Animal Models of Dry Eye: A Critical Assessment of Opportunities and Limitations

Dry eye syndrome, or keratoconjunctivitis sicca (KCS), affects tens of millions of people worldwide, representing one of the most common ocular diseases. The National Eye Institute Industry Workshop on Clinical Trials in Dry Eyes produced a classification that essentially separates dry eye syndrome into two major types: tear-deficient forms (including Sjögren’s syndrome and non-Sjögren’s tear-deficient) and evaporative forms. Recently, it has become clear that the immunopathogenesis of dry eye is complex and multifactorial. Sjögren’s syndrome, which is the classic form of exocrine deficiency associated with KCS, is characterized by a chronic inflammatory infiltration of the lacrimal and salivary glands. 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. However, exactly what factors incite the infiltration of glands by T cells remains unknown. Recently, the observation that lacrimal gland acinar cells may express class II major histocompatibility complex (MHC) molecules, cathepsins B and D, and ribonucleoprotein particle La/SSB proteins has provided some support (but no definitive proof) for the thesis that these cells may be involved in aberrant presentation of autoantigens, thereby potentially capable of priming autoreactive T cells. But the pathogenic mechanisms in dry eye are not limited to those involved in lacrimal inflammation. Indeed, interruption of neuronal stimulation for tear secretion, defects in transmembrane and secretory mucin expression, and Meibomian gland dysfunction can all lead to various forms of KCS. Numerous animal models have been developed to reflect the multiplicity of pathophysiologic mechanisms involved in KCS. Understanding the unique characteristics of these different models of dry eye, and their limitations, will provide a better insight into their use in mechanistic and therapeutic study design.