Objective
Our primary objective is to develop and validate novel humanized mouse models to study the
human immune response in vivo to encapsulated pancreatic islets. This proposal will bring
together scientists from the Diabetes Center of Excellence at the UMass Chan Medical School
and The Jackson Laboratory to work collaboratively to validate these new humanized models.
The ultimate goal is to validated an efficient in vivo tool to screen encapsulation devices that will
accelerate the translation encapsulation devices to the clinic for treatment of T1D.
Background Rationale
While significant progress has been made in the disease management of T1D, a true cure is still
lacking. Transplantation of pancreatic islets is now an FDA approved treatment for individuals
with T1D, and has the ability to restore normal metabolic control of glucose levels, but requires
generalized immune suppression. An alternative to drug induced immune suppression, is to
load islets into protective, semipermeable devices prior to transplant that will prevent recognition
by the immune system and will allow the free exchange of glucose, oxygen and insulin. The
clinical application of encapsulation is limited due to the immune response against the specific
materials used to create the device. The rationale for this proposal is to validate novel in vivo
models to study the human immune response to the encapsulated islets. Our collaborative team
has extensive expertise with T1D disease mechanisms, islet transplantation and the use of
novel humanized mouse models to study human disease.
Description of Project
The standard of care for individuals living with type 1 diabetes (T1D) is the lifelong use of
injectable insulins. While significant technological advancements have been made for
management of T1D with more effective insulin formulations, the delivery of insulin via pump
systems and the use of continuous glucose meters, a cure for the underlying disease has not
been achieved. Transplantation of pancreatic islets is now an FDA approved treatment for
individuals with T1D, and has the ability to restore normal metabolic control of glucose levels.
However the transplanted islets need to be protected from the host immune response, which will
rapidly reject the cells. Rejection of islets is currently managed with the use of drugs which
broadly suppress the immune system. While this immune suppression treatment is effective in
preventing islet rejection, the drugs create a generalized immune suppression, which leaves
patients susceptible to infections and cancers. An alternative to drug induced immune
suppression, is to load islets into protective, semipermeable devices prior to transplant that will
prevent recognition by the immune system and will allow the free exchange of glucose, oxygen
and insulin. This approach is referred to as encapsulation and has been studied extensively as
a tool to protect cellular therapies. While encapsulation of islets for transplant is an exciting
approach to treat T1D, the clinical application of encapsulation is limited due to the immune
response against the specific materials used to create the device. This immune response, often
referred to as a foreign body response (FBR), results in the fibrotic overgrowth of the device
after transplant which reduces the function and survival of the islets within the device. The study
of FBR has been primarily restricted to pre-clinical animal models, which have provided critical
insights into the immune process, but the results from these models have had limited success
being translated to the clinic. Our proposal will leverage novel humanized mouse models to
study the human immune response in vivo to encapsulated islets. This proposal will bring
together scientists from the Diabetes Center of Excellence at the UMass Chan Medical School
and The Jackson Laboratory to work collaboratively to validate these new humanized models to
reproduce the human FBR. The collaborating scientists have expertise with T1D disease
mechanisms, islet transplantation and the use of novel humanized mouse models to study
human disease. The complementary skill sets will provide a strong foundation to complete the
proposed experiments in a timely manner. We anticipate that at the end of the funding period
we will have validated an efficient in vivo tool to screen encapsulation devices that will
accelerate the translation encapsulation devices to the clinic for treatment of T1D.
Anticipated Outcome
We anticipate that at the end of the funding period we will have validated an efficient in vivo tool
to screen encapsulation devices that will accelerate the translation encapsulation devices to the
clinic for treatment of T1D. Our proposal will leverage novel humanized mouse models to study
the human immune response in vivo to encapsulated islets. We will also make the new
humanized models available to other investigators to test T1D-focused therapeutics. If
successful, the platforms may be applicable for the development and testing of cellular
therapies for additional autoimmune disorders.
Relevance to T1D
Despite decades of groundbreaking research into the disease mechanisms of T1D, a cure has
remained elusive. Transplantation of pancreatic islets is now an FDA approved treatment for
individuals with T1D, and has the ability to restore normal metabolic control of glucose levels.
However the transplanted islets need to be protected from the host immune response, which will
rapidly reject the cells. Our proposal will validate a novel in vivo platform to screen protective
devices for islet transplantation. The impact of this project to T1D is the potential for more rapid
application of newly developed devices to clinical transplant of encapsulated islets.