Yang Y G, deGoma E, Ohdan H, Bracy J L, Xu Y, Iacomini J, Thall A D, Sykes M
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129, USA.
J Exp Med. 1998 Apr 20;187(8):1335-42. doi: 10.1084/jem.187.8.1335.
Xenotransplantation could overcome the severe shortage of allogeneic organs, a major factor limiting organ transplantation. Unfortunately, transplantation of organs from pigs, the most suitable potential donor species, results in hyperacute rejection in primate recipients, due to the presence of anti-Galalpha1-3Gal (Gal) natural antibodies (NAbs) in their sera. We evaluated the ability to tolerize anti-Gal NAb-producing B cells in alpha1,3-galactosyltransferase knockout (GalT KO) mice using bone marrow transplantation (BMT) from GalT+/+ wild-type (WT) mice. Lasting mixed chimerism was achieved in KO mice by cotransplantation of GalT KO and WT marrow after lethal irradiation. The levels of anti-Gal NAb in sera of mixed chimeras were reduced markedly 2 wk after BMT, and became undetectable at later time points. Immunization with Gal+/+ xenogeneic cells failed to stimulate anti-Gal antibody production in mixed chimeras, whereas the production of non-Gal-specific antixenoantigen antibodies was stimulated. An absence of anti-Gal-producing B cells was demonstrated by enzyme-linked immunospot assays in mixed KO + WT --> KO chimeras. Thus, mixed chimerism efficiently induces anti-Gal-specific B cell tolerance in addition to T cell tolerance, providing a single approach to overcoming both the humoral and the cellular immune barriers to discordant xenotransplantation.
异种移植可以克服同种异体器官的严重短缺，这是限制器官移植的一个主要因素。不幸的是，由于灵长类动物受体血清中存在抗α1,3-半乳糖基转移酶（Gal）天然抗体（NAbs），将猪（最合适的潜在供体物种）的器官移植到灵长类动物受体中会导致超急性排斥反应。我们使用来自GalT+/+野生型（WT）小鼠的骨髓移植（BMT），评估了在α1,3-半乳糖基转移酶基因敲除（GalT KO）小鼠中使产生抗Gal NAb的B细胞耐受的能力。通过在致死性照射后共同移植GalT KO和WT骨髓，在KO小鼠中实现了持久的混合嵌合体。混合嵌合体血清中抗Gal NAb的水平在BMT后2周显著降低，并在随后的时间点变得无法检测到。用Gal+/+异种细胞免疫未能刺激混合嵌合体产生抗Gal抗体，而刺激了非Gal特异性抗异种抗原抗体的产生。通过酶联免疫斑点试验在混合的KO + WT --> KO嵌合体中证实不存在产生抗Gal的B细胞。因此，混合嵌合体除了诱导T细胞耐受外，还能有效地诱导抗Gal特异性B细胞耐受，为克服不协调异种移植的体液免疫和细胞免疫障碍提供了一种单一的方法。
