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Immune Tolerance

Retraining the Immune System and Reversing Autoimmunity

DRI researchers are working to protect cells in a BioHub by preventing an immune attack – before it even starts – without using harmful anti‐rejection drugs. Scientists are teaching the immune system to see the transplanted islet cells as “self” and allow them to function normally. This is called “transplant tolerance.”

But the challenge is not just getting the body to accept transplanted islet cells. Type 1 diabetes occurs when the immune system mistakenly sees your own islet cells as foreign (a process called “autoimmunity”). So, DRI researchers are studying ways to make the body see your own cells as “self.” This is “self tolerance.”

Bone Marrow-Derived Cells 

Bone marrow could hold the key to transplanting islet cells without the need for harsh anti-rejection drugs.  With this approach, a patient receives the bone marrow of a donor. When the donor's and recipient's bone marrow co-exist, scientists call this "chimerism." In effect, two immune systems have "mixed" together.

The recipient can now receive organs and cells from the bone marrow donor. They will be accepted as "self" and not require the long-term use of harsh anti-rejection drugs.

In the past, this method has been limited because, prior to the bone marrow transplant, the recipient had to undergo harsh pre-treatment. But now, researchers have shown that less intense conditioning still allows for chimerism and tolerance induction.

The DRI is collaborating with Dr. Suzanne Ildstad of the University of Louisville. Dr. Ildstad and her team performed bone marrow transplants using the new protocol in kidney transplant patients. These recipients were able to achieve high levels of chimerism and discontinue the use of anti-rejection drugs for what is now three years.

This achievement in 19 non-diabetic patients has led us to a new collaborative trial in people with type 1 diabetes. The DRI and collaborators plan to transplant islets and bone marrow from the same donors into patients as part of a pilot clinical trial.

Immune Regulating Cells

Another approach focuses on part of the immune system that’s supposed to continuously scan our bodies to determine what is “us” and therefore safe, and what is foreign and dangerous and therefore needs to be destroyed. 

This is the job of regulatory T cells, or “T‐regs.” They regulate the immune system to prevent the body from attacking its own cells. But in type 1 diabetes, the immune system and T-regs fall out of balance. DRI researchers are trying to restore that balance. In experiments so far, they have shown T‐reg therapy can induce tolerance to transplanted tissue and prevent the recurrence of autoimmunity. 

In published research, DRI scientists have found that low doses of IL-2 (interleukin 2) can stimulate T-regs to perform this function, restoring the natural regulatory properties of the immune system.

The DRI is developing plans for new clinical trials using low-dose IL-2 in individuals with type 1 diabetes.

Learning from Cancer

The DRI is also focusing on a part of the immune system known as myeloid-derived suppressor cells (MDSCs). These play an active role in cancer - sending signals to the immune system not to attack tumors, allowing tumors to surivive and grow.

DRI researchers are developing ways to harness this for a more positive purpose: to prevent an immune attack on transplanted islets. In experimental models, the DRI has shown that MDSCs have immunosuppressive properties that may result in prolonged survival of transplanted islets. The MDSCs being tested are obtained from the umbilical cord blood healthy, newborn babies.

DRI scientists are studying another way tumors protect themselves from immune attack: they release the molecule CCL21. In the experimental models, DRI researchers delivered this molecule during cell transplants. Many of the recipients accepted the transplanted cells - without the use of systemic anti-rejection drugs.

The DRI BioHub mini organ mimics the native pancreas
Learn more about the development of the BioHub mini organ to restore natural insulin production in those living with diabetes.
Watch the BioHub video>>

Together with DRI Federation collaborators in Verona, Italy, the DRI is taking a page from cancer research to try to protect insulin-producing cells using myeloid-derived suppressor cells (MDSCs), a subset of immune system cells that prevent the body's attack on cancerous tumors.


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