小柯机器人

美国加州大学Tobias Deuse团队近期取得重要工作进展，他们研究提出合成免疫检查点接合剂可保护HLA缺陷的iPSC及其衍生物免受先天免疫细胞的细胞毒性。相关研究成果2023年11月2日在线发表于《细胞—干细胞》杂志上。

据介绍，同种异体细胞治疗的免疫排斥反应仍然是免疫肿瘤学和再生医学的一个主要问题。到目前为止，与自体替代品相比，异基因细胞产品的持久性和疗效较差。低免疫细胞的工程化可能大大提高其治疗效果。

研究人员提出了一类新的激动性免疫检查点受体，它可以保护人类白细胞抗原（HLA）耗竭的诱导多能干细胞来源的内皮细胞（iEC）免受先天免疫细胞的攻击。对其抑制性受体TIM3和SIRPα具有激动功能的偶联剂有效保护工程化iEC免受自然杀伤（NK）细胞和巨噬细胞的杀伤。SIRPα结合物可以与截短的CD64结合，产生完全免疫逃避的iEC，能够逃避异基因细胞和免疫球蛋白G（IgG）抗体介导的排斥反应。合成免疫检查点结合物具有高的靶向特异性，并且在工程细胞中缺乏逆行信号。

总之，这种模块化设计允许利用更具抑制性的免疫途径进行免疫逃避，并有助于异基因细胞疗法的发展。

附：英文原文

Title: Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity

Author: Alessia Gravina, Grigol Tediashvili, Yueting Zheng, Kumiko A. Iwabuchi, Sara M. Peyrot, Susan Z. Roodsari, Lauren Gargiulo, Shin Kaneko, Mitsujiro Osawa, Sonja Schrepfer, Tobias Deuse

Issue&Volume: 2023/11/02

Abstract: Immune rejection of allogeneic cell therapeutics remains a major problem for immuno-oncology and regenerative medicine. Allogeneic cell products so far have inferior persistence and efficacy when compared with autologous alternatives. Engineering of hypoimmune cells may greatly improve their therapeutic benefit. We present a new class of agonistic immune checkpoint engagers that protect human leukocyte antigen (HLA)-depleted induced pluripotent stem cell-derived endothelial cells (iECs) from innate immune cells. Engagers with agonistic functionality to their inhibitory receptors TIM3 and SIRPα effectively protect engineered iECs from natural killer (NK) cell and macrophage killing. The SIRPα engager can be combined with truncated CD64 to generate fully immune evasive iECs capable of escaping allogeneic cellular and immunoglobulin G (IgG) antibody-mediated rejection. Synthetic immune checkpoint engagers have high target specificity and lack retrograde signaling in the engineered cells. This modular design allows for the exploitation of more inhibitory immune pathways for immune evasion and could contribute to the advancement of allogeneic cell therapeutics.

DOI: 10.1016/j.stem.2023.10.003

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(23)00365-X

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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