TRI Microspheres prevent key signs of dry eye disease in a murine, inflammatory model

Abstract

Dry eye disease (DED) is a highly prevalent, ocular disorder characterized by an abnormal tear film and ocular surface. Recent experimental data has suggested that the underlying pathology of DED involves inflammation of the lacrimal functional unit (LFU), comprising the cornea, conjunctiva, lacrimal gland and interconnecting innervation. This inflammation of the LFU ultimately results in tissue deterioration and the symptoms of DED. Moreover, an increase of pathogenic lymphocyte infiltration and the secretion of pro-inflammatory cytokines are involved in the propagation of DED-associated inflammation. Studies have demonstrated that the adoptive transfer of regulatory T cells (Tregs) can mediate the inflammation caused by pathogenic lymphocytes. Thus, as an approach to treating the inflammation associated with DED, we hypothesized that it was possible to enrich the body’s own endogenous Tregs by locally delivering a specific combination of Treg inducing factors through degradable polymer microspheres (TRI microspheres; TGF-β1, Rapamycin (Rapa), and IL-2). This local controlled release system is capable of shifting the balance of Treg/T effectors and, in turn, preventing key signs of dry eye disease such as aqueous tear secretion, conjunctival goblet cells, epithelial corneal integrity, and reduce the pro-inflammatory cytokine milieu in the tissue.

Treg-inducing microparticles promote donor-specific tolerance in experimental vascularized composite allotransplantation

“…Here, we report that locally administered TRI-MP promotes indefinite allograft survival (>300 d) and donor-specific tolerance in a stringent, complete major histocompatibility complex (MHC)-mismatched rat hindlimb VCA model. Notably, this allotransplantation model involves chronic alloantigen-specific inflammation, making it fundamentally different from other acute models of nonspecific inflammation or contact allergy previously studied by our group (37,38). As such, this study demonstrates the potential of this local immunotherapy strategy for preventing transplant rejection, with broader implications for treatment of a variety of other chronic inflammatory conditions.…”

“…Accordingly, we developed a biodegradable controlled-release system-referred to as Treg-inducing (TRI) microparticles (MP)-to controllably deliver extremely small quantities of factors (ng/kg/d for TGF-β1 and IL-2; μg/kg/d for rapamycin) to the local physiological milieu (36). We previously demonstrated that TRI-MP promotes differentiation of naïve CD4 + T cells to Tregs in vitro (36) and can expand Treg populations in vivo to reduce inflammation and abrogate symptoms in rodent models of dry eye disease and allergic contact dermatitis (37,38).…”

Engineering Immune Tolerance with Biomaterials

“…While these designs do not function as tolerogenic vaccines, they can serve to modulate the phenotype of previously activated T cells, or T cells undergoing priming against self‐antigens being presented as a result of ongoing inflammation. This approach has been applied to locally induce T REG by providing sustained concentrations of regulatory immune signals which favor T REG differentiation over inflammatory T cell phenotypes . Another strategy involves administering MP depots to locally deliver chemoattractants which selectively recruit T REG to sites of inflammation .…”

“…This approach has been applied to locally induce T REG by providing sustained concentrations of regulatory immune signals which favor T REG differentiation over inflammatory T cell phenotypes . Another strategy involves administering MP depots to locally deliver chemoattractants which selectively recruit T REG to sites of inflammation . 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.…”

“…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.…”