Inducing CTLA-4-Dependent Immune Regulation by Selective CD28 Blockade Promotes Regulatory T Cells in Organ Transplantation
Inducing CTLA-4-Dependent Immune Regulation by Selective CD28 Blockade Promotes Regulatory T Cells in Organ Transplantation
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DOI：
10.1126/scitranslmed.3000116
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发表时间：
2010-02-03
影响因子：
17.1
通讯作者：
Vanhove, Bernard
中科院分区：
文献类型：
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作者：
Poirier, Nicolas;Azimzadeh, Agnes M.;Vanhove, Bernard
移植是终末期器官衰竭患者的治疗选择。它的成功受到免疫抑制药物副作用的限制，例如钙调磷酸酶通路抑制剂，通过减少T细胞合成白细胞介素-2来防止排斥反应。此外，现有的药物中没有一种有效地防止器官的最终排斥。阻断CD 28介导的T细胞共刺激途径是一种无毒的替代免疫抑制策略，目前通过阻断抗原呈递细胞上CD 28的受体CD 80/86来实现。然而，CD 80/86与细胞毒性T淋巴细胞相关抗原4（CTLA-4）的相互作用是免疫调节所必需的。因此，CD 28阻断，而不是CD 80/86阻断，可能保留由CTLA-4介导的调节信号，并保留免疫调节。通过使用单价抗体，我们鉴定了真正的CD 28拮抗剂，其诱导与调节性T（Treg）细胞抑制相容的CTLA-4依赖性降低的T细胞功能。在灵长类动物的移植实验中，阻断CD 28增强了移植物内和外周血Treg细胞，诱导了免疫调节的分子特征，并与钙调磷酸酶抑制协同预防了移植物排斥和血管病变。这些发现表明，靶向CD 28的共刺激阻断可保护CTLA-4依赖性免疫调节并促进同种异体移植物存活。
Transplantation is the treatment of choice for patients with end-stage organ failure. Its success is limited by side effects of immunosuppressive drugs, such as inhibitors of the calcineurin pathway that prevent rejection by reducing synthesis of interleukin-2 by T cells. Moreover, none of the existing drugs efficiently prevent the eventual rejection of the organ. Blocking the CD28-mediated T cell costimulation pathway is a nontoxic alternative immunosuppression strategy that is now achieved by blockade of CD80/86, the receptor for CD28 on antigen-presenting cells. However, interaction of CD80/86 with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is required for immune regulation. Therefore, CD28 blockade, instead of CD80/86 blockade, might preserve regulatory signals mediated by CTLA-4 and preserve immune regulation. By using monovalent antibodies, we identified true CD28 antagonists that induced CTLA-4-dependent decreased T cell function compatible with regulatory T (Treg) cell suppression. In transplantation experiments in primates, blocking CD28 augmented intragraft and peripheral blood Treg cells, induced molecular signatures of immune regulation, and prevented graft rejection and vasculopathy in synergy with calcineurin inhibition. These findings suggest that targeting costimulation blockade at CD28 preserves CTLA-4-dependent immune regulation and promotes allograft survival.