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Under the Microscope With Midhat Abdulreda, Ph.D.

Teams of scientists throughout the Diabetes Research Institute are advancing their research through a first-of-its-kind technique that allows them to view, in real time, how transplanted insulin-producing cells function when they are inside a living organism. The 'Living Window' program, as it's called, is a stunning example of how the DRI is combining knowledge, innovation and technology to move us closer to a biological cure for diabetes.

The technique was developed by researchers at the DRI. In pre-clinical studies, insulin-producing islets are transplanted into the eye, then using a sophisticated microscope, researchers can observe the cells through the naturally-transparent cornea in real time -- as if through a living window. They are able to watch as islets engraft onto the iris, grow blood vessels and respond to stimulation. They can also observe how the immune system launches its attack on the islet cells and watch the body’s response to new therapeutic strategies that attempt to protect islets from this deadly immune system attack.

The Living Window program is led by Per-Olof Berggren, Ph.D., a professor in experimental endocrinology at Karolinska Institutet in Stockholm, Sweden, and adjunct professor of surgery at the University of Miami Miller School of Medicine. At the DRI, he is joined by Midhat Abdulreda, post-doctoral Scholar in our Cell Biology and Signal Transduction program, who talked with us about the Living Window.

Why the eye?

The eye is the only perfectly transparent tissue in the body. Through the cornea, it's possible to "see" into the body. And now, through generous funding from the Diabetes Research Institute Foundation, we have an extraordinary opportunity to take advantage of this view. In experimental models, we transplant pancreatic islets into the anterior chamber of the eye; a very simple and minimally-invasive procedure. From there, we can monitor both the integrity and survival of the islets, as well as how the immune system responds during attack after transplantation.

What are the most important observations you've made through the living window?

We recently discovered that T-lymphocytes, which are responsible for islet destruction after transplantation, display a unique behavior during ongoing immune attack against transplanted insulin-producing islets. They move around at a rate far greater than previously thought, which may contribute to rapid graft rejection. Now that we know how those cells behave, we're working to modify that behavior to prevent or delay transplant rejection. Discoveries like this come to light only because we are able to monitor the movement of the same set of islet cells, in real time, over a long period of time, non-invasively.

While we set out to use the living window to monitor transplanted tissue, the technology is also allowing us to explore the eye as a possible clinical site for islet transplantation. In initial living window studies, blood sugars normalized after islets were transplanted into the eye. One reason may be that the anterior chamber - or front - of the eye is one of a few sites in the body that has something called 'immune privilege.' In other words, it appears to be somewhat shielded from the immune system. Researchers have known about this phenomenon for decades but we want to be the first to use it to scientific advantage. The theory is that if foreign tissue, such as insulin-producing islets, is transplanted into the eye, the site's immune privilege – under certain conditions - may help shield the islets from immune system attack.

It's hard to imagine a therapy that involves placing something into the eye.

Many people have that same initial reaction. I'm constantly asked if the work we're doing threatens the eye or interferes with vision. The answer is, we don't believe it does. In our models, we've transplanted islets in a way that does not physically obstruct the pupil and according to the eye experts, there's no indication that we are affecting vision.

So, once you see that this is feasible, the picture changes. It's very exciting. We recently transplanted insulin-producing cells into the eye of a diabetic, non-human primate (baboon). Through the living window, we could see that the transplanted islets engrafted very well. In fact, we could identify the exact point in time when the islets fully established their blood supply, which could never have been done in the living animal without this sophisticated technology. Within three months, and with limited immunosuppression, wild fluctuations in the animal's blood glucose levels were minimized and daily insulin requirements were dramatically reduced. Plus, we were able to achieve these results using just one-fifth of the amount of islets that are typically required for transplantation in other sites, thanks to better survival of the transplanted islets and the relative ease and minimally-invasive impact of transplanting into the eye. The results were so promising we're expanding that study in collaboration with researchers from the College of Medicine at the Seoul National University in South Korea.

What else is on the horizon?

One of the biggest challenges to islet transplantation is the current need for transplant recipients to take powerful anti-rejection drugs for the rest of their lives. We believe the eye may one day be used to deliver local and minimal immunosuppression, through either eye drops or implantable slow-release anti-rejection drugs. This will help prevent or minimize devastating systemic side effects associated with the chronic use of such drugs. More importantly, we think the eye could also play a role in the development of transplant immune tolerance. If we could teach the immune system to accept - or tolerate - transplanted cells (immune tolerance), chronic immunosuppression wouldn't be necessary. That's where this concept of immune privilege re-enters the picture. Could the same mechanisms that maintain immune privilege of the anterior chamber of the eye shield transplanted islets from immune system attack and induce tolerance? If so, it might be possible to transplant a small amount of islets into the eye, establish tolerance to those cells, then transplant more islets - from the same donor - elsewhere in the body.

How will this research lead us to a cure for diabetes?

The living widow technology which has proven to be an extremely valuable and versatile tool for teams throughout the DRI and from other departments; immunologists, nephrologists and developmental biologists are using this technology to advance their research. It offers such an extraordinary opportunity to view biological processes in real time, it's no wonder we're constantly being approached by laboratories and scientists around the world interested in using it for everything from cancer studies to drug screening. For me, however, I'm committed to using these tools to advance our collective efforts to cure diabetes. I recently lost my father to complications of diabetes, so I'm personally invested, as are many of my fellow researchers at the DRI.

(DRIFocus Spring 2011)

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