Mo Juan, Neelam Sudha, Mellon Jessamee, Brown Joseph R, Niederkorn Jerry Y
Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
Invest Ophthalmol Vis Sci. 2017 Jan 1;58(1):137-148. doi: 10.1167/iovs.16-20601.
Severing corneal nerves during corneal transplantation does not affect first corneal transplants, but abolishes immune privilege of subsequent corneal allografts. This abrogation of immune privilege is attributable to the disabling of T regulatory cells (T regs) induced by corneal transplantation. The goal of this study was to determine if severing corneal nerves induces the development of contrasuppressor (CS) cells, which disable T regs that impair other forms of immune tolerance.
Effect of corneal nerve ablation on immune tolerance was assessed in four forms of immune tolerance: anterior chamber-associated immune deviation (ACAID); oral tolerance; corneal transplantation, and intravenously (IV) induced immune tolerance. T regulatory cell activity was assessed by adoptive transfer and by local adoptive transfer (LAT) of suppression assays.
Corneal nerve ablation prevented ACAID and oral tolerance, but did not affect IV-induced immune tolerance. Contrasuppressor cells blocked the action of T regs that were generated by anterior chamber injection, oral tolerance, or orthotopic corneal transplantation. The neuropeptide substance P (SP) was crucial for contrasuppressor activity as CS cells could not be induced in SP-/- mice and the SP receptor inhibitor, Spantide II, prevented the expression of CS cell activity in vivo. Contrasuppressor cells expressed CD11c surface marker that identifies dendritic cells (DC).
The loss of immune privilege produced by corneal nerve ablation following corneal transplantation extends beyond the eye and also affects immune tolerance induced through mucosal surfaces and appears to be mediated by a novel cell population of CD11c+ CS cells that disables T regs.
在角膜移植过程中切断角膜神经不会影响首次角膜移植，但会消除后续角膜同种异体移植的免疫赦免。这种免疫赦免的消除归因于角膜移植诱导的调节性T细胞（Tregs）功能丧失。本研究的目的是确定切断角膜神经是否会诱导抗抑制细胞（CS细胞）的发育，这些细胞会使损害其他形式免疫耐受的Tregs失活。
通过四种免疫耐受形式评估角膜神经切断对免疫耐受的影响：前房相关免疫偏离（ACAID）；口服耐受；角膜移植，以及静脉内（IV）诱导的免疫耐受。通过过继转移和抑制试验的局部过继转移（LAT）评估调节性T细胞活性。
角膜神经切断可阻止ACAID和口服耐受，但不影响IV诱导的免疫耐受。抗抑制细胞可阻断由前房注射、口服耐受或原位角膜移植产生的Tregs的作用。神经肽P物质（SP）对抗抑制活性至关重要，因为在SP基因敲除小鼠中无法诱导CS细胞，并且SP受体抑制剂Spantide II可阻止CS细胞活性在体内的表达。抗抑制细胞表达识别树突状细胞（DC）的CD11c表面标志物。
角膜移植后角膜神经切断导致的免疫赦免丧失不仅限于眼部，还会影响通过黏膜表面诱导的免疫耐受，并且似乎由使Tregs失活的新型CD11c + CS细胞群体介导。
