一种激动型抗 BTLA mAb（3C10）诱导产生了依赖于 IL-10 的调节性 CD4+T 细胞，并延长了小鼠心脏移植物的存活时间。
An agonistic anti-BTLA mAb (3C10) induced generation of IL-10-dependent regulatory CD4+ T cells and prolongation of murine cardiac allograft.
机构信息
1 Department of Cardiovascular Surgery, Teikyo University Hospital, Tokyo, Japan. 2 Department of Immunology, Juntendo University Hospital, Tokyo, Japan. 3 Department of Surgery, Teikyo University, Tokyo, Japan. 4 Department of Cardiovascular and Thoracic Surgery, The 4th Affiliated Hospital of Harbin Medical University, Harbin, China. 5 Address correspondence to: Masanori Niimi, M.D., Ph.D., Department of Surgery, Teikyo University, 2-11-1 Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
出版信息
Transplantation. 2014 Feb 15;97(3):301-9. doi: 10.1097/01.TP.0000438204.96723.8b.
BACKGROUND
The co-inhibitory receptor B and T lymphocyte attenuator (BTLA) has been implicated in the regulation of autoimmunity and may potentially play an important role in allograft tolerance. This study investigated the effect of an agonistic anti-BTLA mAb (3C10) in the fully major histocompatibility complex-mismatched murine cardiac transplantation.
METHODS
CBA mice underwent transplantation of C57BL/6 hearts and received one dose of 3C10 on the day of transplantation (day 0) or four doses of 3C10 on day 0, 3, 6, and 9. Adoptive transfer studies were performed to determine whether regulatory cells were generated. Moreover, to confirm the requirement for regulatory T cell and Th-2 cytokines, anti-interleukin (IL)-2 receptor alpha antibody (PC-61) or anti-IL-10 antibody (JES-2A5) was administered to a 3C10-treated CBA recipient.
RESULTS
CBA mice treated with one and four doses of 3C10 prolonged allograft survival (median survival times [MSTs], 43 and >100 days, respectively). Secondary CBA recipients given whole splenocytes or CD4 cells from primary 3C10-treated CBA recipients had significantly prolonged survival of C57BL/6 hearts (MSTs, >100 in both). Also, flow cytometry studies showed an increased CD4CD25Foxp3 cell population in 3C10-treated mice. Additionally, IL-2 and interferon-γ production were suppressed in 3C10-treated mice, and IL-4 and IL-10 from 3C10-treated CBA mice increased. Moreover, 3C10 directly suppressed alloproliferation in a mixed leukocyte culture. However, administration of PC-61 or JES-2A5 clearly attenuated prolonged survival of 3C10-treated mice (MSTs, 15.5 and 13.5 days, respectively).
CONCLUSION
3C10 could control acute rejection by its suppressive effect on alloreactive T cells and induction of IL-10-dependent regulatory CD4 T cells.
背景
共抑制受体 B 和 T 淋巴细胞衰减器（BTLA）已被牵涉到自身免疫的调控中，并可能在同种异体移植物耐受中发挥重要作用。本研究探讨了一种激动性抗 BTLA mAb（3C10）在完全主要组织相容性复合物错配的小鼠心脏移植中的作用。
方法
CBA 小鼠接受 C57BL/6 心脏移植，并在移植当天（第 0 天）接受一次 3C10 剂量或在第 0、3、6 和 9 天接受四次 3C10 剂量。进行过继转移研究以确定是否产生了调节性细胞。此外，为了确认调节性 T 细胞和 Th-2 细胞因子的需求，给予抗白细胞介素（IL）-2 受体α抗体（PC-61）或抗 IL-10 抗体（JES-2A5）至接受 3C10 治疗的 CBA 受体。
结果
接受一次和四次 3C10 剂量治疗的 CBA 小鼠延长了同种异体移植物的存活时间（中位存活时间[MST]分别为 43 和>100 天）。给予初级 3C10 治疗的 CBA 受体的整个脾细胞或 CD4 细胞的次级 CBA 受体的 C57BL/6 心脏存活时间明显延长（均>100 天）。此外，流式细胞术研究显示 3C10 治疗的小鼠中 CD4CD25Foxp3 细胞群增加。此外，3C10 治疗的小鼠中 IL-2 和干扰素-γ的产生受到抑制，而 3C10 治疗的 CBA 小鼠中的 IL-4 和 IL-10 增加。此外，3C10 直接抑制混合白细胞培养物中的同种增殖。然而，给予 PC-61 或 JES-2A5 明显减弱了 3C10 治疗小鼠的延长存活（MST 分别为 15.5 和 13.5 天）。
结论
3C10 通过对同种反应性 T 细胞的抑制作用和诱导依赖 IL-10 的调节性 CD4 T 细胞，可控制急性排斥反应。
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