Long-term survival of rat to mouse cardiac xenografts with prolonged blockade of CD28-B7 interaction combined with peritransplant T-cell depletion.
Long-term survival of rat to mouse cardiac xenografts with prolonged blockade of CD28-B7 interaction combined with peritransplant T-cell depletion.
复制标题
通过长期阻断 CD28-B7 相互作用并去除移植周围 T 细胞，使大鼠至小鼠心脏异种移植物长期存活。
DOI：
10.1016/s0039-6060(96)80289-3
复制
发表时间：
1996
期刊：
影响因子：
3.8
通讯作者：
Flye,MW
中科院分区：
文献类型：
--
作者：
Rehman,A;Tu,Y;Arima,T;Linsley,PS;Flye,MW
背景人/小鼠CTLA4胞外域的hCTLA4Ig/mCTLA4Ig融合蛋白和人/小鼠免疫球蛋白G1的Fc部分阻断CD28/B7共刺激T细胞激活途径。我们评估了长期 B7-CD28 阻断、T 细胞耗竭或两者对大鼠至小鼠心脏异种移植物的影响。方法接受婴儿 Wistar Furth (RT1u) 大鼠心脏异种移植物的 C57BL/6 (H-2b) 小鼠在第 2 天和第 0 天用抗 CD4 (GK1.5) 和抗 CD8 (2.43) 单克隆抗体（mAb；各 0.2 mg 静脉注射）进行治疗， hcTLA4Ig 或 mCTLA4Ig 从第 0 天到第 14 天每隔一天进行一次，然后每周两次直到第 50 天或第 100 天或两者。通过混合淋巴细胞培养物和细胞介导的细胞毒性来测定细胞反应性的变化，并在移植后连续测量细胞毒性抗体的产生。结果单独使用人 CTLA4Ig 或鼠 CTLA4Ig 会导致大鼠至小鼠心脏异种移植物的显着延长（中位生存时间 [MST] 分别为 22 或 26 天 [p=0.008]，与对照相比）。 hCTLA4Ig 与两剂抗 CD4/CD8 单克隆抗体联合给予 50 天，进一步延长移植物存活期（MST，61 天；p 与对照相比 <0.0001）。在该组合中，当hCTLA4Ig持续至第100天时，移植物存活进一步延长（MST，119天）。 mCTLA4Ig 100 天加上抗 CD4/CD8 同样延长了大鼠异种移植物的存活时间（MST，94 天）。然而，所有心脏异种移植最终都失败了，主要是由于体液排斥。仅在排斥移植物的动物中，细胞毒性抗体滴度迅速上升，而在排斥移植物的动物中，受抑制的细胞介导的免疫已完全恢复。 结论阻断CD28-B7共刺激相互作用可以抑制体液和细胞介导的免疫反应，并导致大鼠对小鼠心脏异种移植物的长期接受。更长时间地给予 CTLA4Ig 和抗 CD4/CD8 单克隆抗体可进一步延长大鼠心脏异种移植物的存活时间，但不能实现无限期存活。
BackgroundThe hCTLA4Ig/mCTLA4Ig fusion protein of the extracellular domain of human/mouse CTLA4 and the Fc portion of the human/mouse immunoglobulin G1 block the CD28/B7 costimulatory T-cell activation pathway. We evaluated the effect of prolonged B7-CD28 blockade, T-cell depletion, or both on rat to mouse cardiac xenografts.MethodsC57BL/6 (H-2b) mice receiving infant Wistar Furth (RT1u) rat cardiac xenografts were treated with anti-CD4 (GK1.5) and anti-CD8 (2.43) monoclonal antibodies (mAb; 0.2 mg intravenous each) on days−2 and 0, hcTLA4Ig or mCTLA4Ig every other day from day 0 until day 14 and then twice a week until day 50 or day 100, or both. Changes in cellular reactivity were assayed by mixed lymphocyte culture and cell-mediated cytotoxicity and the development of cytotoxic antibodies was serially measured after transplantation.ResultsEither human CTLA4Ig or murine CTLA4Ig alone led to significant prolongation of rat to mouse cardiac xenografts (median survival time [MST], 22 or 26 days, respectively [p=0.008], versus control). hCTLA4Ig given for 50 days in combination with two doses of anti-CD4/CD8 monoclonal antibodies further prolonged graft survival (MST, 61 days; p versus control<0.0001). In this combination, when hCTLA4Ig was continued until day 100, the graft survival was further prolonged (MST, 119 days). mCTLA4Ig for 100 days plus anti-CD4/CD8 similarly prolonged rat xenograft survival (MST, 94 days). However, all cardiac xenografts eventually failed, primarily from humoral rejection. Cytotoxic antibody titers rose rapidly only in animals rejecting a graft, and suppressed cell-mediated immunity had completely recovered in rejecting recipients.ConclusionsBlockage of the CD28-B7 costimulatory interaction can inhibit both humoral and cell-mediated immune responses and result in the prolonged acceptance of rat to mouse cardiac xenografts. Longer administration of CTLA4Ig and anti-CD4/CD8 monoclonal antibodies further prolongs but does not achieve indefinite survival of rat cardiac xenografts.