Schröder Carsten, Azimzadeh Agnes M, Wu Guosheng, Price James O, Atkinson James B, Pierson Richard N
Department of Cardiothoracic Surgery, Vanderbilt University, Nashville, TN, USA.
Transpl Immunol. 2003 Oct-Nov;12(1):19-28. doi: 10.1016/S0966-3274(03)00059-5.
INTRODUCTION: Macaque species offer a valuable model for translational allo-transplantation and tolerance studies. Cardiac allograft vasculopathy in Macaca fascicularis is associated with elaboration of anti-donor antibodies. Since T-independent pathways of B cell activation have been described, and anti-B cell strategies have proven to be a fruitful tolerogenic adjunct in rodent and xenogenic models, here we investigate whether an anti-CD20 antibody (rituximab) would be useful to deplete B-cells in a pre-clinical allo-transplantation setting in macaques. METHODS: Three cynomolgus macaques which had previously rejected a cardiac allograft and one with concurrent subacute vascular rejection were treated weekly with rituximab 20 mg/kg i.v. for 4 and 2 weeks, respectively. B-cell levels (CD19+ cells) were measured by flow cytometry in peripheral blood, spleen, lymph node and bone marrow cells at various intervals after initiation of treatment. B-cells and plasma cells were also analyzed by immunohistochemistry at necropsy in spleen, lymph node, tonsil and thymus tissue sections. Anti-donor antibody titers were measured by flow cytometry. RESULTS: B-cells expressing CD19 were not detectable in the peripheral blood in any animal within 24 h after initial treatment, or over the ensuing month. At necropsy, the germinal centers in spleen and lymph node were completely depleted of CD20+ B-cells in 2 animals, leaving a hypocellular trabecular pattern around preserved plasma cell follicles. Substantial but incomplete depletion of B-cells was demonstrated in the other 2 animals, in each instance immunohistochemical findings in spleen and lymph node exhibiting higher sensitivity for residual B-cells compared to FACS. Anti-donor antibody titers exhibited kinetics similar to untreated animals over this short follow-up. COMMENT: Treatment with anti-CD20 very efficiently depletes peripheral and tissue B-cells but not plasma cells in this macaque species. Biopsy of lymph node is necessary and may be sufficient to assess B-cell clearance in secondary lymphoid organs in this model.
引言：猕猴物种为异体移植和免疫耐受研究提供了有价值的模型。食蟹猕猴的心脏同种异体移植血管病变与抗供体抗体的产生有关。由于已经描述了B细胞激活的非T细胞依赖性途径，并且抗B细胞策略已被证明在啮齿动物和异种模型中是一种有效的免疫耐受辅助手段，因此我们在此研究抗CD20抗体（利妥昔单抗）在猕猴临床前同种异体移植环境中耗尽B细胞是否有用。 方法：三只先前已排斥心脏同种异体移植的食蟹猕猴和一只伴有亚急性血管排斥反应的猕猴，分别每周静脉注射20mg/kg利妥昔单抗，持续4周和2周。在治疗开始后的不同时间间隔，通过流式细胞术检测外周血、脾脏、淋巴结和骨髓细胞中的B细胞水平（CD19+细胞）。在尸检时，还通过免疫组织化学分析脾脏、淋巴结、扁桃体和胸腺组织切片中的B细胞和浆细胞。通过流式细胞术测量抗供体抗体滴度。 结果：在初次治疗后24小时内或随后的一个月内，任何动物的外周血中均未检测到表达CD19的B细胞。尸检时，2只动物的脾脏和淋巴结生发中心的CD20+B细胞完全耗尽，在保留的浆细胞滤泡周围留下细胞减少的小梁模式。另外2只动物显示B细胞大量但不完全耗尽，在每种情况下，脾脏和淋巴结的免疫组织化学结果显示，与流式细胞术相比，对残留B细胞的敏感性更高。在这个短期随访中，抗供体抗体滴度表现出与未治疗动物相似动力学。 评论：在这种猕猴物种中，抗CD20治疗非常有效地耗尽外周和组织中的B细胞，但不耗尽浆细胞。淋巴结活检是必要的，并且可能足以评估该模型中二级淋巴器官中的B细胞清除情况。
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