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march/april 2011

Insight

Learning What Makes It Tick

An eye researcher puts her mark on the field of autoimmunity

By Allyson T. Collins, M.S.
NEI Science Writer/Editor

Rachel Caspi, Ph.D.
Rachel Caspi, Ph.D.
Head, Immunoregulation Section
Deputy Chief, Laboratory of Immunology

National Eye Institute (NEI) researcher Rachel Caspi, Ph.D., says she has always been interested in science. "While other little girls collected dolls, I was collecting bugs," she says of her childhood, spent in Poland, Israel and Holland.

As an undergraduate in Israel at Tel Aviv University, she studied vertebrate immune system development and comparative immunology, moving to tumor immunology for her Master's degree. "I like to know what makes it tick," she explains. "We can't cure disease if we don't know its basic mechanisms."

After finishing her doctorate at Bar-Ilan University, her search for a postdoctoral lab led her across the world to NEI, where there were more questions than answers among the small group of vision researchers studying autoimmune eye diseases.

"Autoimmunity of the eye had much less known about it than other types of autoimmunity," she says. "I picked that because it was a new field where one could leave a mark. I was looking to innovate in an area that wasn't saturated with researchers."

Therefore, Caspi came to NEI for her postdoctoral research in 1984 and has never left.

Model Behavior

The eye has a distinctive relationship with the immune system. It is what scientists call a "privileged" site, which means that -- for better or for worse -- it is relatively protected from the immune system. This is due in part to the walls of the blood vessels in the eye, which are relatively impermeable to the leakage of cells and even larger molecules, a phenomenon known as the blood-retinal barrier.

In addition, the eye is able to exert control over immune responses and inflammation that take place in its "territory." Scientists believe that immune privilege has evolved to protect the delicate tissues of the eye from damage as a result of inflammation.

This phenomenon does not always benefit the eye, however. "Although immune privilege protects the eye from day-to-day minor insults and traumas, it seems unable to prevent potentially blinding inflammatory eye diseases that arise as a result of autoimmunity," Caspi explains. "In our research, we want to figure out why."

In the 1980s, scientists had been using a rat model to study autoimmune inflammation in the eye, a collective group of diseases known as autoimmune uveitis. Although the model was useful for studying possible treatments, it did not provide as much information about genetics and immunology.

Caspi and other researchers tried for a long time, unsuccessfully, to produce a mouse model with the same protein that induced autoimmune uveitis in the rat. Around the same time, NEI basic researcher Michael Redmond was studying the biochemistry of another retinal protein, called interphotoreceptor retinoid binding protein (IRBP). NEI immunology researcher Igal Gery began using IRBP in rats, and then Caspi's group tried it in mice.

They found that IRBP induced strong uveitis in mice, which resembled human autoimmune eye disease. This NEI research team published the details of the new mouse model of uveitis in the Journal of Immunology in March 1988.

"This was a fortuitous finding," Caspi says. "The mouse model of uveitis literally catapulted forward our ability to study basic immune mechanisms involved in the disease."

"I like to know what makes it tick," explains Rachel Caspi, Ph.D. "We can't cure disease if we don't know its basic mechanisms."

Immune Education

In the past two decades, scientists have developed increasingly sophisticated tools to study the basic workings of the inflammatory process. Through genetic engineering techniques, they can create mice that express new proteins or have lost proteins, and ask which proteins are important for disease development. Caspi's findings alone have resulted in about 190 co-authored publications involving inflammation of the eye caused by abnormal responses to self-proteins in the eye.

During development in the womb and in early childhood, the body's immune system is trained to accept normal self-proteins and react against intruders. An intruder is also known as an antigen, which is a substance or molecule that stimulates the immune system to produce antibodies that act against it and activate white blood cells that attack it.

One particular type of white blood cell that recognizes antigens is lymphocytes, of which there are several sub-types. The subtype known as T-lymphocytes originates in the bone marrow and spends time developing in an immune system organ called the thymus, located behind the breastbone. While in the thymus, T-lymphocytes are "programmed" to ignore self-proteins and to react against invading pathogens, before they enter the circulating blood.

"Most T-lymphocytes that could mistakenly attack our own tissues are eliminated in this way," Caspi says. "But the process is not 100 percent efficient. A few lymphocytes that have not been properly 'programmed' may leave the thymus."

When properly programmed lymphocytes encounter familiar antigens in healthy tissue, they normally turn off or are silenced through a process known as peripheral tolerance.

This process can fail when it comes to retinal antigens that are separated from the immune system because of the blood-retinal barrier. In this case, T-lymphocytes will not encounter healthy retina cells and become tolerant of them, Caspi explains. Therefore, if these T-lymphocytes somehow become activated within the body, they don't know that the retina is friendly territory.

"It is a double-edged sword because immune privilege is not that helpful in this case," she says. "It prevents retina-specific T-lymphocytes from becoming tolerant. And once they do become activated, immune privilege is helpless against them. T-lymphocytes can penetrate that blood-retinal barrier, incite inflammation, and damage healthy retinal tissue."

Researchers are still working to understand where such T-lymphocytes become activated, since the retinal antigens are not present outside the eye -- whether it is because an invading microbe resembles a retinal antigen or because retinal antigens have broken the blood-retinal barrier after trauma to the eye.

Rachel Caspi
Rachel Caspi, Ph.D.

Analyzing Antigens

Caspi's more than 35 years of work at NEI recently garnered her the 2010 Friedenwald Award from the Association for Research in Vision and Ophthalmology, presented for her outstanding work in understanding autoimmune disease of the eye using animal models.

Among Caspi's current research tasks is to find critical checkpoints in the inflammatory process: how T-lymphocytes are activated, what types of activation cause inflammation, where these cells go, and what types of cells communicate with each other to result in disease.

"This information can help to identify different disease stages as targets for intervention with anti-inflammatory therapies that could be translated to the clinic," Caspi explains.

Caspi and her team are also exploring whether peripheral tolerance to the retina can be "beefed up" by exposing T-lymphocytes to retinal antigens within the body, so T-lymphocytes recognize them as normal instead of as foreign intruders. The scientists have shown in mouse models that by "planting" the retinal protein IRBP outside the eye through genetic manipulation or by infusing blood cells that express IRBP, animals become immunized and resistant to uveitis.

"Someday we may be able to circumvent the inflammatory reaction by expressing retinal antigens outside the eye through genetic therapy," she explains. "We are still working to understand which particular antigens cause this reaction in humans and which part or parts of the antigen are involved. Then we can, perhaps, begin to move toward the clinic."

Current clinical treatments for uveitis are non-specific, meaning that they target a broad range of immune responses, which can cause side-effects and diminish the beneficial aspects of immunity against microorganisms.

"In the future, we hope to be able to use therapies that are more antigen-specific, which target only the harmful responses in a particular autoimmune disease," Caspi says. "Ideally, these therapies would leave the rest of the immune system alone."

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