021 IL-4 Receptor α Blockade Attenuates Allergic Conjunctivitis in a Novel Murine Ocular Model

      Conjunctivitis, a common comorbidity in atopic dermatitis (AD), occurs at an increased frequency in AD patients given treatments that target interleukin-4 receptor alpha (IL-4Rα) or IL-13. However, the mechanisms driving this development of conjunctivitis remain unknown for AD. Wild-type BALB/c mice were treated epicutaneously with MC903 (calcipotriol)+ ovalbumin (OVA) to evoke AD-like disease and challenged ocularly with OVA or with vehicle control (phosphate-buffered saline [PBS]) once daily for 7 days. Induction of conjunctivitis was measured through ophthalmologic clinical outcomes, based on eyelid edema, secretion, squinting and redness (scored 0–12). Skin-sensitized mice were treated with an antibody specific for CD200R3 or CD4 (GK1.5) to deplete basophils and T cells, respectively, or with an IL-4Rα blocking antibody, prior to daily ocular challenge and clinical score assessment. RNA sequencing was performed on conjunctival tissue following pharmacologic IL-4Rα blockade. Data are reported as mean ± SEM. At Day 7, mice challenged ocularly with OVA showed significantly higher ocular clinical scores compared with vehicle-treated mice (7.7±0.5 vs 2±0.2). Basophil-depleted mice showed decreased ocular clinical scores compared with control antibody-treated mice (4.6±0.2 vs 7.8±0.6; P<0.01). Furthermore, treatment with GK1.5 led to a dramatic reduction in ocular clinical scores (3.1±0.3 vs 7.3±1.5; P<0.0001). Anti-IL-4Rα-treated mice displayed attenuated ocular inflammation (4.9±0.7 vs 6.7±0.7; P<0.0001) and normalization of ocular gene expression compared with isotype-treated mice. Our study unveiled anti-IL-4Rα-augmented genes that encode tear proteins and enzymes. In this novel murine model of allergic conjunctivitis, both basophils and CD4+ T cells were necessary for development of conjunctivitis, while IL-4Rα blockade attenuated conjunctivitis development. Anti-IL-4Rα-augmented genes may represent candidate mechanisms for the increased frequency of conjunctivitis in AD patients given treatments targeting IL-4Rα or IL-13.