Daniel P T, Krammer P H
Tumor Immunology Program, German Cancer Research Center, Heidelberg.
J Immunol. 1994 Jun 15;152(12):5624-32.
We have previously described the APO-1 (CD95) cell surface molecule, a novel member of the nerve growth factor/TNF receptor superfamily, identical with the Fas Ag. Triggering of APO-1-induced apoptosis in APO-1+, apoptosis sensitive cells. The data in this study demonstrate that human peripheral blood B cells acquire sensitivity to APO-1-mediated apoptosis on PWM activation. To also study APO-1-mediated apoptosis in an Ag-specific human B cell response, we reconstituted severe combined immunodeficient (SCID) mice i.p. with human PBMC (SCID-hu mice). SCID-hu mice were then injected i.p. with soluble, adjuvant-free tetanus toxoid or diphtheria toxoid, respectively, directly after transfer of the PBMC (day 1) and received an Ag-booster injection on day 14. Two weeks after PBMC transfer human Abs were detected and shown to be Ag specific. SCID-hu mice co-injected with monoclonal anti-APO-1 Ab (IgG3,k) showed significantly suppressed anti-tetanus toxoid or anti-diphtheria toxoid titers, respectively. Sensitivity to anti-APO-1-mediated suppression was only observed in Ag-activated cells from day 0 to day 6 after Ag immunization. Suppression of Ab titers correlated with a decrease of Ag-specific Ig-secreting cells. Re-injection of syngeneic T cells and Ag did not reverse anti-APO-1-induced suppression. These data show a direct suppressive effect of anti-APO-1 on Ag-activated, "specific" B cells. Thus, APO-1-mediated apoptosis in Ag-activated B cells may contribute to the regulation of the humoral immune response.
我们之前已描述过APO-1（CD95）细胞表面分子，它是神经生长因子/TNF受体超家族的一个新成员，与Fas抗原相同。在APO-1阳性、对凋亡敏感的细胞中，APO-1触发诱导凋亡。本研究中的数据表明，人外周血B细胞在PWM激活后获得对APO-1介导凋亡的敏感性。为了研究在抗原特异性人B细胞应答中APO-1介导的凋亡，我们经腹腔注射人外周血单个核细胞（PBMC）重建重症联合免疫缺陷（SCID）小鼠（SCID-hu小鼠）。然后在PBMC转移后（第1天）立即经腹腔分别给SCID-hu小鼠注射可溶性、无佐剂的破伤风类毒素或白喉类毒素，并在第14天给予抗原加强注射。PBMC转移两周后检测到人类抗体，且显示为抗原特异性的。共同注射单克隆抗APO-1抗体（IgG3，κ）的SCID-hu小鼠分别显示出抗破伤风类毒素或抗白喉类毒素滴度显著受到抑制。仅在抗原免疫后第0天至第6天的抗原激活细胞中观察到对抗APO-1介导抑制的敏感性。抗体滴度的抑制与抗原特异性Ig分泌细胞的减少相关。同基因T细胞和抗原的再次注射并未逆转抗APO-1诱导的抑制。这些数据显示抗APO-1对抗原激活的“特异性”B细胞有直接抑制作用。因此，抗原激活的B细胞中APO-1介导的凋亡可能有助于体液免疫应答的调节。
