EDITORIAL

ANIMAL MODELS OF DRY EYE

MODELOS ANIMALES DE OJO SECO

BARABINO S, MD¹

Dry eye syndrome (DES), or keratoconjunctivitis sicca (KCS), affects tens of millions of people worldwide, representing one of the most common ocular pathologies (1). The traditional approach to treat dry eye focuses on tear replacement with artificial tears, or on conserving the patient’s tears by means of occlusion of the tear drainage system, since DES was traditionally considered to be caused solely by an inadequate quantity or quality of the tear film. These therapies have been demonstrated to decrease symptoms and signs of dry eye, and improving the resultant blurred vision, but they can be considered palliative. In fact, even while it is not presently known what triggers the pathogenic mechanism that lead to dry eye, a growing body of evidence suggests that chronic KCS is a complex multifactorial disease characterized by an immune and inflammatory process that affects the lacrimal glands and ocular surface.

Animal models of dry eye, including murine genetic models, which simulate Sjögren’s syndrome, non-Sjögren’s syndrome, and evaporative dry eye have provided important contributions to our understanding of the pathogenic mechanisms involved in the different forms of KCS. The development of murine models of Sjögren’s syndrome, representing the classic form of exocrine deficiency associated with KCS, has been of great help to demonstrate a chronic inflammatory infiltration of the lacrimal and salivary glands where the predominant cell type is CD4+ T cells that appear to have a defect in Fas-mediated apoptosis, thereby rendering their infiltration into exocrine tissue damaging. Moreover, the observation in these models that lacrimal gland acinar cells may express class II major histocompatibility complex (MHC) molecules, cathepsins B and D, and ribonucleoprotein particle La/SSB proteins, provide some support (but no definitive proof) for the thesis that these cells may be involved in aberrant presentation of auto-antigens, thereby potentially capable of priming autoreactive T cells. Animal models have been very useful also in studying non-Sjögren’s dry eye. For instance, the first objective evidence in support of the hypothesis that Meibomian gland duct orifice closure is a characteristic feature of meibomitis-related dry eye was provided using a rabbit model in which the Meibomian gland orifices were individually closed by cauterization. In addition, animal models of dry eye have been used to develop and test new therapeutic strategies for KCS. Dogs developing spontaneous DES have been widely used to develop therapeutic interventions for both veterinary and clinical populations, as exemplified by trials on topical application of cyclosporine A.

In reviewing the opportunities and limitations of all animal models of dry eye (2), we noticed that most of them have focused on some aspects of dry eye without considering it as a disease of the lacrimal gland-ocular surface functional unit. For example, mouse models provided a dart of data on lacrimal gland inflammation, but tear production and its consequences on the ocular surface epithelium of these mice have been poorly studied and never been definitively demonstrated. In my opinion, in the future the study of an animal model should include anatomic and functional changes of the lacrimal gland and the ocular surface. To get this important point a considerable difficulty is the lack of standard techniques to study the tear film and the ocular surface in animals. Clinical tests commonly used in humans to diagnose KCS, such as the Schirmer test and fluorescein and rose bengal staining of the ocular surface, to name a few, have been used in dogs and rabbits because of their large exposed ocular surface, but standard procedures for these tests have not been established. In mice, the globe size does not allow for the use of these tests without modifications, but again there is no established standard. We recently provided a review on uses and limitations of tear film and ocular surface tests in animal models (3), but more should be done in the field. As dry eye experts have recently met in the Dry Eye Workshop held in Puerto Rico in 2004 and provided standards and guidelines to study DES in humans, a similar approach should be used for animal models of dry eye.

A critical area for further studies in KCS is to determine the role of professional (bone marrow-derived) APC of the ocular surface in activating T cells. As demonstrated by Hamrah et al (4) the cornea is endowed with resident several distinct subpopulations of (mostly monocytic CD11b+) CD45+ bone marrow-derived cells whose numbers increase and which acquire an activated phenotype (high MHC class II antigen expression) ocular surface inflammation. Preliminary data from our laboratory [Rashid S, Barabino S, Dana R. Changes in corneal endowment of immune cells in novel dry eye model. Invest Ophthalmol Vis Sci 2005;46:E-3585] have shown that in an experimental model of dry eye the cornea demonstrates a significant increase in the number of activated CD45+CD11b+ monocytes, suggesting that not only the conjunctiva but also the cornea plays a pivotal role in the immunopathogenesis of KCS. Since the study of immune cells in humans is limited to the conjunctiva, animal models will play an important role in this field.

In conclusion, the existing animal models of dry eye mimic different pathogenic mechanisms of KCS, but at the moment none of them seems to precisely mirror the complexity and chronicity of this frequent and debilitating condition. In spite of their small size, the advanced murine immunogenetics and extensive availability of reagents, and knockout and transgenic strains, make the mouse a very attractive model. Further studies incorporating both intrinsic (immune, endocrine, neuronal) and extrinsic (environmental) factors in dry eye pathogenesis in the mouse will offer important advances in the field. Continued efforts to standardize tests to study tear film and ocular surface are absolutely essential if the use of animal models in dry eye studies is to be optimized.

1 Department of Neurosciences, Ophthalmology, and Genetics, University of Genoa, Genoa, Italy. 
E-mail: barabino@vision.eri.harvard.edu

REFERENCES

1. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol 2003; 136: 318-326.

2. Barabino S, Dana MR. Animal models of dry eye: a critical assessment of opportunities and limitations. Invest Ophthalmol Vis Sci 2004; 45: 1641-1646.

3. Barabino S, Chen W, Dana MR. Tear film and ocular surface tests in animal models of dry eye: uses and limitations. Exp Eye Res 2004; 79: 613-621.

4. Hamrah P, Huq SO, Liu Y, Zhang Q, Dana MR. Corneal immunity is mediated by heterogeneous population of antigen-presenting cells. J Leukoc Biol 2003; 74: 172-178.