Cornea and Ocular Surface Disease Unit, Eye Repair Lab, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Lymphocyte Activation Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Exp Eye Res. 2021 Nov;212:108825. doi: 10.1016/j.exer.2021.108825. Epub 2021 Nov 3.
to assess the effect of topical administration of the Neurokin-1 receptor (NK1R) antagonist Fosaprepitant in a pre-clinical model of ocular Graft-versus-Host disease (GVHD).
BALB/c mice were pre-conditioned by myeloablative total body irradiation and subjected to allogeneic bone marrow transplantation and mature T cell infusion (BM + T). BM-transplanted mice (BM) were used as controls. Ocular GVHD was specifically assessed by quantifying corneal epithelial damage, tear secretion, blepharitis and phimosis, 3 times/week for 28 days post-transplantation. A group of BM + T mice received Fosaprepitant 10 mg/mL, 6 times/day, topically, from day 7-29 after transplantation. After sacrifice, the expression of NK1R, CD45, CD3, and CXCL10 was quantified in the cornea, conjunctiva, and lacrimal gland by immunohistochemistry.
BM + T mice developed corneal epithelial damage (day 0-29, p < 0.001), blepharitis (day 0-29, p < 0.001), and phimosis (day 0-29, p < 0.01), and experienced decreased tear secretion (day 21, p < 0.01) compared to controls. NK1R was found upregulated in corneal epithelium (p < 0.01) and lacrimal gland (p < 0.01) of BM + T mice. Fosaprepitant administration significantly reduced corneal epithelial damage (p < 0.05), CD45 (p < 0.05) and CD3 (p < 0.01) immune cell infiltration in the cornea and conjunctiva (p < 0.001 and p < 0.001, respectively). In addition, Fosaprepitant reduced the expression of CXCL10 in the cornea (p < 0.05) and in the lacrimal gland (p < 0.05).
Our results suggest that NK1R represents a novel druggable pathway for the therapy of ocular GVHD.
评估神经激肽-1 受体（NK1R）拮抗剂 Fosaprepitant 在眼移植物抗宿主病（GVHD）的临床前模型中的局部给药效果。
BALB/c 小鼠经全身照射预处理，接受同种异体骨髓移植和成熟 T 细胞输注（BM+T）。BM 移植小鼠（BM）用作对照。通过每周 3 次评估 28 天的角膜上皮损伤、泪液分泌、睑缘炎和包茎，来特异性评估眼部 GVHD。从移植后第 7 天至第 29 天，一组 BM+T 小鼠接受 Fosaprepitant 10mg/mL，每天 6 次局部治疗。处死小鼠后，通过免疫组化定量评估角膜、结膜和泪腺中的 NK1R、CD45、CD3 和 CXCL10 的表达。
BM+T 小鼠发生角膜上皮损伤（第 0-29 天，p<0.001）、睑缘炎（第 0-29 天，p<0.001）和包茎（第 0-29 天，p<0.01），并出现泪液分泌减少（第 21 天，p<0.01），与对照组相比。在 BM+T 小鼠的角膜上皮（p<0.01）和泪腺（p<0.01）中发现 NK1R 上调。Fosaprepitant 给药可显著减少角膜上皮损伤（p<0.05）、角膜和结膜中的 CD45（p<0.05）和 CD3（p<0.01）免疫细胞浸润（分别为 p<0.001 和 p<0.001）。此外，Fosaprepitant 降低了角膜（p<0.05）和泪腺（p<0.05）中 CXCL10 的表达。
我们的结果表明，NK1R 代表了眼部 GVHD 治疗的一种新的可靶向途径。
