Site - Engineering a home for islets
Sustain - Ensuring islet cell survival
Supply - Creating more islets
Sustain - Ensuring Islet Cell Survival
Until scientists can protect transplanted islets without the use of immunosuppressive drugs and, most importantly, halt autoimmunity – the body’s attack on its own insulin-producing cells – many research advances will remain limited to a select group of people with type 1 diabetes. For this reason, the Sustain area is an urgent DRI research priority. From developing safe and effective immunotherapies to safeguarding transplanted islets locally, DRI scientists are addressing the complex immune-related issues to sustain the survival of the insulin-producing cells.
Halting Autoimmunity in Type 1 Diabetes
Much has been learned about the immune system in recent years leading researchers to modify immune responses using the body’s own cells and safer therapies rather than toxic agents. These harsh drugs, while effective at preventing the rejection of transplanted islets, do not address the underlying autoimmune disease process at work in type 1 diabetes. In fact, DRI researchers have shown that autoimmunity can recur despite the use of continuous immunosuppression to prevent rejection. Armed with new knowledge, investigators are developing and testing several strategies to better control immune system function.
Targeting Multiple Immune Pathways
There is growing evidence that type 1 diabetes is a multi-factorial disease and that inflammation and beta cell dysfunction may also be important in the development and progression of the disease process. To date, however, the majority of approaches to combat T1D have involved single agents that primarily targeted the immune system. DRI researchers are now exploring approaches using several agents that simultaneously address the multiple immune pathways implicated in the disease.
Combinatorial therapies have been used with success in treating HIV and cancer, which are also diseases involving multiple pathways. Even data emerging from the DRI’s own clinical islet transplant trials, together with results of studies conducted by other diabetes groups, have demonstrated better outcomes using a combination of agents. These findings have led DRI researchers to believe that a similar approach may be successful in combatting type 1 diabetes. This hypothesis will be tested in a first-of-its-kind, FDA-approved clinical trial involving a combination of agents that target the key immune pathways involved in type 1 diabetes.
DRI researchers are gearing up for a new clinical trial that will target multiple immune pathways in T1D:
- Innate immunity: stopping the harmful inflammation
- Adaptive immunity: stopping the immune cells that get recruited to attack
- Regulatory immunity: stimulating the protective response
- Promote beta-cell health: strengthening the beta cell
Regulating the Immune System
Traditional immunosuppressive drugs deliberately reduce the activation of immune responses to prevent the rejection of transplanted tissues. But rather than suppress the immune system and make it weaker, researchers are working to more effectively control, or regulate it. Research has also shown that autoimmunity is caused by an imbalance between “soldier” immune cells that attack unwanted invaders and regulatory immune cells, T regs, which prevent the soldiers from destroying the body’s own tissues.
In patients with type 1 diabetes, the regulatory arm of the immune system is impaired and cannot fend off the attackers. This loss of balance, or regulation, results in the continued destruction of the target, which in this case are the insulin-producing cells. At the DRI, a number of research projects are underway that aim to boost the numbers of T reg cells. Among them is another FDA-approved clinical trial that will test whether a naturally occurring protein can correct autoimmunity in those with T1D.
“In autoimmune disease, including type 1 diabetes, autoimmunity is facilitated greatly by an imbalance between the regulation of the immune system and the effector arm of the immune system…so it is important that we try to restore more proper balance.”
DRI researchers are also exploring the possibility of infusing T regs into recipients with T1D to increase the levels of these regulatory cells. One potential strategy, called adoptive T reg therapy, aims to correct the imbalance by giving T regs from one’s self or from another individual. In ongoing studies, the DRI team has identified critical factors for successful adoptive T reg therapy, which includes creating adequate space for the new cells, creating a supportive environment for the cells’ long-term survival and function, and, importantly, ensuring that the T regs are specific to insulin-producing cells, which is critical for halting the autoimmune attack while keeping other immune functions intact.
Adoptive T reg therapy has achieved 100% diabetes remission in study models for more than 400 days, which is “pretty remarkable.” The next step is to translate this immunotherapy approach to the preclinical setting and then to patients living with type 1 diabetes.
Designing Safer Immunomodulatory Agents
Scientists are also working to inhibit immune responses using specifically targeted immunomodulatory agents that are safer and more effective than existing antibody-based treatments. These small-molecule drugs can block certain cell-to-cell communications – or co-stimulatory interactions – that set off an attack on the insulin-producing cells.
The DRI’s drug discovery team has recently identified the first small molecules that were capable of interfering with two interactions that are important for type 1 diabetes onset and progression in preclinical models.
The ultimate goal is to develop clinically approved drug-like compounds that can be taken orally as tablets or capsules.
