Kirk Allan D, Hale Douglas A, Mannon Roslyn B, Kleiner David E, Hoffmann Steven C, Kampen Robert L, Cendales Linda K, Tadaki Douglas K, Harlan David M, Swanson S John
Transplantation and Autoimmunity Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Transplantation. 2003 Jul 15;76(1):120-9. doi: 10.1097/01.TP.0000071362.99021.D9.
Profound T-cell depletion before allotransplantation with gradual posttransplant T-cell repopulation induces a state of donor-specific immune hyporesponsiveness or tolerance in some animal models. Alemtuzumab (Campath-1H, Millennium Pharmaceuticals, Cambridge, MA) is a humanized CD52-specific monoclonal antibody that produces profound T-cell depletion in humans and reduces the need for maintenance immunosuppression after renal transplantation. We therefore performed a study to determine if pretransplant T-cell depletion with alemtuzumab would induce tolerance in human renal allografts and to evaluate the nature of the alloimmune response in the setting of T-cell depletion.
Seven nonsensitized recipients of living-donor kidneys were treated perioperatively with alemtuzumab and followed postoperatively without maintenance immunosuppression. Patients were evaluated clinically by peripheral flow cytometry, protocol biopsies evaluated immunohistochemically, and real-time polymerase chain reaction-based transcriptional analysis.
Lymphocyte depletion was profound in the periphery and secondary lymphoid tissues. All patients developed reversible rejection episodes within the first month that were characterized by predominantly monocytic (not lymphocytic) infiltrates with only rare T cells in the peripheral blood or allograft. These episodes were responsive to treatment with steroids or sirolimus or both. After therapy, patients remained rejection-free on reduced immunosuppression, generally monotherapy sirolimus, despite the recovery of lymphocytes to normal levels.
T-cell depletion alone does not induce tolerance in humans. These data underscore a prominent role for early responding monocytes in human allograft rejection.
在同种异体移植前进行深度T细胞清除，并在移植后使T细胞逐渐重新增殖，在一些动物模型中可诱导出供体特异性免疫低反应性或耐受性状态。阿仑单抗（Campath-1H，千年制药公司，马萨诸塞州剑桥）是一种人源化的抗CD52单克隆抗体，可在人体内产生深度T细胞清除，并减少肾移植后维持免疫抑制的需求。因此，我们开展了一项研究，以确定移植前使用阿仑单抗进行T细胞清除是否会诱导人类肾移植受者产生耐受性，并评估在T细胞清除情况下同种免疫反应本质。
7例活体供肾的未致敏受者在围手术期接受阿仑单抗治疗，术后不进行维持免疫抑制治疗。通过外周流式细胞术对患者进行临床评估，通过免疫组织化学对方案活检进行评估，并基于实时聚合酶链反应进行转录分析。
外周血和二级淋巴组织中的淋巴细胞清除效果显著。所有患者在第一个月内均发生了可逆性排斥反应，其特征主要为单核细胞（而非淋巴细胞）浸润，外周血或移植肾中仅有罕见的T细胞。这些排斥反应对类固醇或西罗莫司或两者联合治疗有效。治疗后，尽管淋巴细胞恢复到正常水平，但患者在减少免疫抑制（通常为西罗莫司单药治疗）的情况下仍未发生排斥反应。
单纯的T细胞清除并不能诱导人类产生耐受性。这些数据强调了早期反应性单核细胞在人类同种异体移植排斥反应中的重要作用。
