Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX.
Am J Transplant. 2013 Dec;13(12):3076-84. doi: 10.1111/ajt.12466. Epub 2013 Oct 1.
Th1 CD4+ cells are believed to be the primary mediators of corneal allograft rejection. However, rejection of fully allogeneic C57BL/6 corneal allografts soared from 50% to 90% in both interferon-gamma (IFN-γ)(-/-) and anti-IFN-γ-treated BALB/c mice. In contrast, similar deficits in IFN-γ in BALB/c hosts enhanced immune privilege of BALB.B (minor histocompatibility [minor H] antigen-matched, major histocompatibility complex [MHC]-mismatched) and NZB (MHC-matched, minor H antigen-mismatched) corneal allografts-decreasing rejection from 80% to ~20%. This effect of IFN-γ was independent of CD4+ T cell lineage commitment as both anti-IFN-γ-treated acceptor and rejector mice displayed a Th2 cytokine profile. The presence of IFN-γ prevented the generation of alloantigen-specific CD4+CD25+ T regulatory cells (Tregs) in hosts receiving either MHC only mismatched BALB.B or minor only histocompatibility (minor H)-mismatched NZB corneal allografts. Tregs in these hosts promoted corneal allograft survival by suppressing Th2 effector cells. By contrast, IFN-γ was necessary for the generation of CD4+CD25+ Tregs that prevented rejection of fully allogeneic C57BL/6 corneal allografts in BALB/c hosts. These findings suggest that MHC-matching in combination with blockade of IFN-γ holds promise as a means of enhancing corneal allograft survival.
Th1 CD4+ 细胞被认为是角膜同种异体移植物排斥的主要介导者。然而，在干扰素-γ（IFN-γ）（-/-）和抗 IFN-γ 处理的 BALB/c 小鼠中，完全同种异体 C57BL/6 角膜移植物的排斥率从 50%飙升至 90%。相比之下，在 BALB/c 宿主中 IFN-γ 类似的缺陷增强了 BALB.B（次要组织相容性[次要 H]抗原匹配，主要组织相容性复合体[MHC]不匹配）和 NZB（MHC 匹配，次要 H 抗原不匹配）角膜移植物的免疫特权-排斥率从 80%降至约 20%。IFN-γ 的这种作用与 CD4+T 细胞谱系的决定无关，因为接受抗 IFN-γ 治疗的供体和受体小鼠均表现出 Th2 细胞因子谱。IFN-γ 的存在阻止了在接受 MHC 仅不匹配的 BALB.B 或仅次要组织相容性（次要 H）不匹配的 NZB 角膜同种异体移植物的宿主中产生同种抗原特异性 CD4+CD25+T 调节细胞（Tregs）。在这些宿主中，Tregs 通过抑制 Th2 效应细胞促进角膜移植物存活。相比之下，IFN-γ 是生成防止 BALB/c 宿主中完全同种异体 C57BL/6 角膜移植物排斥的 CD4+CD25+Tregs 所必需的。这些发现表明，MHC 匹配结合 IFN-γ 阻断有望成为增强角膜移植物存活的一种手段。
