Christophe Baudouin MD, PhD, Professor and Chairman of ophthalmology
Course and current status
Born in 1961, I am professor of Ophthalmology in Paris since 1995, after achieving my MD in Nice in 1989 and a PhD in Paris in 1992. Since 1995, I am chairman of the department of Ophthalmology, Ambroise Paré Hospital, APHP, University of Versailles, and became in 2000 also the chairman of a large department of Ophthalmology in Quinze-Vingts National Ophthalmology Hospital, Paris. Since 1997, I coordinate a group of research involved in ocular surface immunology and toxicology. Since 2004 I am the Director of an INSERM-labelled research group, now located in Vision Institute, University of Paris 6, a research center dedicated to ophthalmology and recently labelled as Laboratory of Excellence (Labex from the French Government). I am also the Editor-in-chief of the French Journal of Ophthalmology, president of the Ophthalmological Society of Paris, vice-president of the French Glaucoma Society, elected member of the Board of the French Society of Ophthalmology, and member of eight international societies. I was awarded in 2011 silver fellow of ARVO.
Scientific summary
In vitro studies on the ocular toxicological effects of preservatives
My group has conducted numerous ocular toxicology studies. Based on ex vivo immunopathological observations, in vitro studies have been largely developed in human conjunctival, corneal epithelial and trabecular cell lines. A large number of molecules have thus been analyzed in the past decade, mainly focusing on antiglaucoma drugs and the preservatives included in eye drops. The team is now recognized worldwide as a toxicological reference team for assessing new compounds and alternatives to preservatives. All preservatives were shown to be cytotoxic for all types of ocular cells, and were found to be responsible for apoptosis and the production of free radicals, even at very low concentrations. The issue of preservative-free eye drops has therefore become a major therapeutic topic to which our team continues to make a significant contribution. We also study toxic profiles, the pro- or anti-oxidant effects of the most important anti-glaucomatous eye drops, mainly eye drops of the prostaglandin family, as little is known on the actual cellular effects possibly induced by prostaglandins, particularly in the inflammatory pathways. Using this original approach, our team has become an international reference in ocular toxicology, and works regularly with industry to test new molecules and their alternatives seeking to remove or reduce the impact of preservatives.
Experimental studies: Models of the toxic effects of drugs
The team has developed various animal models and new tools for refining these models used to study ocular diseases such as allergy, dry eye syndrome, uveitis, and glaucoma and to test the toxic and/or proinflammatory effects of ocular drugs given over the short or long term. New ocular surface imaging techniques using in vivo confocal microscopy, as well as flow cytometry in impression cytology specimens or biopsies, have now been developed in animals in a series of complementary investigations, making it possible to refine the Draize test, a standard toxicological test for ocular drug safety assessment, but until now only based on poorly sensitive and specific clinical criteria. By sparing large numbers of experimental animals and greatly improving the data collected with a precise follow-up over time before sacrificing the experimental animal, we are following the “Three Rs” principle as set out by the ECVAM recommendations (Balls et al. “The Three Rs: The Way Forward. 1995). This research investigating new ex vivo and in vivo tests using fewer animals with a much more accurate information, is a major advancement in ocular toxicology.
Clinical and immunopathological studies in human diseases
Two key research orientations have been developed over the past few years – inflammation and apoptosis – directly applied to the physiopathology and the therapy of major ocular pathologies such as the immuno-inflammatory diseases of the conjunctiva and cornea (atopy, Sjögren syndrome, scarring autoimmune diseases, etc.) and glaucoma. From a scientific point of view, the major input of my group has been considering the epithelial cell as both a target and a source for inflammatory cytokines. The group has developed original techniques in this area and is internationally known for its work on the immunopathology of the ocular surface and the pharmacotoxicology of antiglaucoma drugs. Using conjunctival imprints, a type of painless and noninvasive biopsy, we have been able to discover and quantify subclinical inflammation in clinically noninflammatory eye diseases. We thus explored dry eye syndromes caused by inflammatory, autoimmune and iatrogenic mechanisms, revealing an abnormal expression of class II antigen HLA DR by conjunctival epithelial cells. Furthermore, the overexpression of class II antigens is also a characteristic of the immunology of eyes receiving topical treatments over the long term, especially those treated for glaucoma with eye drops administered for the rest of the patient’s life. This original clinical approach developed by our team using flow cytometry and confocal microscopy. Furthermore, this technique was used as a fundamental basis for treating severe dry eye disease with topical cyclosporine and for monitoring ocular surface inflammation in several international multicenter clinical trials now referenced as a standard by EMA. New applications in the field of chemokine research in the anterior segment of the eye, with regard to the detrimental effects of currently used antiglaucoma drugs over the long term, or kerato-uveitis, have recently been investigated and identification of chemokines and their receptors involved in ocular diseases has now become a major aspect of our research. These pioneering data were the basis for major innovations using the above-mentioned in vitro and experimental laboratory strategies.
Present research and expectations
We are now concentrating on the involvement of the trabeculum, both as an effector and a target of inflammation. The trabeculum is the key structure involved in glaucoma and likely other diseases. The trabecular meshwork is a filter regulating intraocular pressure by controlling aqueous humor outflow. An increased matrix synthesis together with dramatic cell loss, for still unknown reasons in a genetically determined background, result in increased pressure, causing glaucoma. A better understanding of the pathophysiology of this impairment has become a major field of research with many therapeutic questions to be solved. We raised the hypothesis that low-grade inflammatory changes, similar to those observed in the ocular surface, play a role in trabecular meshwork degeneration, in both the ageing process and glaucoma. Moreover, we are investigating whether the toxic effects diffusing from the ocular surface subjected to glaucoma medications and their preservatives also influence trabecular impairment, as clinical observations suggest. Established cell lines of human trabeculum are being used in the laboratory to study several chemokines, in particular IL-8, SDF1/CXCL12 and MCP-1/CCL2, with and without cytokine or toxic stimulations. Preliminary results have shown that they are expressed in physiological conditions and that their expression is increased by cytokines, such as TNF or toxic preservatives such as benzalkonium chloride. These results open up important perspectives on the role of trabecular cells in the immune privilege of the eye, an immunopathological characteristic of the eye, and on how inflammatory mechanisms influence the degeneration of trabecular cells during glaucoma. These cytokines/chemokines are being tested on our in vitro and ex vivo models in trabecular specimens to study their direct or inducible pro- or anti-apoptotic effects. Animal models with chronic high intraocular pressure are also used to study the effects of various chemokines, both to better understand the pathophysiological mechanisms at work and to develop new therapeutic strategies. Chemokine, immune cell and antiglaucoma medication involvement in the apoptosis of the trabeculum is a major pathophysiological concern in the comprehension of the initial lesions of glaucoma disease and the development of new innovative pharmacological strategies.
