Murine Islet Allograft Tolerance Upon Blockade of the B-Lymphocyte Stimulator, BLyS/BAFF
Murine Islet Allograft Tolerance Upon Blockade of the B-Lymphocyte Stimulator, BLyS/BAFF
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DOI：
10.1097/tp.0b013e318246621d
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发表时间：
2012-04-15
期刊：
影响因子：
6.2
通讯作者：
Noorchashm, Hooman
中科院分区：
文献类型：
--
作者：
Parsons, Ronald F.;Yu, Ming;Noorchashm, Hooman
背景。免疫排斥是临床移植长期成功的主要障碍。 B 淋巴细胞及其分泌产物同种抗体在同种异体移植排斥的发病机制中的重要性已被接受。此外，现在已经清楚，外周 B 细胞稳态和耐受性的主要调节因子是 B 淋巴细胞刺激因子 (BLyS)，也称为 B 细胞激活因子 (BAFF)。最近，出现了一类针对 BLyS 及其细胞因子家族的新型临床免疫治疗药物，用于治疗 B 细胞介导的疾病。在这项研究中，我们通过小鼠胰岛移植模型证明了 BLyS 定向免疫疗法在预防同种异体移植排斥反应中的潜在效用。使用单克隆抗体 Benlysta 的鼠类似物进行体内 BLyS 中和，诱导成熟外周 B 细胞的短暂消耗。随后，将完全主要组织相容性复合体不匹配的胰岛移植到幼稚糖尿病小鼠中，然后接受短疗程的雷帕霉素治疗。结果。 BLyS 中和后，同种异体胰岛移植物可无限期存活。为了实现移植物的长期存活，雷帕霉素诱导治疗是必要的，但还不够。耐受状态与以下因素相关：(1) 供体特异性抗体反应的消除，(2) 所有淋巴器官中未成熟/过渡 B 细胞的短暂优势，(3) B 细胞耗竭期间 CD4 T 细胞活化受损，以及 (4) 存在“调节”细胞因子环境。结论。体内 BLyS 中和可有效诱导体液耐受并促进小鼠同种异体胰岛移植物的长期存活。因此，针对稳态调节剂 BLyS 的 B 淋巴细胞定向免疫疗法可能有效促进移植耐受。
Background. Immunologic rejection is a major barrier to successful long-term outcomes in clinical transplantation. The importance of B lymphocytes-and their secretory products, alloantibodies-in the pathogenesis of allograft rejection is accepted. Furthermore, it is now clear that the dominant regulator of peripheral B-cell homeostasis and tolerance is the B-Lymphocyte Stimulator (BLyS), also referred to as the B-cell activating factor (BAFF). Recently, a novel class of clinical immunotherapeutic agents specific for BLyS, and its family of cytokines, has emerged for the treatment of B-cell-mediated diseases. In this study, we demonstrate the potential utility of BLyS-directed immunotherapy in preventing allograft rejection using a murine islet transplantation model.Methods. A transient period of mature peripheral B-cell depletion was induced by means of in vivo BLyS neutralization using a murine analog of the monoclonal antibody, Benlysta. Subsequently, fully major histocompatibility complex-mismatched islets were transplanted into naive diabetic mice followed by a short course of rapamycin.Results. After BLyS neutralization, indefinite islet allograft survival was achieved. Induction therapy with rapamycin was necessary, but not sufficient, for the achievement of this long-term graft survival. The tolerant state was associated with (1) abrogation of the donor-specific antibody response, (2) transient preponderance of immature/transitional B cells in all lymphoid organs, (3) impaired CD4 T-cell activation during the period of B-cell depletion, and (4) presence of a "regulatory" cytokine milieu.Conclusions. In vivo BLyS neutralization effectively induces humoral tolerance and promotes long-term islet allograft survival in mice. Therefore, B-lymphocyte-directed immunotherapy targeting the homeostatic regulator, BLyS, may be effective in promoting transplantation tolerance.