Treg-recruiting microspheres prevent inflammation in a murine model of dry eye disease

Abstract

Dry eye disease (DED) is a common ocular disorder affecting millions of individuals worldwide. The pathology of DED involves the infiltration of CD4 lymphocytes, leading to tear film instability and destructive inflammation. In the healthy steady state, a population of immunosuppressive T-cells called regulatory T-cells (Treg) regulates proliferation of immune cells that would otherwise lead to a disruption of immunological homeostasis. For this reason, it has been suggested that Tregs could restore the immunological imbalance in DED. To this end, one possible approach would be to recruit the body's own, endogenous Tregs in order to enrich them at the site of inflammation and tissue destruction. Previously, we have demonstrated a reduction of inflammation and disease symptoms in models of periodontitis corresponding to recruitment of endogenous Tregs, which was accomplished by local placement of controlled release systems that sustain a gradient of the chemokine CCL22, referred to here as Treg-recruiting microspheres. Given that DED is characterized by a pro-inflammatory environment resulting in local tissue destruction, we hypothesized that the controlled release of CCL22 could also recruit Tregs to the ocular surface potentially mediating inflammation and symptoms of DED. Indeed, data suggest that Treg-recruiting microspheres are capable of overcoming the immunological imbalance of Tregs and CD4 IFN-γ cells in the lacrimal gland. Administration of Treg-recruiting microspheres effectively mitigated the symptoms of DED as measured through a number of outcomes such as tear clearance, goblet cells density and corneal epithelial integrity, suggesting that recruitment of endogenous Treg can mitigate inflammation associated with DED.

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

“…[271] Furthermore, as little as picograms-to-nanograms of active agent are required in new local delivery systems that could induce the body’s own cells to treat diseases such as DED. [85] In addition, modern ophthalmic therapeutic approaches are becoming more interdisciplinary, combining biologicals/small molecules/cells with engineered polymeric materials in order to create drug delivery systems that even mimic the body’s natural functions. As the understanding of these disease mechanisms has evolved, the body’s natural process of restoring homeostasis may serve as an important inspiration for the development of safer, targeted ocular drug delivery therapies.…”

“…[84] Additionally, PLGA-based release systems have been studied as a promising candidate for the treatment of DED and uveitis, and they have been demonstrated a valid candidate for sustained release of therapeutics after a single administration through injection into ocular tissues. [85,86] In addition, a unique gelling, eye drop-like formulation has been recently reported that is able to comfortably retain the therapeutic drug in the lower fornix (topically) for a period of one month, while simultaneously releasing glaucoma medication over the period of time (without any injection into ocular tissues). [87] Although micro- and nanoparticles seem to possess significant potential as ocular drug delivery systems, limitations include encapsulation efficiency of drug (especially in smaller, nanoparticle formulations with high surface area), stability of the molecules during particle fabrication, control of particle size and drug release rate, and large-scale manufacturing of sterile preparations.…”

“…These endogenous Treg-recruiting formulations were indeed shown to be capable of shifting the ratio of Tregs and CD4 + IFN-γ + cells in the lacrimal gland (Figure 6). [85] In addition, the local administration of Treg-recruiting microspheres prevented the symptoms of DED such as aqueous tear production, goblet cell density and corneal fluorescein staining. [85] Ultimately, this evidence suggests that recruitment of endogenous Treg can prevent the signs and underlying inflammation associated with dry eye.…”

Engineering Immune Tolerance with Biomaterials

“…These treatments can be applied to organ‐specific or local autoimmune disease by administering depots at the site of inflammation to locally recruit T REG to suppress inflammation. The Little group, for example, has shown PLGA MPs encapsulating the chemokine CCL22 recruits T REG to injection sites and prevents inflammation in models of dry eye disease and periodontal disease . A key advantage of this strategy is that local recruitment and retention of T REG to sites of inflammation could provide site‐targeted immunosuppression; this possibility is in contrast to systemic expansion of polyclonal T REG that could cause broad immunosuppression.…”

Visions of Eye Commensals: The Known and the Unknown About How the Microbiome Affects Eye Disease

“…Common treatments include the frequent use of artificial tears to lubricate and anti‐inflammatories to control the ocular surface inflammation. In an attempt to boost the anti‐inflammatory nature of the host's immune system, multiple groups have aimed to enhance T regulatory (T reg ) cells, which can suppress excessive immune responses and potentially limit disease . Indeed, while boosting the T reg response is beneficial in some models, the question of what is stimulating the inflammatory response in the first place, has not been sufficiently assessed .…”