Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival
Tumor necrosis factor receptor superfamily member 25 (TNFRSF25) agonists in islet transplantation: Endogenous in vivo regulatory T cell expansion promotes prolonged allograft survival
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DOI：
10.1111/ajt.16940
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发表时间：
2022-01-12
影响因子：
8.8
通讯作者：
Shapiro, A. M. James
中科院分区：
文献类型：
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作者：
Marfil-Garza, Braulio A.;Pawlick, Rena L.;Shapiro, A. M. James
调节性T细胞（TCRs）调节同种免疫应答，并可能有助于移植后免疫抑制的最小化或撤销。然而，目前的方法依赖于复杂的离体Treg扩增方案。在此，我们探索内源性体内Treg扩张通过抗体介导的激动刺激肿瘤坏死因子受体超家族成员25（TNFRSF 25）途径和其潜力，以延长移植物存活在小鼠模型的胰岛同种异体移植。用单剂量的TNFRSF 25激动性抗体（4C 12或mPTX-35）或IgG对照处理C57 BL/6雄性小鼠。使用链脲佐菌素诱导糖尿病。四天后，完成流式细胞术以证实Treg扩增，并移植500个胰岛（CBA/J雄性小鼠）。每周三次评估血糖，直至排斥/终点。移植后36小时评估早期移植物内Treg浸润。TNFRSF 25抗体能够实现显著的Treg扩增，并且与对照相比，治疗的小鼠具有显著延长的移植物存活（p < .001）。此外，Treg扩增的程度与移植物存活显著相关（p <0.001）。免疫组化显示长期存活的移植物中有明显的Treg浸润;移植物内Treg浸润发生在移植后早期。总之，单剂量的TNFRSF 25抗体能够实现体内Treg扩增，这促进了延长的移植物存活。TNFRSF 25介导的体内Treg扩增可能有助于在器官移植中实现持久的免疫耐受。
Regulatory T cells (Tregs) modulate alloimmune responses and may facilitate minimization or withdrawal of immunosuppression posttransplant. Current approaches, however, rely on complex ex vivo Treg expansion protocols. Herein, we explore endogenous in vivo Treg expansion through antibody-mediated agonistic stimulation of the tumor necrosis factor receptor superfamily member 25 (TNFRSF25) pathway and its potential to prolong graft survival in a mouse model of islet allotransplantation. C57BL/6 male mice were treated with a single dose of TNFRSF25 agonistic antibodies (4C12 or mPTX-35) or IgG control. Diabetes was induced using streptozotocin. Four days later, flow cytometry was completed to corroborate Treg expansion, and 500 islets (CBA/J male mice) were transplanted. Glycemia was assessed thrice weekly until rejection/endpoint. Early intra-graft Treg infiltration was assessed 36 h posttransplant. TNFRSF25 antibodies enabled pronounced Treg expansion and treated mice had significantly prolonged graft survival compared with controls (p < .001). Additionally, the degree of Treg expansion significantly correlated with graft survival (p < .001). Immunohistochemistry demonstrated marked Treg infiltration in long-term surviving grafts; intra-graft Treg infiltration occurred early posttransplant. In conclusion, a single dose of TNFRSF25 antibodies enabled in vivo Treg expansion, which promotes prolonged graft survival. TNFRSF25-mediated in vivo Treg expansion could contribute to achieving lasting immunological tolerance in organ transplantation.