Protecting Transplanted Islets
The second arm of the DRI’s two-pronged strategy to sustain insulin-producing cells aims to protect islets at the site of implantation. These approaches include physically shielding the cells with protective coatings, transplanting islets together with other cell types that may offer beneficial effects, and inducing tolerance locally with immunomodulatory agents.
Coating Cells with Protective Barriers
The idea of putting islets within a type of bubble that protects them from the immune system may sound simple enough but it has proven to be a complex challenge for scientists. This area of research, called cell encapsulation, has been investigated extensively as a potential therapy for type 1 diabetes. However, there has been limited success in applying this approach to patients due to several obstacles, including:
- the size and thickness of the capsules
- the coating material
- the lack of vital oxygen and nutrients within the capsules
To address these issues, DRI scientists are developing a variety of approaches that have shown promise in early studies.
Building Better Coatings
Since traditional microcapsules are very large and leave too much space between the capsule barrier and the islet within, DRI scientists and collaborators have pioneered a new cell encapsulation method called conformal coating. Similar to “shrink wrapping,” the conformal coating technology wraps each islet within an ultra-thin, protective barrier that conforms to the unique size and shape of each cell. One of the many benefits of this approach is that the coated islets remain similar in size to uncoated or “naked” islets, facilitating placement of these protected cells in any site currently being tested for islet transplantation, including the tissue-engineered BioHub platform. Another advantage of the conformal coating technology: it can be used to wrap not just islets, but any type of insulin-producing cell, including stem cell-derived beta cells. The DRI team has now demonstrated that the conformal-coated islets can normalize blood sugar levels without the need for anti-rejection drugs in experimental models.
DRI researchers have shown that islets within conformal coatings secrete insulin in a very physiological way, which eliminates the delay seen with traditional, larger microcapsules. They are also working to add components that can modulate the immune system locally, either by embedding agents within the coating material or placing them within a BioHub platform.
Delivering Agents Locally
New developments in bioengineering and nanotechnology are paving the way to microscopically package beneficial agents, like immunomodulatory, anti-inflammatory drugs, and factors that enhance beta cell function, together with the insulin-producing cells. Rather than require islet transplant patients to take handfuls of anti-rejections drugs, which shut down their entire immune system, researchers are developing methods to deliver these agents locally at the site of implantation, where the attack on the cells actually occurs. One option is to embed these tiny particles directly within the conformal coating material itself, enhancing its protection. A second option is to place these nanoparticles within a tissue-engineered BioHub scaffold.
Optimizing the Capsule Environment
Beyond overcoming the inability for oxygen and nutrients to reach the cells within and avoiding immune destruction, DRI researchers hypothesize that adverse conditions within the capsule itself may also lead to transplant failure. The build-up of waste and the onset of inflammation after the cells are encapsulated and then transplanted is also one of the biggest obstacles to successful clinical application.
To address this challenge, DRI researchers are developing and testing innovative strategies to reduce inflammation, and even “scavenge” dangerous free-radicals that are produced by the immune system while offering another benefit: generating oxygen within the capsule itself.
Among the biggest causes for failure in microencapsulation is the lack of oxygen and nutrients for the islets within. To address this challenge, DRI researchers are producing innovative metal particles that immediate convert free-radicals into oxygen within the capsule environment, which is exactly what the cells need for long-term survival and function.
Giving Islets a “Helper” Hand
Certain cells within the body have very powerful therapeutic properties that have been shown to enhance islet transplant outcomes. Mesenchymal stem cells (MSCs), in particular, are one cell type that is being studied extensively by DRI researchers. MSCs have the ability to generate other tissues, like bone, ligaments, muscle, and fat, to name a few. But reseachers have also discovered that these cells can hamper inflammation, promote tissue repair, and enhance blood vessel growth, all critical factors for long-term islet transplant survival.
DRI researchers first began testing the co-transplantation of MSCs several years ago. Among their many findings, they discovered that the inclusion of these cells led to significantly better islet engraftment and function. Research efforts have since focused on better characterizing different MSC populations within the body, as well as identifying an optimal MSC source for clinical use.
“The work with mesenchymal stem cells (MSCs) is very exciting because instead of having one pathway that you’re targeting with one antibody or one drug…you’re essentialy transplanting a mini immunomodulatory, anti-inflammatory factory.”
DRI scientists have also shown that not all MSCs are alike, that certain subpopulations of these cells are more effective than others for suppressing immune cells. In one promising approach, researchers aim to isolate these special MSC cell types, culture these cells together with islets, and then transplant the entire cell mixture into recipients.
“Mesenchymal stem cells (MSCs) can actually generate therapeutic effects by regulating the immune system…we exploit the activity of these MSCs…trying to hijack those properties of immune modulation and try to prevent the immune system attack on the islets after transplantation.”