Department of Surgery, University of Chicago, Chicago, Illinois, USA.
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
J Clin Invest. 2021 Jan 4;131(1). doi: 10.1172/JCI140715.
Immunological tolerance to semiallogeneic fetuses is necessary to achieving successful first pregnancy and permitting subsequent pregnancies with the same father. Paradoxically, pregnancy is an important cause of sensitization, resulting in the accelerated rejection of offspring-matched allografts. The underlying basis for divergent outcomes following reencounter of the same alloantigens on transplanted organs versus fetuses in postpartum females is incompletely understood. Using a mouse model that allows concurrent tracking of endogenous fetus-specific T and B cell responses in a single recipient, we show that semiallogeneic pregnancies simultaneously induce fetus-specific T cell tolerance and humoral sensitization. Pregnancy-induced antibodies, but not B cells, impeded transplantation tolerance elicited by costimulation blockade to offspring-matched cardiac grafts. Remarkably, in B cell-deficient mice, allogeneic pregnancy enabled the spontaneous acceptance of fetus-matched allografts. The presence of pregnancy-sensitized B cells that cannot secrete antibodies at the time of heart transplantation was sufficient to precipitate rejection and override pregnancy-established T cell tolerance. Thus, while induction of memory B cells and alloantibodies by pregnancies establishes formidable barriers to transplant success for multigravid women, our observations raise the possibility that humoral desensitization will not only improve transplantation outcomes, but also reveal an unexpected propensity of multiparous recipients to achieve tolerance to offspring-matched allografts.
同种半异体胎儿的免疫耐受对于实现首次妊娠的成功和允许与同一父亲的后续妊娠是必要的。矛盾的是，妊娠是致敏的一个重要原因，导致与后代匹配的同种异体移植物的加速排斥。在产后女性中，移植器官与胎儿上相同同种异体抗原再次相遇时出现不同结果的根本基础尚未完全理解。使用一种允许在单个受者中同时跟踪内源性胎儿特异性 T 和 B 细胞反应的小鼠模型，我们表明同种半异体妊娠同时诱导胎儿特异性 T 细胞耐受和体液致敏。妊娠诱导的抗体，但不是 B 细胞，阻碍了对后代匹配心脏移植物的共刺激阻断引起的移植耐受。值得注意的是，在 B 细胞缺陷小鼠中，同种异体妊娠使胎儿匹配的同种异体移植物能够自发接受。在心脏移植时不存在能够分泌抗体的妊娠致敏 B 细胞足以引发排斥反应并推翻妊娠建立的 T 细胞耐受。因此，尽管妊娠诱导的记忆 B 细胞和同种抗体的产生为多胎妊娠女性的移植成功建立了巨大的障碍，但我们的观察结果提出了这样一种可能性，即体液脱敏不仅将改善移植结果，而且还将揭示多胎受者对后代匹配同种异体移植物产生耐受的意外倾向。
