Reza Dana, M.D., M.P.H., M.Sc.

Question: What are the main issues in ocular inflammation?

Answer: Inflammation is one of the most common, and evolutionarily conserved, responses in the body. Injury (mechanical or chemical), infection, surgery, toxin exposure, allergy, growth of many cancers, etc, all lead to inflammation.In the eye, as well, inflammation is a common response, ranging from allergic eye disease to contact-lens intolerance to dry eye. Sometimes the inflammatory response is severe enough to endanger sight. Since the eye is constantly exposed to the outside world, potentially harmful and immunogenic materials land on it frequently. Most of the time, the eye can deal with these insults in a way that neutralizes or clears them (say through the tears or antibodies in the tear film) in a manner that is not threatening to sight. However, sometimes inflammation can lead to profound changes in eye tissues, leading to scarring, accumulation of fluids, and other pathological changes (such as growth of new blood vessels) not compatible with good vision.
Question: How common are ocular inflammatory disorders, and why should we be concerned about this?

Answer: Inflammation is extremely common. In fact, it is not even conceivable for a healthy normal person not to have some degree of an inflammatory response in the eye virtually every several weeks or so. Whether it is something that lands on our eye surface, or wearing a contact lens that irritates our eye, or getting dry eye on a plane trip or during prolonged computer terminal work, or having an allergic response, or a response to an irritant such as soap or shampoo going in our eyes, inflammation occurs, often (but not always) leading to a red eye. Most of these cases, of course, resolve rapidly with or without medicines. It is when inflammation becomes severe and/or chronic that it can jeopardize vision. In particular, autoimmune conditions, like lupus or rheumatoid arthritis, can pose a significant risk to vision; the same processes that can lead to joint disease can also cause havoc with intraocular tissues. Another problem is that the medicines currently available have two major limitations: first, they have suboptimal efficacy -— they simply do not work very well in cases of severe eye inflammation. Second, these non-specific medications, in particular steroids, are fraught with numerous complications, including opportunistic infection, tissue thinning and atrophy, and development of glaucoma and cataract. Therefore, there is a real and pressing need for better and more effective treatment strategies for ocular inflammatory disorders. There is a lot of talk about inflammation and immunity playing a role in chronic eye diseases. What is that about? In years past, the concept of “inflammation” was that unless the tissue is red, swollen and painful, there is no inflammation. This antiquated, and erroneous, concept has now given way to a more precise understanding of the role that inflammation and immunity can play in a wide array of disorders, including aging, cancer, growth of blood vessels, transplant rejection, and many chronic disorders, including cardiovascular diseases and macular degeneration.

Two principles are now understood: first, cells that are derived from the bone marrow and comprise our lymphocytes (white blood cells) play a critical role in the induction, amplification, and maintenance of inflammation in many chronic conditions that afflict our bodies, including our eyes. Second, even cells that are not traditionally thought of as being “immune cells”, such as those that make up our epithelial tissues or our blood vessels, can under certain conditions act similarly to white blood cells by secreting factors that promote inflammation. So we now understand inflammation as much more than just the role of antibodies and lymphocytes in response to acute challenges such as infection.

Question: What are the main issues in the cornea field?

Answer: The current hot topics are corneal transplantation and dry eye disease. Corneal transplantation is by far the most common type of tissue transplantation; indeed there are more corneal transplants performed than all other forms of grafts (heart, kidney, pancreas, lung, bone marrow) combined; nearly 40,000 cases are performed annually. Corneal transplantation is important since it is the ultimate cure for blinding corneal disease, which is the second most common reason for vision loss in the world (a fact that is often overlooked in the United States and Western Europe, where because of the significant aging of the population, chronic conditions such as macular degeneration are becoming increasingly prevalent). There are two main issues that now plague corneal transplantation: first, the current treatments to prevent or treat rejection are not very good; in fact they have barely changed in over 50 years. Second, there is an acute shortage of adequate corneas for transplantation. There are millions of people blind from corneal disease worldwide, but currently less than 5% of these are getting appropriate treatment because there are just not enough donor tissues or eye banks.

