APRIL/BLyS 阻断可减少致敏小鼠的同种异体抗体。
APRIL/BLyS Blockade Reduces Donor-specific Antibodies in Allosensitized Mice.
机构信息
Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, WI.
Division of Transplant, Department of Surgery, University of Wisconsin-Madison, Madison, WI.
出版信息
Transplantation. 2019 Jul;103(7):1372-1384. doi: 10.1097/TP.0000000000002686.
BACKGROUND
Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy.
METHODS
C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 10 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 μg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot.
RESULTS
APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups.
CONCLUSIONS
APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.
背景
移植等待名单上高度致敏的候选者仍然是一个重大挑战，因为目前的脱敏方案降低供体特异性抗体（DSA）的成功率各不相同。因此，需要改进治疗方法。增殖诱导配体（APRIL）和 B 淋巴细胞刺激物（BLyS）是 B 淋巴细胞和浆细胞的关键存活因素，浆细胞是同种抗体产生的主要来源。我们研究了 APRIL/BLyS 阻断在小鼠肾移植模型中对 DSA 的影响，作为一种潜在的新型脱敏策略。
方法
C57BL/6 小鼠通过腹腔（IP）注射 2×10 BALB/c 脾细胞致敏。致敏后 21 天，动物接受 100μg BLyS 阻断（B 细胞激活因子受体免疫球蛋白）或 APRIL/BLyS 阻断（跨膜激活剂和钙调节剂和 cyclophilin 配体相互作用者免疫球蛋白）治疗，每周三次，持续 21 天。然后，动物被安乐死或随机接受对照 Ig、BLyS 阻断或 APRIL/BLyS 阻断的肾移植。移植后 7 天处死动物。通过流式细胞术、免疫组织化学和酶联免疫斑点法评估 BLyS 阻断或 APRIL/BLyS 阻断治疗小鼠的 B 淋巴细胞和 DSA。
结果
与对照组相比，APRIL/BLyS 抑制通过流式细胞交叉配型导致 DSA 显著降低（P < 0.01）。与对照组相比，APRIL/BLyS 阻断也显著耗尽了 IgM 和 IgG 分泌细胞和 B 淋巴细胞群（P < 0.0001）。移植小鼠的 APRIL/BLyS 阻断也导致 B 淋巴细胞群减少；然而，各组之间的排斥率没有差异。
结论
跨膜激活剂和钙调节剂和 cyclophilin 配体相互作用者免疫球蛋白的 APRIL/BLyS 阻断显著耗尽了 B 淋巴细胞并降低了该致敏小鼠模型中的 DSA。APRIL/BLyS 抑制可能是一种用于致敏移植候选者的临床有用的脱敏策略。
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