Blank M, George J, Barak V, Tincani A, Koike T, Shoenfeld Y
Department of Medicine B, Sheba Medical Center, Tel-Hashomer, Israel.
J Immunol. 1998 Nov 15;161(10):5303-12.
Oral tolerance was induced in BALB/c mice by feeding low dose beta2-glycoprotein I (beta2GPI). The beta2GPI-fed mice did not develop serologic and clinical markers of experimental antiphospholipid syndrome (APS) upon immunization with the autoantigen. The treated group was characterized by low titers of serum anti-beta2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. Beta2GPI given orally before priming with beta2GPI resulted in complete prevention of experimental APS development; beta2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of beta2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to beta2GPI in comparison with beta2GPI-immunized mice fed with OVA. When nontolerant beta2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to beta2GPI was observed. The induction of suppression was beta2GPI specific and driven, as well as TGF-beta mediated. The beta2GPI-specific response of T lymphocytes from the beta2GPI-fed mice was reversed by anti-TGF-beta Abs. The tolerance was adoptively transferred by CD8+ T cells from the tolerized mice into naive mice. Those CD8+ cells were MHC class I restricted, found to secrete TGF-beta, and had no cytolytic activity. Oral administration of beta2GPI suppressed priming of CTLs in the recipient mice. In sum, beta2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of beta2GPI in the pathogenesis of the disease.
通过喂食低剂量β2-糖蛋白I（β2GPI）在BALB/c小鼠中诱导口服耐受。用自身抗原免疫后，喂食β2GPI的小鼠未出现实验性抗磷脂综合征（APS）的血清学和临床标志物。治疗组的特征为血清中抗β2GPI和抗心磷脂抗体滴度低、无胚胎吸收、血小板减少症发病率低以及活化部分凝血活酶时间（aPTT）值正常。在以β2GPI进行初次免疫前口服给予β2GPI可完全预防实验性APS的发生；在疾病早期给予β2GPI可减轻临床表现。然而，免疫后70天给予β2GPI对疾病表现的影响较小。与喂食卵清蛋白（OVA）的β2GPI免疫小鼠相比，耐受小鼠对β2GPI的T淋巴细胞增殖反应减弱。当未耐受的β2GPI致敏T淋巴细胞与来自耐受小鼠的T淋巴细胞混合时，在暴露于β2GPI后观察到增殖受到显著抑制。抑制作用的诱导具有β2GPI特异性，由转化生长因子-β（TGF-β）介导。抗TGF-β抗体可逆转来自喂食β2GPI小鼠的T淋巴细胞的β2GPI特异性反应。耐受可通过来自耐受小鼠的CD8 + T细胞过继转移至未致敏小鼠。那些CD8 +细胞受MHC I类分子限制，可分泌TGF-β，且无细胞溶解活性。口服给予β2GPI可抑制受体小鼠中细胞毒性T淋巴细胞（CTL）的致敏。总之，β2GPI诱导的口服耐受在实验性APS中具有免疫调节作用，证明了β2GPI在该疾病发病机制中的重要性。
