Ogawa Haruko, Mohiuddin Muhammad M, Yin Deng-Ping, Shen Jikun, Chong Anita S, Galili Uri
Department of Cardiovascular-Thoracic Surgery Rush University, Chicago, IL 60612, USA.
Transplantation. 2004 Feb 15;77(3):366-73. doi: 10.1097/01.TP.0000109276.57772.6D.
Immune response to incompatible ABO antigens on allografts may result in rejection, accommodation, or immune tolerance. Our objective has been to develop a model for studying these three types of immune response to incompatible carbohydrate antigen in alpha1,3-galactosyltransferase knockout (KO) mice. KO mice lack the alpha-gal epitope and can produce the anti-Gal antibody against it after immunization with pig kidney membranes (PKM) that express this epitope.
KO mice were transplanted with syngeneic wild-type (WT) heart expressing alpha-gal epitopes. Subsequently, the mice were lethally irradiated and received lymphocytes including memory anti-Gal B cells from PKM immunized KO mice. Immune response to incompatible alpha-gal epitopes on the graft was determined by transplanted-heart function and by production of anti-Gal after PKM immunizations.
Anti-Gal B cells exposed for 1 to 2 weeks to alpha-gal epitopes of WT hearts differentiate into cells producing noncytolytic accommodating antibodies. Exposure for longer periods (2-4 weeks) induces a transition from accommodation into tolerance, indicated by the inability of mice to produce anti-Gal antibodies despite repeated PKM immunizations. WT hearts in accommodating and in tolerized mice continue to function for months.
In the absence of T-cell help, anticarbohydrate B cells exposed to incompatible carbohydrate antigens of transplanted organs differentiate first into cells capable of producing accommodating antibodies, but, after prolonged exposure, these B cells gradually become tolerized. These findings suggest that prolonged T-cell suppression in recipients of ABO-incompatible allografts may result in a similar induction of tolerance to incompatible blood-group antigens.
同种异体移植物上针对不相容ABO抗原的免疫反应可能导致排斥、适应或免疫耐受。我们的目标是建立一个模型，用于研究α1,3-半乳糖基转移酶基因敲除（KO）小鼠对不相容碳水化合物抗原的这三种免疫反应类型。KO小鼠缺乏α-半乳糖表位，在用表达该表位的猪肾膜（PKM）免疫后可产生针对它的抗Gal抗体。
将表达α-半乳糖表位的同基因野生型（WT）心脏移植到KO小鼠体内。随后，对小鼠进行致死性照射，并接受来自PKM免疫的KO小鼠的淋巴细胞，包括记忆性抗Gal B细胞。通过移植心脏功能和PKM免疫后抗Gal的产生来确定对移植物上不相容α-半乳糖表位的免疫反应。
暴露于WT心脏α-半乳糖表位1至2周的抗Gal B细胞分化为产生非细胞溶解性适应性抗体的细胞。暴露更长时间（2 - 4周）会诱导从适应向耐受的转变，表现为尽管反复进行PKM免疫，小鼠仍无法产生抗Gal抗体。处于适应和耐受状态的小鼠体内的WT心脏可继续发挥功能数月。
在没有T细胞辅助的情况下，暴露于移植器官不相容碳水化合物抗原的抗碳水化合物B细胞首先分化为能够产生适应性抗体的细胞，但在长时间暴露后，这些B细胞逐渐变得耐受。这些发现表明，在ABO不相容同种异体移植受者中延长T细胞抑制可能导致对不相容血型抗原产生类似的耐受性诱导。