In dry eye, the issues are different. First, dry eye is rarely a cause of blindness, but it does lead to significant disability in many people, as well as loss of work time and normal functionality. Second, the numbers: there are well over 10 million people in the US alone with significant dry eye disease, and tens of millions more who occasionally have dry eye problems, so the magnitude of the problem is huge. Third, in dry eye there are few treatments available that really do much besides marginally improving symptoms. One of the main discoveries in the past decade is that inflammation appears to play an important role in sustaining the disease mechanisms in dry eye. And so there is a lot of interest now in figuring out exactly how inflammation and immunity contribute to dry eye, and consequently coming up with new therapeutic targets.

Question: What is the problem with the current approaches to treating corneal transplant rejection?

Answer: Corneal transplants do well in recipients who may have corneal scarring, but without accompanying inflammation or blood vessel ingrowth (the cornea normally has no blood or lymph vessels). However, when the host bed (the place where the new cornea will be placed) is inflamed (which accounts for nearly one-third of all transplants performed), the fate of corneal transplants becomes worse than that of solid organ grafts. The numbers reflect this clearly: with the use of topical steroids (which can, and often do, cause cataracts and glaucoma), corneal transplants survive nearly 90% of the time if performed in uninflamed eyes. However, if an eye that is inflamed, say from alkali injury or infection, undergoes corneal transplantation, well over 50% of these grafts are rejected even if we place these patients on strong, systemic immunosuppressive medications. This is far worse than survival rates for heart and kidney grafts.

Question: Could you tell us about some of the new ways being developed in your lab to address the issues raised above in relation to corneal conditions?

Answer: We have a broad program in corneal and ocular-surface inflammation research. My lab’s main interest is in figuring out, at the molecular level, how immune and inflammatory cells are recruited; how do they get into tissues, and then how do they leave the eye tissues to get into lymphoid tissues (such as our lymph nodes) to activate our T cells to induce immune responses? These are fundamental issues in a wide array of immune and inflammatory states, from transplantation to dry eye to allergy. We are also keenly interested in the interface of inflammation with the growth of blood and lymph vessels. Lymphatics (lymph vessels) are critical for movement of antigens and immune cells from the tissues to lymphoid tissues, as they are also for cancer metastasis. We have done a fair amount of work understanding how cells in the cornea contribute to lymphatic growth. Other interests in the lab are focused on ways of reducing the cell damage and death that result from transplantation and injury. We have had a nice collaboration with the lab of Andrius Kazlauskas, developing new ways of affecting (suppressing) corneal cell death for applications in transplantation. Another project is focused on the contribution of the cornea itself in modulating inflammation. The cornea is a unique tissue that plays a very important role, through cell membrane-expressed as well as secreted factors, in suppressing immunity, and we are very interested in dissecting how it performs these unique tasks. Finally, we have an active program developing and testing new targets in dry eye. We see a lot of potential in making important contributions here.

Question: What do you see on the horizon?

Answer: As I have indicated above, the need for developing new strategies in preventing and treating eye-surface disease is huge. The currently available therapies leave much to be desired; they either don’t work very well, or have too many unacceptable side-effects, or compliance is a problem because patients don’t like using them (for example, they may burn). In many ways, the future is already upon us, in the sense that in this decade there will be a lot more discovery about how, specifically (at the molecular level), diseases are induced and then sustained. The growth of molecular biology on the one hand, and biotechnology on the other, has provided us with unprecedented opportunities. Already, we are faced with a situation where our preclinical (on cell and animal models) and clinical testing of new scientific paradigms is far behind what is known about disease pathogenesis. The hurdles that stand between discovery science and the art of drug development are many, and difficult, ones. These include: a fall in the number of clinician-scientists, the growing gap between the PhD “basic scientists” and MD “pure clinicians”, the divide between important discoveries (made and published) and what the pharmaceutical industry is aware of and able to develop, and also regulatory hurdles.

Question: What does the Schepens environment offer in terms of research?

Answer: The environment that we have here at SERI, and that is developing in the Harvard Ophthalmology Department, allows us unique opportunities to make important inroads in responding to these hurdles. These institutions are leading the way in recruiting, training and hopefully retaining clinician-scientists in vision research. We are fostering numerous mechanisms for optimizing the interaction between clinicians and lab researchers. Finally, ongoing efforts to enhance the exchange of information with our industry partners -- so that our discoveries are propelled forward, potentially into clinical applications -- are a must if we are to make meaningful contributions to how our patients, our families, and our friends, are treated in years to come.