CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2.
CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2.
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DOI：
10.1084/jem.181.5.1869
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发表时间：
1995-05-01
期刊：
影响因子：
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通讯作者：
Turka LA
中科院分区：
文献类型：
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作者：
Sayegh MH;Akalin E;Hancock WW;Russell ME;Carpenter CB;Linsley PS;Turka LA
用融合蛋白CTLA4Ig阻断CD28-B7 T细胞共刺激通路，在体外和体内抑制同种异体免疫反应，诱导小鼠和大鼠对同种异体心脏移植物的耐受，但体内介导耐受状态的机制尚不清楚。在这里，我们报道了CTLA4Ig在大鼠肾移植模型中的作用和可能的机制。对LEW大鼠进行肾切除，并接受来自主要组织相容性复合物不相容的WF大鼠的同种异体肾移植。虽然所有未治疗和对照免疫球蛋白（Ig）治疗的动物急性排斥同种异体移植物并死亡，但86%的大鼠在移植后第2天接受单次注射CTLA4Ig，存活时间延长（60-100天），肾功能保存完好。相比之下，在移植当天接受CTLA4Ig的动物中，只有29%的动物延长了生存时间。长期幸存者（bb0 ~ 100天）表现出供者特异性耐受性，接受供者匹配的WF，但强烈排斥第三方BN心脏异体移植。移植后1周取样的移植物免疫组织学分析显示，对照组和CTLA4Ig处理的动物均有单核细胞浸润，CTLA4Ig处理组CD4+细胞百分比更高。然而，虽然这与对照移植物中的血管炎和小管炎有关，但在ctla4ig处理的动物中没有组织损伤的证据。在对照动物中，导致移植物排斥的免疫反应的特征是辅助性T (Th) 1型细胞因子白介素(IL)-2和干扰素- γ的表达。相比之下，在CTLA4Ig处理的动物中，持续的CD4+浸润而没有移植排斥反应与Th2相关的细胞因子IL-4和IL-10的染色增加有关。此外，CTLA4Ig处理动物的移植物的IgG1染色显著上调，但IgG2a或IgG2b染色不上调。在接受CTLA4Ig治疗的动物中，50%的动物恢复了同种异体移植排斥反应。这些结果证实了同种异体抗原攻击后阻断CD28-B7通路诱导供体特异性接受血管化器官移植物，并在该模型中表明CTLA4Ig在体内抑制Th1但保留Th2细胞因子。
Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig- treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig- treated animals was associated with increased staining for the Th2- related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig- treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig- treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.