Eyeworld Supplements

JULY 2021 | WHITE PAPER | 4 Sponsored by Regener-Eyes ® disrupt the epithelial barrier of the ocular sur- face. 5–6 Regener-Eyes ® significantly attenuates the concentration of IL-12 in the supernatants of activated human peripheral blood mononuclear cells (pbMNCs) and alleviates production of IFN-γ in activated lymphocytes. 15 Regener-Eyes ® contains GRO-γ, which is able to suppress DCs:T cell cross-talk and efficiently inhibits the DC-de- pendent generation of inflammatory Th1 cells. 9,15 GRO-γ-treated DCs had a tolerogenic phenotype characterized by increased secretion of immuno- suppressive IL-10, and reduced production of in- flammatory cytokines IL-12 and IFN-γ. 16 Accord- ingly, it is expected that topical administration of Regener-Eyes ® affects the cross-talk between antigen-presenting, IL-12-producing DCs and na- ive CD4+ T cells in lymph nodes, thereby pre- venting DC-dependent generation of IFN-γ-pro- ducing Th1 lymphocytes. Since IFN-γ-producing Th1 lymphocytes enhance the inflammatory properties of macrophages and induce their po- larization in pro-inflammatory (M1) cells, by de- livering GRO-γ, Regener-Eyes ® may prevent Th1 cell-dependent activation of intraocular M1 mac- rophages and attenuates M1 macrophage-driven eye inflammation in DED patients. 1,9,15 Downregulated levels of FABP proteins were noticed in the tears of patients suffering from Sjögren's syndrome and DED. 17 FABP proteins regulate transepithelial water transport and maintain the epithelial barrier at the ocular sur- face. 17 Accordingly, the reduced expression and production of FABP proteins leads to disturbanc- es in the epithelial barrier, causing increased tear evaporation and DED. 17 Regener-Eyes ® contains a high concentration of FABP1 pro- teins, which are thought to regulate transepithe- lial water transport, support tear stability, and lymphocytes in the lacrimal glands and ocular sur- faces of DED patients. 5–6,12,15 When Regener-Eyes ® containing IL-1Ra binds to the IL-1 receptor (IL-1R) on the endothelial cells of the eyes of DED patients, binding of IL-1β to IL-1R is blocked and the pro-inflammatory signals from IL-1R are stopped. Accordingly, various pro-inflammatory events, initiated by IL-1β:IL-1R binding, includ- ing the synthesis and releases of chemokines and the enhanced influx of leukocytes in inflamed eyes, are inhibited by Regener-Eyes ® containing IL-1Ra. 1,9,15 IL-1β acts synergistically with TNF-α to in- duce the enhanced recruitment of monocytes and lymphocytes in inflamed lacrimal glands and eyes of DED patients. 5–6 The binding of TNF-α to TNF-α receptors on endothelial cells attract circu- lating DCs, monocytes and lymphocytes, thereby creating an inflammatory loop within inflamed eyes. 5–6 Regener-Eyes ® contains sTNFRI and sTN- FRII, which bind to TNF-α and prevent TNF-α-de- pendent recruitment of circulating inflammatory immune cells in the eyes of DED patients. 1,9 Cross-talk between IL-1β and TNF-α-recruit- ed DCs, T cells, and macrophages on the ocular surface and inflamed lymph nodes is crucial- ly important for the development and progres- sion of DED. 4–5 DCs capture antigens and pres- ent them to the naive CD4+ T cells in regional lymph nodes. DCs, through the secretion of IL-12, induce differentiation of naive CD4+ T cells in effector, IFN-γ-producing Th1 cells, which, in turn, in an IFN-γ-dependent manner, promote polarization of resident macrophages in the inflammatory M1 phenotype. 5 In the eyes of DED patients, inflammatory (M1) macro- phages produce large amounts of TNF-α, nitric oxide, and matrix metalloproteinases, which continued on page 5

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