecture protecting transplanted islets from the host immune system attack while maintaining their function. A number of cell encapsulation technologies have made their way into clinical studies; however, providing an oxygen- and nutrient- rich environment with simultaneous immune protection for the transplanted islets remain a challenge. Some strategies use a physical barrier to prevent immune destruction of the transplant. Although immune rejection is prevented, blood supply is hindered resulting in lack of oxygen and nutrients supply, leading to the islet death. Thus, significantly improved immunosuppressive strategies are urgently needed to improve transplant outcome without affecting transplanted cells or the quality of lives of transplant recipients.
As key immune rejection events occur at the site of transplant and surrounding microenvironment, local immunosuppressant release is a logical approach to address immune rejection of the transplanted islets. Previous approaches for local immunosuppression use hydrogels or scaffolds, which have limited drug release duration and require repeated administration. Further, existing strategies for local immunosuppression lack blood vessel support, thus attenuating the function of transplanted islets. To address for the need of an effective local immunosuppression strategy that protects and supports islet engraftment, we leverage our innovative encapsulation strategy, the NICHE. The NICHE is a dual-reservoir encapsulation platform, each for immunosuppressant and cell transplantation. The NICHE sustainably elutes immunosuppressants directly into the vascularized transplant chamber, providing immune protection in an oxygen- and nutrient- rich environment, which is conducive for cell engraftment. As such, the adverse side effects of whole-body immunosuppression are avoided.
By using the NICHE to recapitulate an ideal transplant microenvironment, we are able to study how individual immunosuppressants works in a local setting, and comprehensively assess its impact on immune protection, which is largely unexplored. We will also evaluate the safety of direct exposure of transplanted cells to immunosuppressants, as well as potential undesirable distribution to other organs, which could contribute to adverse effects. Overall, results from this study will provide clinically relevant insights into future implementation of local immunosuppression for transplantation as a step towards improving treatment outcome and quality of lives of transplant patients for T1D management.
Description of Project
Islet transplantation offers the potential of restoring the body’s natural ability to produce insulin and control diabetes without relying on pharmaceuticals. Currently, individuals receiving islet transplantation require lifelong whole-body immunosuppressants to avoid immune rejection of the transplant. These whole-body immunosuppressive regimens are associated with life-threatening adverse effects, including increased risk of infections and cancer, severely impacting their quality of life. Moreover, these immunosuppressants are oftentimes toxic to the transplanted islets. Unfortunately, as whole body immunosuppressants are not fully directed to the transplant site, transplantation eventually fails due to immune rejection. As such, a transformative approach is urgently needed to better protect transplanted islets to improve treatment outcome and the quality of lives of transplant recipients.
To this end, we posit that administering immunosuppressants directly to the transplant site could address the aforementioned challenges. To study this, we will leverage our NICHE platform, which sustainably elutes immunosuppressants within the transplant site in a controlled manner, creating a locally immune protected microenvironment. With this approach, drug exposure is limited to only where needed, thus obviating the adverse effects of conventional whole-body immunosuppression.
Given that immunosuppressants are commonly used systemically in the clinic, the effects of local administration and its safety are understudied. In this proposal, we will investigate the mechanism of actions of relevant immunosuppressants when delivered in a controlled and sustained manner locally, directly within the transplant site. In addition, we will investigate the safety of local immunosuppression on transplanted islets, as well as pharmacokinetics and biodistribution to other parts of the body and assess systemic toxicity. Overall, this study will allow us to obtain novel scientific insight and identify immunosuppressants and potential combinations that are safe and hold promise to improve transplant outcome when used in a local setting. Results from this study could provide the foundation for future clinical application of local immunosuppression. Achievement of our goal could profoundly impact the field of islet transplantation, providing transplant recipients a life independent of toxic whole-body immunosuppression.
Anticipated Outcome
In this proposal we will use the neovascularized implantable cell homing and encapsulation (NICHE), as an ideal platform to study and identify novel, local and safe and effective immunosuppressants. The objective is to identify novel local immunosuppressive strategies to protect transplanted islets, without exposing the whole-body to toxic drugs that are harmful to transplant recipients. Exploring different immunosuppressants in a local setting is innovative and will allow us to understand their respective impact on the immune response at the transplant site, as well as determine their effect on overall health and well-being. We anticipate that the proposed work will generate new relevant scientific insight and foster new development in local immunosuppression strategies. Further, it will better position our NICHE platform for clinical translation, towards the goal of improving type 1 diabetes management by providing a safe approach for the transplantation of insulin producing cells.
Relevance to T1D
Type 1 diabetes (T1D) affects ~3 million people in the United States including children and adolescents and places a $15 billion annual burden on the healthcare system. T1D is caused by the autoimmune destruction of pancreatic islets, including insulin-producing beta cells, leading to daily dependence on insulin administration via repeated injections or the use of continuous subcutaneous pumps. Islet transplantation is a promising treatment option to replace destroyed pancreatic beta cells or pharmaceutics such as synthetic insulin for individuals with T1D. However, in its current approach, foremost among the challenges is the need for lifelong immunosuppressive drugs, which is treatment limiting and associated with serious adverse effects.
Alternative immunosuppressant strategies are needed for effective long-term protection of transplanted cells, while avoiding deleterious adverse effects to patients. Local immunosuppression represents an approach largely understudied, which holds immense promise to address the current challenges of transplantation. To this end, we developed the neovascularized implantable cell homing and encapsulation (NICHE) platform. The NICHE achieves sustained releases of immunosuppressants directly into a vascularized pancreatic islet transplant bed, minimizing systemic drug exposure and related adverse effects. In previous studies, we showed that with local immunosuppression, the NICHE promotes long term islet allograft engraftment and function with no systemic adverse effects.
In this context, the NICHE represents the ideal platform technology to investigate novel local immunosuppressive approaches using both established or experimental therapeutics, by examining their mechanism of action and effect on the immune microenvironment at the transplant site. Our proposal is highly relevant to T1D for the following reasons: 1) the proposed investigation will provide valuable, novel scientific insight into local immunosuppression, which will yield new developments in islet transplantation technologies; 2) the results will be readily applicable to our local immunosuppression NICHE platform, which has already shown significant promise for the transplantation of pancreatic islets for T1D with undetectable adverse effects.