Sonoda Y, Sano Y, Ksander B, Streilein J W
Department of Ophthalmology, Tokyo Medical College, Japan.
Invest Ophthalmol Vis Sci. 1995 Feb;36(2):427-34.
Corneal allografts placed orthotopically induce a unique and unusual response in recipient mice. More orthotopic corneal allografts are accepted indefinitely than similar skin allografts. Of the rejected corneal grafts, class I major histocompatibility complex (MHC)-incompatible grafts are rejected less frequently than grafts that express only minor histocompatibility complex (minor H) or MHC plus minor H alloantigens. To describe the spectrum of T cells activated (or not) by orthotpic corneal grafts, the authors examined the development of delayed hypersensitivity (DH) to donor-specific alloantigens.
Recipient BALB/c mice received orthotopic corneal allografts from donor mice that were MHC incompatible at MHC loci only, multiple minor H loci only, or MHC plus multiple minor H loci. These groups of mice were examined to determine when alloantigen-specific DH developed.
The authors report that all mice, whether they accept or reject grafts, acquire donor-specific DH within 4 weeks of engraftment. This reactivity is primarily directed at minor H, rather than MHC-encoded, alloantigens. Through time, spontaneous DH reactivity disappears in all mice, and thereafter, donor-specific DH can be induced by cognate immunization only in mice that have rejected their cornea grafts.
These results can be explained in the context of "direct" and "indirect" pathways of allorecognition. Because normal corneas lack passenger leukocytes, the potential for direct recognition of alloantigens on orthotopic corneal grafts is small. Therefore, T cells activated by orthotopic corneal allografts must recognize donor-derived antigens primarily on recipient antigen presenting cells, that is, through the indirect pathway of allorecognition. Because minor H antigens are the dominant cellular proteins in grafts, it is proposed that minor H determinants are the most immunogenic alloantigens in orthotopic corneal grafts because they are the major source of peptides that will be loaded onto recipient class II molecules for T-cell recognition. We further predict that long-term acceptance of corneal allografts is promoted when recipient mice acquire anterior chamber associated immune deviation (impaired and suppressed DH) directed at minor H alloantigens of the grafts.
原位植入的同种异体角膜移植在受体小鼠中会引发一种独特且不寻常的反应。与相似的皮肤同种异体移植相比，更多的原位角膜同种异体移植能被长期接受。在被排斥的角膜移植中，I类主要组织相容性复合体（MHC）不相容的移植比仅表达次要组织相容性复合体（次要H）或MHC加次要H同种异体抗原的移植被排斥的频率更低。为了描述由原位角膜移植激活（或未激活）的T细胞谱，作者检测了对供体特异性同种异体抗原的迟发型超敏反应（DH）的发展情况。
受体BALB/c小鼠接受来自供体小鼠的原位角膜同种异体移植，这些供体小鼠仅在MHC位点不相容、仅在多个次要H位点不相容或在MHC加多个次要H位点不相容。检测这些小鼠组以确定同种异体抗原特异性DH何时出现。
作者报告称，所有小鼠，无论它们接受还是排斥移植，在植入后4周内都会产生供体特异性DH。这种反应性主要针对次要H，而非MHC编码的同种异体抗原。随着时间推移，所有小鼠的自发DH反应性都会消失，此后，只有在角膜移植被排斥的小鼠中，通过同源免疫才能诱导出供体特异性DH。
这些结果可以在同种异体识别的“直接”和“间接”途径的背景下得到解释。由于正常角膜缺乏过客白细胞，原位角膜移植上的同种异体抗原被直接识别的可能性很小。因此，由原位角膜同种异体移植激活的T细胞必须主要在受体抗原呈递细胞上识别供体来源的抗原，即通过同种异体识别的间接途径。由于次要H抗原是移植中主要的细胞蛋白，因此有人提出次要H决定簇是原位角膜移植中最具免疫原性的同种异体抗原，因为它们是将被加载到受体II类分子上以供T细胞识别的肽的主要来源。我们进一步预测，当受体小鼠获得针对移植次要H同种异体抗原的前房相关免疫偏离（受损和受抑制的DH）时，角膜同种异体移植的长期接受会得到促进。
