Sayegh M H, Akalin E, Hancock W W, Russell M E, Carpenter C B, Linsley P S, Turka L A
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Exp Med. 1995 May 1;181(5):1869-74. doi: 10.1084/jem.181.5.1869.
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.
用融合蛋白CTLA4Ig阻断CD28 - B7 T细胞共刺激途径可在体外和体内抑制同种免疫反应，并诱导小鼠和大鼠对心脏同种异体移植产生耐受，但介导体内耐受状态的机制尚不清楚。在此，我们报告CTLA4Ig在大鼠肾移植模型中的作用及潜在机制。将LEW大鼠肾切除，接受来自主要组织相容性复合体不相容的WF大鼠的肾移植。所有未治疗和接受对照免疫球蛋白（Ig）治疗的动物均急性排斥其移植肾并死亡，而86%在移植后第2天单次注射CTLA4Ig的大鼠存活时间延长（> 60 - 100天）且肾功能得以保留。相比之下，仅29%在植入当天接受CTLA4Ig治疗的动物存活时间延长。长期存活者（> 100天）表现出供体特异性耐受，接受与供体匹配的WF移植肾，但急性排斥第三方BN心脏同种异体移植。对移植后1周采集的移植肾进行免疫组织学分析显示，对照动物和接受CTLA4Ig治疗的动物均有单核细胞浸润，CTLA4Ig治疗组中CD4 +细胞百分比更高。然而，对照移植肾中这种情况与血管炎和肾小管炎相关，而接受CTLA4Ig治疗的动物没有组织损伤的证据。导致对照动物移植肾排斥的免疫反应以1型辅助性T（Th）细胞细胞因子白细胞介素（IL）-2和干扰素 -γ的表达为特征。相比之下，接受CTLA4Ig治疗的动物中持续存在的CD4 +浸润而无移植肾排斥与Th2相关细胞因子IL - 4和IL - 10染色增加有关。此外，来自接受CTLA4Ig治疗动物的移植肾中IgG1的移植内染色显著上调，但IgG2a或IgG2b没有。对接受CTLA4Ig治疗的动物给予重组IL - 2后，50%受试动物的移植肾排斥得以恢复。这些结果证实，同种异体抗原刺激后阻断CD28 - B7途径可诱导对血管化器官同种异体移植的供体特异性接受，并表明在该模型中CTLA4Ig在体内抑制Th1细胞因子但不影响Th2细胞因子。
