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New discovery may help transplants survive


Blocking growth factor stops rejection process

For the first time scientists have found that a growth factor called vascular endothelial growth factor receptor-3 (VEGFR-3), known to cause the growth of lymphatic vessels in the body, controls how immune cells traffic (move) within the eye and also stimulates the immune system to reject corneal transplants--the most common type of transplantation performed. The researchers from the Schepens Eye Research Institute and the Massachusetts Eye and Ear Infirmary, both affiliates of Harvard Medical School, have also found that when this growth factor is blocked, corneal transplants survive. The study, published in the August issue of Nature Medicine, is the first to make a link between VEGEFR-3 and the body’s immune response, and may hold significant promise not only for new treatments to prevent transplant rejection but also for diseases such as cancer that may proliferate because of VEGF-3.

"What we have discovered is a previously unknown connection or ’pathway’ that stimulates the immune response in the eye and in other parts of the body," says Reza Dana, MD, MPH, a Senior Scientist at the Schepens Eye Research Institute, an Associate Professor and corneal specialist at the Massachusetts Eye and Ear Infirmary and Harvard Medical School, and the senior author of the study.

Each year, nearly 40 thousand Americans receive corneal transplants to replace injured or diseased corneas. Approximately 90 percent of corneal transplants are successful because the eye is intrinsically less likely to reject transplanted material than other parts of the body. However, to suppress rejection of corneal transplants, patients need to use steroid drops – which can cause glaucoma, cataract development, and infection -- for years. Even then, many corneal transplants fail, and their failure can cause devastating vision loss. If transplants are placed in eyes suffering from inflammation (caused by a full-blown immune response to the original injury or disease), rejection rates go well over 50 percent, regardless of the therapy employed.

"We are trying to understand what is happening at the molecular level so that we can arrest this process," says Dana, who has devoted much of his research to finding the mechanisms that trigger immune responses, and, in the case of corneal transplants, the "unwanted" immune response that causes corneal transplant rejection.

VEGFR-3’s role in activating the immune response in the cornea is the most recent in a series of discoveries by Dana and his research team in their exploration of the immune response to corneal transplants.

In the normal immune response, cells known as antigen-presenting cells (APCs) are activated when they detect the presence of proteins (also known as "antigens") from foreign intruders such as bacteria, or, in the case of transplantation, proteins from other people. The job of the APCs -- which exist in all body tissues -- is to notify the immune system of the foreign tissue, pick up that tissue and then travel through vessels known as lymphatics to the lymph nodes where they can activate immunity. In the lymph nodes, APCs present the foreign protein to T Cells, which then custom design an immune attack to destroy the invader.

In previous work, Dana and his team found that removing the lymph nodes that drain the eyes prevented rejection of transplants that were vulnerable. They also found that VEGFR-3, known to cause the growth of lymphatic vessels, was expressed on the APCs and new lymphatic vessels were present in the corneas that were inflamed (or under immune attack.)

In the August Nature Medicine study, Dana and his colleagues hypothesized that when a cornea becomes inflamed, VEGFR-3 becomes activated on the antigen-presenting cells. They also believed that VEGFR-3 then triggered the APCs to move into the lymphatic vessels en route to the lymph nodes to make contact with the T-cells.

Using in-the-dish (in vitro) and living mice (in vivo), the team was able to show that VEGFR-3 was responsible for mobilizing APCs to move into the lymphatic system. Next, the research team blocked VEGFR-3 in mice using a specific protein (immunoglobulin) known to impede its function. When the VEGFR-3 was blocked, the APCs were also prevented from entering the lymphatic system, and the immune response was arrested. "We had never seen this connection before," says Dana. He added that while this connection was determined for the eye, it may well operate in other tissues as well.

While Dana says it is not yet clear exactly how this discovery will translate to the clinical setting, he believes continued study of this new pathway has potential for improving transplantation in the eye and potentially other parts of the body.

And, it could be a new piece of the cancer puzzle. "It has been shown that antigen presenting cells around tumors also express VEGFR-3 and we already know that access to lymphatics and lymph nodes is the way cancers spread through the body," he says.

"The findings of Dr. Dana and his colleagues provide new insights into transplant immunology and biology which go well beyond the eye, and offer new therapeutic approaches in organ transplantation and cancer treatment. Dr. Dana is clearly one of the outstanding physician scientists in our department," says Joan W. Miller, MD, Chief and Chair of Ophthalmology at Massachusetts Eye and Ear Infirmary and Harvard Medical School.

Patti Jacobs | EurekAlert!
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