**4. Targeting lymphocytes as therapy for DED**

The findings summarized here strongly indicate that resident lymphocytes can rapidly be activated when the microenvironment in the ocular surface is altered by the lack of tears (aquodeficient) or have altered composition (evaporative). Evidence now suggests that innate and adaptive lymphocytes regulate the onset and persistence of DED. For instance, NK are shown to switch their cytokine response, which is critical for initiating DED, whereas other innate lymphocytes such as γδ T cells and NKT cells are mostly suppressive in homeostasis, and DED may parallel the loss of these populations. Regarding the adaptive lymphocytes, T and B populations are responsible for promoting chronicity. The important role of lymphocytes during DED is also supported using diverse therapeutics aimed to attenuate lymphocyte activation; thus, controlling lymphocyte populations has long been considered an efficient therapy for DED. These strategies include diverse methods of controlling T cells response; for instance, cyclosporine A (CsA) eyedrops targeted cell proliferation [72, 73]. It has been reported that commercially available CsA formulations such as Restasis (0.05% CsA, Allergan) and Ikervis (0.1% CsA, Santen) are highly effective in treating DED, however, side effects which are thought to be vehicle-related, have been reported [74, 75]. Therefore, improving CsA delivery is the current challenge. Recently, results from phase II and phase III clinical trials have been released. Wirta *et al.* published their results from a USA-centered phase II trial (efficacy, safety and tolerability) using a water- and oil-free emulsion containing a 0.1% CsA dose termed CyclASol for 16 weeks that resulted in earlier and more effective relief in adult DED patients compared to Restasis (Allergan) administered under the same protocol [76]. In an independent study, CsA was encapsulated in nanomicelles to enhance its effectiveness. The authors hypothesized that given the hydrophobic nature of CsA that dampens aqueous solubility encapsulating CsA in nanomicelles would help to solubilize CsA and ultimately increase its efficacy.

The 0.09% CsA nanomicellar solution, termed OTX-101, was administered for 84 days in individuals (18–90 years old) and significantly increased integrity of the ocular surface [77]. Thus, CsA still remains as one of the most recommended DED therapies and these efforts to enhance its effects by using novel ways of delivery with promising results keep expectations high to achieve complete DED remission.

Additional DED therapies targeting lymphocytes include eyedrops containing anti-CD4 antibodies suppressing cell activation [78] and more recently, blocking T cell infiltration by antagonizing LFA1 (Lifitegrast) [79]. Therapies increasing regulatory lymphocytes are another method of ameliorating DED. Rebamipide, which promotes the expansion of regulatory adaptive lymphocytes, yielded promising results in autoimmune DED [80]. More sophisticated agents such as histone deacetylase inhibitor (HDACi)-containing microspheres aimed at stabilizing regulatory T cells have also shown beneficial effects on DED symptoms [59].

Thus, currently approved drugs as well as experimental evidence (NK depletion) show that regulating both innate and adaptive lymphocytes can be a complimentary therapy for strategies to restore healthy tears. The more we understand about how lymphocytes participate in DED, the greater the possibilities of mitigating DED.

## **5. Conclusion**

There has been a tremendous breakthrough concerning DED research, from previously being considered only as a syndrome to what is now recognized as the most common eye pathology. Experimental models have been instrumental for the better understanding of DED immunopathology; unfortunately, human studies are underrepresented. Convincing evidence obtained mostly from animal studies shows that lymphocytes have important implications in DED, placing Th1, Th17, and B cells as the main pathological subtypes, which seem to be in constant competition with immune cell populations mostly displaying regulatory features such as Tregs that are ultimately responsible for lessening the intensity of disease-promoting counterparts. Contrary to the extensive work that has been done describing how adaptive cells are active players in both promoting and regulating DED, evidence is just starting to uncover surprising roles attributed to innate and innate-like lymphocytes. As we have reviewed here, strong evidence, up to now, suggests possible "program switching" in resident innate cell populations like NKs whereas other cells such as NKT and T cells rather display a regulatory role contributing to a tolerogenic microenvironment on the ocular surface. More recently, cell populations like ILCs have been described expanding upon eye tissues injury, which paves the way to uncover novel roles for these ILCs in a variety of eye pathologies, similarly to other organs. Continued research will help to clarify how these populations contribute to DED immunopathology. It is evident that additional human studies would complement and validate these findings, with the ultimate goal of identifying new therapeutic targets based on modulating lymphocyte responses. We have also shown that some of the most effective DED treatments indeed target lymphocyte populations (cyclosporine A and LFA-1 inhibitors) and current trials are aimed to develop a more efficacious way to deliver these drugs with proved benefit in DED therapy.

#### **Acknowledgements**

J.L.R. is funded by the programa de apoyo a proyectos de investigación e innovación tecnológica (PAPIIT,) project number IN224520. A.V.M. is funded by PAPIIT, project number IN226220.

*Lymphocytes in Dry Eye Disease DOI: http://dx.doi.org/10.5772/intechopen.98969*
