Gill, Ronald G., PhD
Dissecting islet transplant-reactive T cells in autoimmune diabetes
General Research Subject: Type 1 Diabetes
Focus: Immunology, Transplantation
Type of Grant: Basic Science
Project Start Date: January 1, 2013
Project End Date: December 31, 2015
Diabetes Type: Type 1 diabetes
Any type of beta cell replacement strategy as a therapy for type 1 diabetes will require overcoming the barrier of T lymphocyte-dependent immunity. An ongoing debate for many years has centered on the fundamental contribution of pre-existing islet-specific autoimmunity versus more conventional transplantation immunity in the aggressive demise of islet transplants (allografts). Thus, our initial goal in this pre-clinical project is to fill this foundational gap in basic knowledge by identifying the T cells (autoreactive versus alloreactive) that target islet transplants in spontaneously diseased non-obese diabetic (NOD) mice (Aim 1). We also will determine the potential role for an unusual population of T cells simultaneously recognizing both autoantigens and transplantation antigens in triggering aggressive graft injury (Aim 2).
In addition, NOD mice are known to be profoundly resistant to transplant tolerance, though it is essentially unknown what types of T cells (autoreactive and/or alloreactive) are responsible for 'breaking through' tolerance-promoting therapies. Thus, a key secondary project goal is to identify the graft-reactive T cells (autoreactive and/or alloreactive) that resist a tolerizing therapy and trigger islet transplant rejection in NOD recipients (Aim 3). Taken together, we believe that identifying the fundamental nature of T cells that target islet transplants in the setting of autoimmune diabetes addresses a basic deficit in current understanding. Moreover, identifying the types of T cells responsible for resisting tolerance-promoting therapies will be essential for the continuing development of intervention strategies aiming to block these rate-limiting cellular pathways currently impeding allograft survival.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?
This project focuses on pancreatic islet transplantation as a treatment for autoimmune type 1 diabetes (T1D). Specifically, the main goal of this project is determine what type(s) of immune cells are responsible for targeting transplanted insulin-producing islet grafts. It is clear in both experimental models and in T1D patients that islet transplants can restore exquisite blood sugar control. However, both the pre-existing islet-reactive autoimmunity and more conventional transplantation rejection responses can recognize and destroy such grafts.
There is very little current understanding whether such islet rejection is mediated by auto-reactive (islet-specific) immune thymus-derived (T) cells, by T cells that typically destroy other types of tissue/organ transplants, or a combination of both. Moreover, previous experimental studies indicate that autoimmune recipients are resistant to the induction of transplantation immune 'tolerance,' but it is not clear what types of immune cells 'break through' these tolerance-promoting therapies. This project aims to address both of these issues in the hope that identifying the key T cell barriers to successful islet graft survival will aid in the ongoing design of strategies that prevent graft rejection and restore immune tolerance.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Islet beta cell replacement therapy - whether through the transplantation of whole organ pancreas, isolated insulin-producing islets, or with some future source of surrogate beta cell implantation - is currently impeded by the recipient's immune response that destroys the introduced tissue. This is especially the case in T1D patients in which the original islet-directed autoimmunity is known to recur in the islet graft. This problem is currently addressed by general, non-specific immune-suppressive drug treatment of the recipient. However, such chronic therapy is itself toxic making an essential long-term goal in the field to achieve a state of 'tolerance' in which the immune system can now co-exist with grafted insulin-producing tissues. To make transplantation of insulin-producing cells increasingly available to T1D patients, we must solve the key barrier found in the immune response.
This project proposes to clarify the specific types of immune cells responsible for injuring grafted islet tissue in the hope of making these cells therapeutic targets for restoring immune tolerance in T1D. As such, our long-term goal is to develop strategies that will eventually reduce or eliminate the need for immune-suppressive drug treatment in islet transplant recipients.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?
I have been involved in T1D-related research for nearly 25 years now, mostly at the Barbara Davis Center for Childhood Diabetes. For most of this time, we have used pre-clinical models to understand how the immune system injures islet transplants and to develop approaches for inducing immune tolerance to these tissues. Moreover, I also initiated a clinical islet transplant program at the University of Colorado in which several T1D patients were grafted with pancreatic islets derived from deceased organ donors.
Importantly, we experienced first hand at our Center the remarkable capacity that islet transplants have for regulating blood glucose (preventing both high and low levels) in these patients. However, most of these transplants generally do not function well for many years and these patients must continue to take immune-suppressive medications. Therefore, one of our main goals is to understand how exactly the immune system is targeting islet grafts in the setting of autoimmune T1D (the main subject of this project). We then would use this information to design more effective and specific interventions to stop this response and restore immune tolerance to islet tissue.
In what direction do you see the future of diabetes research going?
The pancreatic islet serves as an exquisite glucose 'thermostat' that maintains blood glucose values within a very limited range. In T1D, the original islets are largely or completed destroyed, so one major ongoing goal in the field is to implant new islet tissue or surrogate islet cells (e.g. stem cells). It is clear from both basic research and clinical findings that islet grafts can restore blood glucose control, but long-term success of this approach is impeded by the recipient's own immune response to the transplant. Unfortunately, the underlying autoimmune disease found in T1D has the ability to re-occur and damage either foreign islet grafts or even 'self'-derived islet cells. Thus, regardless of the specific source of islet cells used to correct diabetes in T1D patients, we must better understand how the immune system reacts to islet cells and improve our ability to prevent this response.
Importantly, controlling the immune response in autoimmune T1D patients will be useful at several stages including primary disease prevention, for potentially preserving remaining islet cells in new-onset patients, and for preventing the destruction of newly implanted islet cells in patients with established disease.
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